[xls] · web view... lower clearance and higher oral bioavailability compared to 9a. following...

ID Catalog NO Name Alternative Names CAS SMILES MW Target1 HY-15602B Ledipasvir (DGS-5885 D-ta1502654-87- O=C(OC)N[C 1039.087 HCV; HCV Pr2 HY-12177 Aliskiren (h CGP 60536;C173334-58-2 O=C(O)/C=C1219.589 Autophagy; R3 HY-B0219 Allopurinol 315-30-0 O=C1C2=C( 136.1115 Xanthine Oxi4 HY-13966 2-Deoxy-D-gl2-Deoxy-D-ar154-17-6 OC1O[C@@H]164.1565 Hexokinase5 HY-19992 3-BromopyruvBromopyruvic 1113-59-3 O=C(O)C(CB 166.9581 Hexokinase6 HY-B0483 Tioxolone 4991-65-5 O=C1OC2=C168.1699 Carbonic An7 HY-B1462 Chlorzoxazone 95-25-0 O=C1OC2=CC169.5652 Cytochrome 8 HY-B0597 FondaparinuxFondaparin 114870-03-0 O[C@H]([C@@1729.089 Factor Xa9 HY-B0496 PMSF Phenylmethyls329-98-6 O=S(CC1=CC174.1927 Proteasome

10 HY-B0099 Edaravone MCI-186;MCI 89-25-8 O=C1N(C2=C174.1992 MMP11 HY-15893 DMOG Dimethyloxall89464-63-1 O=C(OC)CNC175.1394 HIF/HIF Proly12 HY-B0809 Theophylline 1,3-Dimethyl58-55-9 O=C(N1C)N( 180.164 Adenosine Re13 HY-13995A Sevelamer (hydrochloride 152751-57-0 NCC(CC(CC)CN186.08 (mon FXR14 HY-B0464 Hydralazine (hydrochlorid 304-20-1 NNC1=NN=C196.6369 HIF/HIF Proly15 HY-76316 Bergaptol 5-Hydroxyps 486-60-2 O=C1C=CC(C202.1629 Cytochrome 16 HY-14252 Milrinone Win 47203 78415-72-2 CC(N1)=C(C 211.2194 Phosphodiest17 HY-15700 PluriSln 1 NSC 14613 91396-88-2 O=C(C1=CC 213.2352 Stearoyl-CoA18 HY-N0733 Glucosamine D-(+)-Glucos66-84-2 O=C[C@H](N215.6321 Autophagy; H19 HY-B0365A Memantine (hydrochloride41100-52-1 N[C@@]1(C2)215.7628 Autophagy; C20 HY-30151 Methoxsalen 8-Methoxypso298-81-7 O=C1OC(C(C216.1895 Cytochrome 21 HY-N0370 Bergapten 5-Methoxyps484-20-8 O=C1C=CC2216.1895 Autophagy; 22 HY-B0368 Captopril SA333 62571-86-2 O=C(O)[[email protected] Angiotensin-23 HY-12318 IBMX IMX;Isobutyl 28822-58-4 O=C(N1C)N( 222.2438 Phosphodiest24 HY-B0782 Acetazolamide 59-66-5 CC(NC1=NN=222.2454 Autophagy; C25 HY-100788 2-PMPA 2-(Phosphono173039-10-6 O=C(O)C(CP 226.1211 Carboxypept26 HY-B1232 Metyrapone Su-4885 54-36-4 CC(C1=CC=C226.2738 Autophagy; 27 HY-12519 Oltipraz RP 35972;NS64224-21-1 S=C1SSC(C 226.3416 HIF/HIF Proly28 HY-B0428 Ozagrel OKY046;OKY-82571-53-7 O=C(O)/C=C228.2466 Factor Xa29 HY-15664 Bivalirudin ( Bivalirudin 128270-60-0 O=C(N1CCC[2295.315 Thrombin30 HY-B0763 Ibudilast KC-404;AV-4 50847-11-5 CC(C)C(C1= 230.3055 Phosphodiest31 HY-19817 PRT4165 PRT 4165;PR 31083-55-3 O=C1/C(C(C 235.2375 E1/E2/E3 En32 HY-B0553 Methazolami L584601 554-57-4 CC(/N=C1SC 236.272 Carbonic An33 HY-14164 Zileuton A 64077;Abb111406-87-2 CC(N(O)C(N 236.2902 5-Lipoxygen34 HY-19749 PD 151746 PD151746;PD179461-52-0 O=C(O)/C(S 237.2501 Proteasome35 HY-12821 AEBSF 30827-99-7 O=S(C1=CC=239.6948 Thrombin36 HY-13555 β-LapachoneARQ-501;NSC4707-32-8 O=C(C1=C2O242.2699 Autophagy; I37 HY-101836 DKM 2-93 65836-72-8 O=C(NCC1=C243.68676 E1/E2/E3 En38 HY-N1430 Oxyresveratrtrans-Oxyres 29700-22-9 OC1=CC=C(/244.2427 Autophagy; T39 HY-10291 (R)-Flurbipro E7869;Tarenf51543-40-9 O=C(O)[[email protected] RAR/RXR40 HY-100110 KNK437 KNK-437;KNK218924-25-5 O=CN1C(/C( 245.2307 HSP41 HY-13025 HIV-1 integra(Z)-4-(3-(az 544467-07-4 OC(/C(O)=C 247.2069 HIV; HIV Inte42 HY-14874 Topiroxostat FYX 051;FYX 577778-58-6 N#CC1=NC=248.2428 Xanthine Oxi

43 HY-B0428A Ozagrel (sod OKY-046 sod 130952-46-4 O=C([O-])/ 250.2284 Factor Xa44 HY-17538 ZLN005 ZLN 005;ZLN49671-76-3 CC(C1=CC=C250.3382 PGC-1α45 HY-10978 AN-2728 Crisaborole 906673-24-3 N#CC1=CC=C251.0451 Phosphodiest46 HY-B0128 Diphylline Diprophylline479-18-5 O=C(N1C)N( 254.2426 Adenosine Re47 HY-12364A C75 (trans) C 75 trC-75 191282-48-1 O=C([C@@H]254.3221 Fatty Acid S48 HY-B0327 Irsogladine Dicloguamin 57381-26-7 NC1=NC(N)=256.0914 mAChR; Phos49 HY-N0102 Isoliquiritige GU17;ISL;Iso 961-29-5 O=C(C1=CC=256.2534 Aldose Reduc50 HY-101106 AR7 AR-7;AR 7 80306-38-3 CC1=CC=C(C257.71488 RAR/RXR51 HY-15827 NSC 405020 NSC405020; 7497-07-6 O=C(NC(C)CC260.1596 MMP52 HY-101429 RG13022 Tyrphostin 136831-48-6 N#C/C(C1=C266.29456 Tyrosinase53 HY-N0163 Magnolol 528-43-8 OC1=CC=C( 266.3343 Autophagy; 54 HY-70072 D609 D 609;D-609 83373-60-8 S=C(OC1C2C266.4645 Phospholipas55 HY-70083 SPK-601 LMV-601;SPK1096687-52- [H][C@]12[C 266.4645 Phospholipas56 HY-15485 Zardaverine 101975-10-4 O=C1C=CC(C268.2162 Phosphodiest57 HY-A0006 Pentostatin Deoxycoform53910-25-1 O[C@H]1C(N268.2691 Adenosine D58 HY-N0196 Baicalein 5,6,7-Trihyd 491-67-8 O=C1C=C(C2270.2369 Xanthine Oxi59 HY-N0382 Galangin Norizalpinin; 548-83-4 O=C1C(O)=C270.2369 Autophagy; 60 HY-15683 IDO5L 914471-09-3 ON/C(C1=NO271.6356 Indoleamine 61 HY-17406 Tolcapone Ro 40-7592 134308-13-7 O=C(C1=CC(273.2408 COMT62 HY-16900 Rolipram SB95952;ZK661413-54-5 O=C1NCC(C2275.3428 Phosphodiest63 HY-16900A (R)-(-)-Rolip (R)-Rolipram;85416-75-7 O=C1NC[C@@275.3428 Phosphodiest64 HY-B0392 (S)-(+)-Roli (+)-Rolipram85416-73-5 O=C1NC[[email protected] Phosphodiest65 HY-B0715 Pentoxifyllin PTX;Oxpentify6493-05-6 O=C(N1CCCC278.307 Autophagy; P66 HY-13983 NLG919 NLG-919 1402836-58- OC(C1CCCCC282.3801 Indoleamine 67 HY-15859 Atglistatin 1469924-27- O=C(NC1=CC283.3681 ATGL68 HY-14595 Biochanin A 4-Methylgeni491-80-5 OC1=C2C(OC284.2635 FAAH69 HY-N0560 Oroxylin A Baicalein 6- 480-11-5 O=C1C=C(C2284.2635 Autophagy; H70 HY-100872 KRIBB11 KRIBB-11;KR 342639-96-7 CNC1=CC=C(284.27338 HSP71 HY-13599 Cladribine 2-Chloro-2′- 4291-63-8 OC[C@@H]1[285.687 Adenosine D72 HY-14254 Olprinone (H Loprinone (H119615-63-3 CC(N1)=C(C 286.7163 Phosphodiest73 HY-A0060 Malotilate NKK 105 59937-28-9 O=C(OC(C)C)288.383 5-Lipoxygen74 HY-B0523A Anagrelide ( BL4162A 58579-51-4 ClC1=C(CN( 292.549 Phosphodiest75 HY-B0240 Disulfiram Tetraethylth 97-77-8 S=C(SSC(N(C296.5392 Aldehyde De76 HY-N0125 Diosmetin 520-34-3 O=C1C=C(C2300.2629 Cytochrome 77 HY-19340 TMS (E)-2,3',4,5' 24144-92-1 COC1=CC=C(300.349 Cytochrome 78 HY-15127 Isotretinoin 13-cis-Retino4759-48-2 CC1(C)C(/C=300.4351 RAR/RXR79 HY-14649 Retinoic acidATRA;Tretinoi302-79-4 CC1(C)C(/C=300.4351 PPAR; RAR/R80 HY-100359 CL-82198 CL82198;CL 307002-71-7 O=C(C1=CC 302.3682 MMP81 HY-12033 2-Methoxyest2-ME2;NSC-6362-07-2 OC1=CC2=C([302.4079 Autophagy; H82 HY-14291 Vildagliptin LAF237;NVP-274901-16-5 O[C@@]1(C2303.3993 Dipeptidyl P83 HY-B0397 Dichlorphen Diclofenamid120-97-8 O=S(C1=CC(C305.1588 Carbonic An84 HY-14280 Entacapone 130929-57-6 O=C(N(CC)CC305.286 COMT85 HY-12354 SB-3CT SB 3CT;SB3C292605-14-2 O=S(CC1SC1306.3999 MMP

86 HY-12312 TCS 401 TCS-401;TCS243966-09-8 O=C(C1=C(N306.7227 Phosphatase87 HY-10505 Orteronel TAK-700;TAK566939-85-3 O=C(C1=CC=307.3465 Cytochrome 88 HY-10865 LY2183240 LY 2183240; 874902-19-9 O=C(N(C)C) 307.3498 FAAH89 HY-B0134 Bestatin Ubenimex 58970-76-6 CC(C)C[C@@308.3728 Aminopeptid90 HY-13513 U-104 NSC-213841;178606-66-1 O=S(C1=CC=309.3161 Carbonic An91 HY-13233A Talabostat ( PT-100;Valbo150080-09-4 CC(C)[C@H](310.1754 Dipeptidyl P92 HY-70003 CarboxypeptiCPG2 Inhibito192203-60-4 O=C(SC(C=C313.3263 Carboxypept93 HY-70005 CPA inhibitorcarboxypepti223532-02-3 O=C(N(CC(C 313.3477 Carboxypept94 HY-10285 Saxagliptin BMS-477118 361442-04-8 N#C[C@@H]1C315.41 Dipeptidyl P95 HY-14268 Febuxostat TEI 6720;TM 144060-53-7 CC(COC1=CC316.3748 Xanthine Oxi96 HY-10212 BIIB021 CNF2024;BII 848695-25-0 ClC1=C2C(N 318.7615 Autophagy; 97 HY-66009 Epalrestat ONO2235 82159-09-9 O=C(O)CN(C 319.3986 Aldose Reduc98 HY-79511 FAAH-IN-2 4-(3-Chloro- 184475-71-6 OC1=CC2=C(319.7181 FAAH99 HY-B0486 Lonidamine DICA;Diclond50264-69-2 O=C(C1=NN(321.1581 Hexokinase

### HY-18936 Alda-1 349438-38-6 O=C(NCC1=C324.1588 Aldehyde De### HY-B0653A Levobupivaca(S)-(-)-Bupi 27262-48-2 O=C([C@H]1324.8887 Autophagy; P### HY-101054 NQ301 NQ-301;NQ 3130089-98-4 O=C1C(NC2=325.74578 Thrombin### HY-B0107 Acitretin Ro 10-1670 55079-83-9 CC(/C=C/C(C326.4294 RAR/RXR### HY-14823 Sobetirome GC-1; QRX-4 211110-63-3 O=C(O)COC1328.4022 LXR### HY-B0779 Teprenone Geranylgeran6809-52-5 CC(CC/C=C(C330.5472 HSP### HY-13289A Nepicastat (hSYN-117 hydr170151-24-3 FC1=CC(F)= 331.8117 Dopamine β-### HY-B0204 Pimobendan pimobendan 74150-27-9 O=C1CC(C)C334.3718 Phosphodiest### HY-101503 HTS01037 HTS-01037;H682741-29-3 O=C(C1=C(N337.37084 FABP### HY-10864 URB-597 URB597;KDS-546141-08-6 O=C(OC1=CC338.4003 Autophagy; ### HY-10790 Cilomilast SB-207499;S153259-65-5 O=C([C@H]1343.4168 Phosphodiest### HY-12832 JNJ-42041935 1193383-09- OC(C(C=N1) 346.6493 HIF/HIF Proly### HY-14171 Bexarotene 153559-49-0 CC1(C2=C(C 348.4779 Autophagy; ### HY-15682 TTNPB Ro 13-7410;A71441-28-6 O=C(O)C1=C348.4779 RAR/RXR### HY-14652 Tamibaroten Am80;Am 8094497-51-5 O=C(C1=CC=351.4388 RAR/RXR### HY-10475 AM580 Am 580;Am-5102121-60-8 CC(CC1)(C) 351.4388 Autophagy; ### HY-15388 Tazarotene 118292-40-3 O=C(C1=CC=351.4619 RAR/RXR### HY-13297 PYZD-4409 PYZD4409;PY423148-78-1 FC1=CC=C(N2351.6739 E1/E2/E3 En### HY-13426 FG-4592 Roxadustat; 808118-40-3 O=C(O)CNC( 352.3407 HIF/HIF Proly### HY-15468 IOX2 IOX 2;IOX-2 931398-72-0 O=C(O)CNC( 352.3407 HIF/HIF Proly### HY-10522 HIV-1 integra3-Quinolineac957890-42-5 ClC1=CC=C(353.842 HIV; HIV Inte### HY-N0055 Chlorogenic 3-O-Caffeoyl 327-97-9 O=C([C@@]1354.3087 HIF/HIF Proly### HY-N1067 Xanthohumol 6754-58-1 O=C(C1=C(OC354.3964 COX; DGAT### HY-100901 CDD3505 CDD-3505;C 173865-33-3 O=[N+]([O- 355.38928 Cytochrome ### HY-16500 Tolrestat AY-27773 82964-04-3 O=C(O)CN(C 357.3475 Aldose Reduc### HY-15408 Trelagliptin SYR-472;SYR865759-25-7 N#CC1=CC=C357.3821 Dipeptidyl P### HY-15282 E-64 66701-25-5 O=C([C@H]1357.4054 Autophagy; C### HY-17356 Fenofibrate 49562-28-9 CC(C)(OC1= 360.8313 Autophagy; ### HY-B0109A Dorzolamide L671152 hydr130693-82-2 O=S(C(S1)= 360.901 Carbonic An

### HY-10453 MLN2238 Ixazomib;ML 1072833-77- CC(C)C[C@@361.0287 Autophagy; ### HY-30234A Clemizole (hydrochloride) 1163-36-6 ClC1=CC=C(362.2961 HCV; HCV Pro### HY-15193 EMD638683 EMD 638683 1181770-72- CC1=C(CC)C364.3433 SGK### HY-15205 Ganetespib STA-9090;ST 888216-25-9 CN1C2=CC=C364.3978 HSP### HY-B0209 Metolazone 17560-51-9 O=S(C1=CC2365.8345 Thrombin### HY-18643 TZ9 TZ-9 1002789-86- O=C(OCC1=N366.3309 E1/E2/E3 En### HY-17464 Cilostazol OPC 13013;O73963-72-1 O=C1NC2=C369.4607 Autophagy; P### HY-13296 PYR-41 PYR41;PYR 4 418805-02-4 O=C(N1)/C( 371.301 E1/E2/E3 En### HY-10079 GMX1778 CHS-828;GM 200484-11-3 N#CN/C(NCC371.8639 Nampt### HY-N0035 Arctigenin (-)-Arctigenin7770-78-7 O=C1OC[[email protected] Autophagy; ### HY-B1472 Deoxycortico11-Deoxycort56-47-3 C[C@@]12[C372.4978 Mineralocort### HY-13635 Finasteride MK906;MK 9098319-26-7 O=C([C@H]1C372.5441 5 alpha Redu### HY-90009 Nortadalafil Demethyl Tad171596-36-4 O=C1NCC(N(375.3774 Phosphodiest### HY-18077A Papaverine (hydrochloride61-25-6 COC1=CC2=C375.846 Phosphodiest### HY-10595 Ro 28-1675 Ro 028-1675 300353-13-3 O=C(NC1=NC378.5089 Glucokinase### HY-15190 NVP-HSP990 HSP-990 934343-74-5 CC1=C2C(C[ 379.3876 HSP### HY-13402 Varespladib LY 315920;L 172732-68-2 O=C(O)COC1380.3939 Phospholipas### HY-B2015 Carbosulfan 55285-14-8 O=C(OC1=C(380.5447 Cytochrome ### HY-15192 GSK 650394 GSK650394; 890842-28-1 O=C(O)C(C=382.4544 SGK### HY-101769 UAMC00039 (dUAMC 00039 d697797-51-6 O=C(N1CCCCC382.75614 Dipeptidyl P### HY-14877 Anagliptin SK-0403 739366-20-2 O=C(C1=CN2383.4475 Dipeptidyl P### HY-B0588 BrinzolamideAL4862;AL 4 138890-62-7 O=S(C(S1)= 383.5072 Carbonic An### HY-18964 MG-101 Calpain inhib110044-82-1 O=C(N[C@H]383.5255 Proteasome### HY-10227 Bortezomib PS-341;PS34 179324-69-7 OB(O)[C@H] 384.2372 Autophagy; ### HY-B0231 Enalaprilat (dihydrate) 84680-54-6 O=C(O)[[email protected] Angiotensin-### HY-101214 UK-371804 UK371804;UK256477-09-5 CC(C(O)=O) 385.82594 Ser/Thr Prot### HY-50709 A939572 stearoyl-CoA 1032229-33- O=C(N1CCC(387.86 Stearoyl-CoA### HY-15768 GM6001 Galardin;Ilo 142880-36-2 O=C(N[C@@H388.4607 MMP### HY-70006 TOK-001 VN/124-1;Ga 851983-85-2 C[C@@]12C(388.5451 Cytochrome ### HY-15453 CPI-613 CPI 613;CPI6 95809-78-2 O=C(O)CCC 388.5865 Pyruvate De### HY-90009A Tadalafil 171596-29-5 O=C([C@@]1389.404 Phosphodiest### HY-14950 Dalcetrapib JTT-705;RO- 211513-37-0 CC(C)C(SC1 389.5945 CETP### HY-17408 Mevastatin Compactin;M73573-88-3 CC[C@H](C) 390.5131 Autophagy; ### HY-16670 Dafadine-A Dafadine A 1065506-69- O=C(N1CCC(391.4629 Cytochrome ### HY-50876 FK866 Daporinad;A 658084-64-1 O=C(C1=CC=391.506 Autophagy; ### HY-75054 Abiraterone (CB-7630;CB7154229-18-2 O=C(O[C@@H391.5457 Cytochrome ### HY-15373 Fenretinide 4-HPR;(4-Hyd65646-68-6 CC(/C=C/C= 391.5457 Autophagy; ### HY-15424 5-IodotuberciNSC 113939; 24386-93-4 NC1=C2C(N(392.1498 Adenosine Ki### HY-76847 ChenodeoxychCDCA 474-25-9 O=C(O)CC[[email protected] FXR### HY-10231 PX-478 685898-44-6 [O-][N+](CC 394.1215 Autophagy; H### HY-32219 T863 DGAT-1 inhib701232-20-4 O=C(O)C[[email protected] DGAT### HY-12286 PI-1840 1401223-22- O=C(N(C(C) 394.4668 Proteasome### HY-13009 PF-04620110PF 046201101109276-89- O=C(C[C@@H396.4397 DGAT

### HY-10240 R-7128 RG 7128;Meri940908-79-2 O=C1N=C(C=399.4139 HCV; HCV Pr### HY-15455 Roflumilast 162401-32-3 O=C(NC1=C(403.2075 Phosphodiest### HY-N0504 Lovastatin Mevinolin 75330-75-5 O=C([C@@H]404.5396 HMG-CoA Red### HY-14413 SR3335 ML-176;SR 3 293753-05-6 O=S(C1=CC=C405.3359 ROR### HY-15592 CabotegravirGSK-12657441051375-10- FC1=C(CNC( 405.3522 HIV; HIV Inte### HY-13749 Sitagliptin MK-0431;MK0486460-32-6 O=C(N1CC2=407.3136 Autophagy; D### HY-18208 Omapatrilat BMS-186716 167305-00-2 O=C([C@@H]408.5349 Angiotensin-### HY-14463 AT13387 Onalespib;A 912999-49-6 OC1=CC(O)=409.5212 HSP### HY-13269 BMS-707035 BMS 707035 729607-74-3 FC1=CC=C(C410.42 HIV; HIV Inte### HY-19636 JNJ-4216527 JNJ42165279 1346528-50- O=C(N1CCN(410.8024 FAAH### HY-18680 PU-WS13 PU-WS-13 1454619-14- CC(NCCCN1C411.3519 HSP### HY-15407 AHU-377 Sacubitril;A 149709-62-6 O=C(CCC(O) 411.4908 Neprilysin### HY-15100 Balicatib AAE581;AAE 354813-19-7 CCCN1CCN(C411.5404 Cathepsin### HY-B0091 Adapalene CD 271;CD27106685-40-9 O=C(C1=CC2412.5201 RAR/RXR### HY-16968 SW033291 SW-033291 459147-39-8 NC1=C(S(CC 412.5913 15-PGDH### HY-14984 N6022 N 6022;N-60 1208315-24- OC(CCC1=CC414.4565 GSNOR### HY-12754 ML228 ML-228;CID- 1357171-62- C1(C2=NC= 415.4891 HIF/HIF Proly### HY-100736 ML348 ML-348;ML 3 899713-86-1 O=C(NC1=CC415.7941 Phospholipas### HY-101243 XMD16-5 1345098-78- O=C1NC2=CN416.47566 Tyrosinase### HY-B0279 Ramipril 87333-19-5 O=C([C@@H]416.5106 Angiotensin-### HY-18768 NCT-501 1802088-50- O=C(N1C)N( 416.5172 Aldehyde De### HY-B0385 Gabexate (meFOY 56974-61-9 O=C(OCC)C1417.4772 Factor Xa; P### HY-17502 Simvastatin MK 733 79902-63-9 CCC(C)(C)C 418.5662 Autophagy; ### HY-B0140 Aminophylline 317-34-0 O=C(N1C)N( 420.4264 Phosphodiest### HY-50670 DGAT-1 inhibDGAT-1 inhibi942999-61-3 O=C(O)CC12420.5041 DGAT### HY-12222 INT-747 Obeticholic 459789-99-2 C[C@@]([C@]420.6252 FXR### HY-18967 Aldose reductase-IN-1 1355612-71- O=C1C2=NC=421.3532 Aldose Reduc### HY-12807 FIPI 5-Fluoro-2-i 939055-18-2 O=C(C(N1)= 421.4674 Autophagy; P### HY-14739 Choline FenoABT-335;ABT856676-23-8 O=C(C1=CC=C421.9144 Cytochrome ### HY-B1203A Fludrocortiso9α-Fludrocort514-36-3 C[C@@]12[C422.487 Autophagy; M### HY-10629 LXR-623 WAY-252623;875787-07-8 ClC1=C(CN2 422.7784 LXR### HY-100221 AM-2394 AM2394;AM 1442684-77- O=C(NC)NC1423.465 Glucokinase### HY-B1135 Benzbromarone 3562-84-3 O=C(C1=CC(424.0834 Xanthine Oxi### HY-16107 BMS-303141 BMS303141; 943962-47-8 O=S(C1=CC(424.2977 ATP Citrate ### HY-10398 CTS-1027 RS 130830;R193022-04-7 O=C(NO)C1( 425.8832 MMP### HY-14806 Teneligliptin 760937-92-6 O=C([C@H]1426.5782 Dipeptidyl P### HY-12472 TAK-063 1238697-26- FC1=CC(N2N428.4185 Phosphodiest### HY-10038 A 922500 DGAT-1 Inhib959122-11-3 O=C(NC1=CC428.4798 DGAT### HY-101761 TM5441 TM-5441;TM 1190221-43- ClC1=CC=C(428.82248 PAI-1### HY-15407A AHU-377 (hemSacubitril h 1369773-39- O=C(CCC([O 430.52 Neprilysin### HY-14422 SR1078 SR 1078;SR- 1246525-60- O=C(NC1=CC=431.2524 ROR### HY-14664A Fluvastatin (sodium) 93957-55-2 O=C([O-])C 433.4478 Autophagy; ### HY-15250 JZL195 JZL 195;JZL- 1210004-12- O=C(OC1=CC433.4565 FAAH; MAGL

### HY-13671 LW6 HIF-1α inhibi 934593-90-5 O=C(OC)C1=435.5121 HIF/HIF Proly### HY-A0043A Cilazapril ( Ro 31-2848 92077-78-6 O=C([C@@H]435.5139 Angiotensin-### HY-50903 Rivaroxaban BAY 59-7939366789-02-8 O=C(N(C1=C435.8813 Factor Xa### HY-15689 INCB 024360Epacadostat 1204669-58- BrC1=C(F)C 438.2328 Indoleamine ### HY-50911 WAY-362450XL335;WAY 3629664-81-9 O=C(C1=CN(438.4665 FXR### HY-15253 Tiplaxtinin PAI-039;Tipla393105-53-8 O=C(C(O)=O439.3834 PAI-1### HY-B0144 Pitavastatin Pitavastatin 147526-32-7 O=C([O-])C 440.49 Autophagy; ### HY-13238A Dolutegravir GSK-134957 1051375-19- O=C(C1=CN(441.3606 HIV; HIV Inte### HY-B0130A Perindopril ( Perindopril t 107133-36-8 O=C([C@H]1N441.6046 Angiotensin-### HY-B1451 Imidapril (hy TA-6366 89396-94-1 O=C([C@H]( 441.9058 Angiotensin-### HY-13469 Debio 0932 CUDC-305;De1061318-81- NC1=NC=CC2442.5776 HSP### HY-75800 VX-222 VCH222;VX221026785-59- O=C(O)C1=C445.6147 HCV; HCV Pr### HY-70035 Otamixaban FXV 673;FXV193153-04-7 N=C(C1=CC=446.4984 Factor Xa### HY-B0165A Pravastatin (sodium) 81131-70-6 O[C@@H](C[446.5096 HMG-CoA Red### HY-14740 Elvitegravir GS-9137;JTK 697761-98-1 O=C(O)C1=C447.8838 HIV; HIV Inte### HY-B0655 Zofenopril (c SQ26991 81938-43-4 O=C(N(C[[email protected] Angiotensin-### HY-13067 Celastrol Tripterin 34157-83-0 OC1=C(C2=C450.6096 Autophagy; ### HY-19330 DASA-58 DASA58;DAS1203494-49- NC1=CC=CC(453.5324 HIF/HIF Proly### HY-14376 PF-04457845PF 044578451020315-31- O=C(NC1=NN455.4324 FAAH### HY-14380 PF-3845 PF 3845;PF3 1196109-52- O=C(N1CCC(456.4602 FAAH### HY-50667 Apixaban BMS-562247-503612-47-3 NC(C1=NN(C459.4971 Factor Xa### HY-12085 Apremilast CC 10004;CC608141-41-9 CC(NC1=CC=460.5002 Phosphodiest### HY-B0093A Benazepril (hCGS 14824A 86541-74-4 O=C1N(CC(O460.9505 Angiotensin-### HY-15832 GSK 283037 GSK28303711404456-53- ClC1=CN=C(461.02 Phospholipas### HY-A0023 Alogliptin (B SYR 322 850649-62-6 O=C(C=C(N1461.513 Dipeptidyl P### HY-12808 STF-118804 894187-61-2 O=C(NCC1=C461.5328 Nampt### HY-18082 AGI-5198 IDH-C35;AGI 1355326-35- FC1=CC=CC(462.5591 Isocitrate D### HY-19329 HA130 HA-130 1229652-21- O=C1N(CC2=463.2858 Phosphodiest### HY-10215 NVP-AUY922 Luminespib; 747412-49-3 O=C(C1=NOC465.5414 Autophagy; ### HY-101712 TRC051384 TRC 051384;867164-40-7 O=C(NC1=CC465.54474 HSP### HY-13070 MK-8245 MK 8245;MK 1030612-90- O=C(CN1N=C467.2491 Stearoyl-CoA### HY-13528 Clinofibrate S-8527 30299-08-2 CCC(OC1=CC468.5818 HMG-CoA Red### HY-10284 Linagliptin BI 1356;BI-1 668270-12-0 O=C1N(C2=C472.5422 Dipeptidyl P### HY-13735A Quinacrine (dMepacrine di 69-05-6 CC(NC1=C(C472.8787 Autophagy; P### HY-18690 Enasidenib AG-221 1446502-11- CC(O)(C)CNC473.375 Isocitrate D### HY-15976 P7C3 301353-96-8 OC(CNC1=CC474.1884 Nampt### HY-B0477 Quinapril (hydrochloride) 82586-55-8 O=C([C@H]1474.9771 Angiotensin-### HY-15408A Trelagliptin SYR-472 succ1029877-94- O=C(C=C(N1475.4702 Dipeptidyl P### HY-18234A Leupeptin (hemisulfate) 103476-89-7 O=C[C@@H](475.59 Cathepsin### HY-14992 Bay 60-7550 BAY 607550;439083-90-6 O=C1N=C(NN476.5674 Phosphodiest### HY-13421 SR1001 SR-1001 1335106-03- CC(NC1=NC(C477.4018 ROR### HY-18741 VR23 VR-23 1624602-30- O=S(N1CCN(477.8782 Proteasome### HY-13344 PF-8380 PF 8380;PF8 1144035-53- O=C(N1CCN(478.3252 Phosphodiest

### HY-16082 AZD7545 AZD 7545;AZ252017-04-2 O=C(N(C)C)C478.8698 PDHK### HY-10942 NVP-BEP800 VER-82576;V847559-80-2 O=C(C1=CC2480.4106 HSP### HY-N0293 Paeoniflorin Peoniflorin 23180-57-6 O[C@H]1[[email protected] HIF/HIF Proly### HY-N0565B Doxycycline Doxycycline 24390-14-5 O=C(C(C1=O)480.8955 MMP### HY-10626 T0901317 T 0901317;T 293754-55-9 OC(C(F)(F)F 481.3327 FXR; LXR### HY-15734 AGI-6780 AGI 6780;AG 1432660-47- O=S(C1=CC=481.5111 Isocitrate D### HY-10353A Raltegravir ( MK0518 potas871038-72-1 O=C(C(N=C(482.5067 HIV; HIV Inte### HY-B1080 Tilorone (dihydrochloride) 27591-69-1 O=C1C2=C(C483.4709 HIF/HIF Proly### HY-18252 Avanafil TA1790;TA 1 330784-47-9 COC1=C(Cl) 483.9507 Phosphodiest### HY-15872A FTI-277 (hydrochloride) 180977-34-8 CSCC[C@@H]484.0749 Farnesyl Tra### HY-B0331A Enalapril (maleate) 76095-16-4 O=C(O)[[email protected] Angiotensin-### HY-B0218 Orlistat Tetrahydroli 96829-58-2 O=C1[C@@H]495.7348 Fatty Acid S### HY-10912 Fexaramine 574013-66-4 CN(C)C1=CC496.6398 FXR### HY-17378 Dabigatran (ethyl ester) 429658-95-7 O=C(N(C1=N499.5643 Thrombin### HY-17504 RosuvastatinRosuvastatin147098-20-2 O=C([O-])C[ 500.57 Autophagy; ### HY-100793 SR12813 SR-12813;S 126411-39-0 OC1=C(C(C)(504.5336 HMG-CoA Red### HY-B0312 Dipyridamole 58-32-2 OCCN(CCO)C504.6256 Phosphodiest### HY-17430 Amprenavir 161814-49-9 O=C(O[C@@H505.6269 HIV; HIV Pro### HY-19919 BMS-779788 XL652;BMS78918348-67-1 OC(C)(C)C1 509.0594 LXR### HY-N0892 AKBA Acetyl-11-ket67416-61-9 C[C@@]([C@@512.7205 HIF/HIF Proly### HY-B0384 Temocapril (hydrochloride110221-44-8 O=C(O)CN1C513.0698 Angiotensin-### HY-15178 Oglemilast GRC 3886;G 778576-62-8 O=C(C1=C2C516.3021 Phosphodiest### HY-18253 Udenafil DA8159 268203-93-6 O=S(C1=CC=516.6561 Phosphodiest### HY-10452 MLN9708 Ixazomib cit 1239908-20- O=C(O)CC1( 517.1216 Autophagy; ### HY-12270 T-5224 T5224;T 522 530141-72-1 OC1=NOC2=C517.5266 MMP### HY-10469 GSK256066 GSK-256066;801312-28-7 O=C(N)C1=C518.5842 Phosphodiest### HY-10237 Boceprevir EBP 520;SCH394730-60-0 O=C(N1[C@@H519.6767 HCV; HCV Pr### HY-15249 JZL 184 JZL184;JZL-1 1101854-58- OC(C1=CC=C520.4875 MAGL### HY-13749B Sitagliptin MK-0431 pho654671-77-9 [H]O[H].O=C523.3241 Autophagy; D### HY-B0442A Vardenafil (hydrochloride)224785-91-5 CCCC1=NC(C525.0639 Phosphodiest### HY-15836 BAY 87-2243 1227158-85- FC(F)(F)OC 525.5256 HIF/HIF Proly### HY-10042 Odanacatib MK-0822;MK 603139-19-1 N#CC1(NC([ 525.5588 Cathepsin### HY-B0375A Argatroban Argipidine m 141396-28-3 O=C([C@@H]526.6494 Thrombin### HY-17443B Sivelestat (s EI546 sodium201677-61-4 [O-]C(CNC( 528.5059 Elastase### HY-13613 Dutasteride GG 745;GI 1 164656-23-9 O=C([C@H]1C528.5297 5 alpha Redu### HY-13634A Ezatiostat TER199;TLK1168682-53-9 O=C(OCC)[C 529.6483 Gutathione S### HY-B0105 Ketoconazole(±)-Ketocona65277-42-1 CC(N1CCN(C2531.43092 Cytochrome ### HY-12113 Oprozomib ONX-0912;ON935888-69-0 C[C@]1(OC1 532.6092 Autophagy; ### HY-B0378A Moexipril (hyRS10085;RS 82586-52-5 O=C([C@H]1535.029 Angiotensin-### HY-77521 Dabigatran (ethyl ester hy211914-50-0 NC(C1=CC=C536.0252 Thrombin### HY-13041 LX-1031 LX1031;LX 1 945976-76-1 NC1=NC(C2=538.5177 Tryptophan H### HY-B0190A Nafamostat (FUT-175 82956-11-4 CS(=O)(O)= 539.5819 Ser/Thr Prot### HY-50108 GW 4064 GW-4064;GW278779-30-9 O=C(C1=CC=542.8376 FXR

### HY-100447 TM5275 (sodTM 5275 sod 1103926-82- O=C(O)C1=C544.9813 PAI-1### HY-15651 Alvelestat AZD9668;AZD848141-11-7 O=C(C1=CC(545.5335 Elastase### HY-17040 Darunavir TMC114;TMC206361-99-1 O=C(O[C@@H547.6636 HIV; HIV Pro### HY-18977 KML29 KML-29 1380424-42- O=C(N1CCC(C549.4164 MAGL### HY-12176 Aliskiren CGP 60536;C173334-57-1 COCCCOC1=C551.7583 Autophagy; R### HY-10941 VER-155008 1134156-31- O[C@@H]([C556.4006 Autophagy; ### HY-75957 DMP 777 L-694458;DM157341-41-8 CCC[C@H](C 564.6725 Elastase### HY-18777 KC7F2 927822-86-4 O=S(C1=CC(570.3812 HIF/HIF Proly### HY-17379 Atorvastatin Atorvastatin 134523-03-8 FC1=CC=C(C577.6708632Autophagy; ### HY-N0153 Naringin Naringoside 10236-47-2 O=C1C[C@@H580.5346 Autophagy; ### HY-13207 ONX-0914 PR-957;ONX 960374-59-8 O=C(N[C@@H580.6719 Proteasome### HY-18767 Ivosidenib AG-120;AG 11448347-49- ClC1=C([C@ 582.9609 Isocitrate D### HY-18767A (R,S)-Ivoside (R,S)-AG-120;(R,S)-AG 12 FC1(F)CC(N 582.9609 Isocitrate D### HY-B0382 Fosinopril (s SQ28555 88889-14-9 O=C([O-])[ 585.6443 Angiotensin-### HY-10211 17-AAG Tanespimyci 75747-14-7 O=C(C(NC(/ 585.6884 Autophagy; ### HY-17041 Darunavir (E TMC114;TMC635728-49-3 O=C(O[C@@H593.732 HIV; HIV Pro### HY-100739 RA190 RA-190;RA 1 1617495-03- O=C1/C(CN(C596.7594 Proteasome### HY-12089 Torcetrapib CP-529414 262352-17-0 O=C(N1[C@H]600.4733 CETP### HY-10627A GW3965 (hydrGW 3965 hydr405911-17-3 ClC1=C(C(F 618.5133 LXR### HY-15098 Apoptozole 1054543-47- NC(C(C=C1) 625.5603 HSP### HY-16972 SR9243 SR-9243 1613028-81- BrC1=CC(CC626.6241 LXR### HY-10274 Dabigatran eBIBR 1048;B 211915-06-9 O=C(N(C1=N627.7332 Thrombin### HY-14588 Lopinavir ABT-378;ABT192725-17-0 CC1=C(OCC(628.8008 HIV; HIV Pro### HY-14806A Teneligliptin Teneligliptin 906093-29-6 O=C(N1CSCC628.855 Dipeptidyl P### HY-70069 GSK256066 (2,GSK-256066;1415560-64- OC(C(F)(F) 632.6075 Phosphodiest### HY-12090 Anacetrapib MK 0859;MK-875446-37-0 O=C1O[C@@H]637.5084 CETP### HY-13327 Evacetrapib LY2484595;L1186486-62- O=C([C@H]1C638.647 CETP### HY-15136 Lonafarnib Sch 66336;S 193275-84-2 O=C(N1CCC(638.8217 Autophagy; F### HY-12024 Alvespimycin17-DMAG;KOS467214-21-7 C/C1=C\C=C653.2065 HSP### HY-15287A Nelfinavir (M AG 1343 Mes159989-65-8 [H][C@]12C 663.8881 HIV; HIV Pro### HY-15025A Sildenafil (ci UK-92480 cit171599-83-0 O=C1C(N(C) 666.6999 Autophagy; P### HY-10521 Darapladib SB-480848;S356057-34-6 FC1=CC=C(C666.7711 Phospholipas### HY-17007 Saquinavir Ro 31-8959 127779-20-8 O=C(N[C@@H670.8408 HIV; HIV Pro### HY-10235 Telaprevir VX-950;VX95402957-28-2 O=C(N([C@@679.8493 HCV; HCV Pr### HY-P0018 Pepstatin Pepstatin A;I 26305-03-3 CC(C[C@H]( 685.8921 Cathepsin### HY-B0689A Indinavir (sulMK-639 sulfa157810-81-6 O=C([C@@H]711.868 HIV; HIV Pro### HY-10455 Carfilzomib PR 171;PR17 868540-17-4 C[C@@]1(C( 719.9099 Autophagy; ### HY-90001 Ritonavir A 84538;ABT155213-67-5 O=C(N[C@@H720.9442 HIV; HIV Pro### HY-10274A Dabigatran eBIBR 1048MS;872728-81-9 O=C(N(C1=N723.8389 Thrombin### HY-10238 Danoprevir ITMN-191;R7850876-88-9 O=S(NC([[email protected] HCV; HCV Pr### HY-10264B Edoxaban (tosylate monoh1229194-11- O=C(N(C)C) 738.2744 Factor Xa### HY-10466 Daclatasvir BMS-790052;1009119-64- O=C([C@@H]738.875 HCV; HCV Pr### HY-17508 Clarithromycin 81103-11-9 C[C@@](OC)747.9534 Autophagy; B

### HY-10241 Simeprevir TMC435;TMC923604-59-5 COC1=C(C)C749.9391 HCV; HCV Pr### HY-13055 LX1606 (HippTelotristat 1137608-69- O=C([C@H]( 754.1546 Tryptophan H### HY-17003 Saquinavir ( Ro 31-8959/ 149845-06-7 NC(C[C@H]( 766.9465 Autophagy; H### HY-10493 Cobicistat GS-9350;GS 1004316-88- CN(C(N[C@@776.0227 Cytochrome ### HY-N0431 Astragaloside IV 84687-43-4 O[C@H]1[[email protected] ERK; JNK; M### HY-17367A Atazanavir (sBMS 232632 s229975-97-7 O=C(OC)N[C 802.934 HIV; HIV Pro### HY-12530 Velpatasvir GS-5816;GS 1377049-84- O=C(N([[email protected] HCV; HCV Pr### HY-15602 Ledipasvir GS-5885;GS 1256388-51- O=C(OC)N[C 888.9999 HCV; HCV Pr### HY-12403 Angiotensin (Angiotensin-(51833-78-4 O=C(N(CCC1899.0048 Angiotensin ### HY-100595 StibogluconaSodium stibo16037-91-5 [O-][SbH](O 910.9 Phosphatase### HY-15602A Ledipasvir (aGS-5885 ace 1441674-54- O=C(OC)N[C 947.079 HCV; HCV Pr### HY-18204A LCZ696 Valsartan/sa 936623-90-4 O=C(CCC([O 957.99 Angiotensin R

Pathway Formula Solubility References listReferences link list Clinical InformationAnti-infecti C53H60F2N8DMSO: ≥ 28 [1] http://w LaunchedAutophagy; MC64H110N6O10 mM in D [1] Yuji Naka [1] http://p LaunchedMetabolic En C5H4N4O DMSO: 14 m [1] Pacher P, [1] http://w LaunchedMetabolic En C6H12O5 DMSO: ≥ 51 [1] Zhu Z, e [1] http://w Phase 1Metabolic En C3H3BrO3 H2</s[1] Gong L, e[1] https:// No Development ReportedMetabolic En C7H4O3S 10 mM in D [1] http://en [1] http://en No Development ReportedMetabolic En C7H4ClNO2 DMSO: ≥ 31 [1] Yamamura[1] http://w LaunchedMetabolic En C31H44N3NaH2</s[1] Bauer KA.[1] https:// LaunchedMetabolic En C7H7FO2S 10 mM in D [1] Sekar, M. [1] http://w No Development ReportedMetabolic En C10H10N2O 10 mM in D [1] http://w LaunchedMetabolic En C6H9NO5 DMSO: 10 m [1] Baader E,[1] http://w No Development ReportedAutophagy; GC7H8N4O2 DMSO: 21 m [1] Deree J, [1] http://w LaunchedMetabolic En (C3H7N . C3H10 mM in D [1] Sevelame[1] http://en LaunchedMetabolic En C8H9ClN4 H2</s[1] Bourreli, [1] http://w LaunchedMetabolic En C11H6O4 10 mM in D [1] Basavara [1] http://w No Development ReportedMetabolic En C12H9N3O DMSO: ≥ 46 [1] Shakur Y,[1] http://w LaunchedMetabolic En C12H11N3O 10 mM in D [1] Zhang L, [1] https:// No Development ReportedAutophagy; MC6H14ClNO5H2</su[1] Jamialahm[1] http://w LaunchedAutophagy; MC12H22ClN 10 mM in D [1] Robinson,[1] http://w LaunchedMetabolic En C12H8O4 10 mM in D [1] Alsharari [1] http://w LaunchedAutophagy; MC12H8O4 10 mM in D [1] Lee YM, e[1] http://w Phase 3Metabolic En C9H15NO3S 10 mM in D [1] Tzakos, A[1] http://w LaunchedMetabolic En C10H14N4O2DMSO: ≥ 35 [1] http://w Phase 2Autophagy; MC4H6N4O3S2DMSO: ≥ 41 [1] Leaf DE, [1] http://w LaunchedMetabolic En C6H11O7P H2</s[1] Rais R, e [1] https:// No Development ReportedAutophagy; MC14H14N2O H2O: ≥ 38 mg/mL LaunchedMetabolic En C8H6N2S3 10 mM in D [1] Lee WH, e[1] http://w Phase 3Metabolic En C13H12N2O210 mM in D [1] Nakazawa,[1] http://w LaunchedMetabolic En C100H138DFDMSO: ≥ 31 [1] Ciborowsk[1] http://w LaunchedMetabolic En C14H18N2O 10 mM in D [1] Kishi, Y. [1] http://o LaunchedMetabolic En C15H9NO2 10 mM in D [1] Ismail IH [1] http://w No Development ReportedMetabolic En C5H8N4O3S210 mM in D [1] Casini, A [1] http://w LaunchedMetabolic En C11H12N2O210 mM in D [1] https:// LaunchedMetabolic En C11H8FNO2SDMSO: ≥ 37 [1] Wang KK, [1] http://w No Development ReportedMetabolic En C8H11ClFNODMSO: ≥ 30 [1] https:// No Development ReportedAutophagy; CC15H14O3 10 mM in D [1] Park EJ, [1] http://w No Development ReportedMetabolic En C11H14ClNODMSO: ≥150[1] Roberts [1] https:// No Development ReportedAutophagy; MC14H12O4 DMSO: ≥ 34 [1] Lorenz. e [1] www.ncbiNo Development ReportedMetabolic En C15H13FO2 10 mM in D [1] You X, et [1] https:// Phase 2Cell Cycle/D C13H11NO4 DMSO: ≥ 34 [1] Barrio S [1] www.ncbiNo Development ReportedAnti-infecti C11H9N3O4 10 mM in D [1] Hobaika, [1] http://w No Development ReportedMetabolic En C13H8N6 DMSO: 23.5 [1] Sato T, e [1] http://w Launched

[1] Link JO, et al. Discovery of ledipasvir (GS-5885): a potent, once-daily oral NS5A inhibitor for the treatment of hepatitis C virus infection. J Med Chem. 2014 Mar 13;57(5):2033-46. [2] Hernandez D, et al. Natural prevalence of NS5A polymorphisms in subjects infected with hepatitis C virus genotype 3 and their effects on the antiviral activity of NS5A inhibitors. J Clin Virol. 2013 May;57(1):13-8.

[1] Yoshida, H., et al. Neuroprotective effects of edaravone: a novel free radical scavenger in cerebrovascular injury. CNS Drug Rev, 2006. 12(1): p. 9-20. [2] Okamura, K., et al. Edaravone, a free radical scavenger, attenuates cerebral infarction and hemorrhagic infarction in rats with hyperglycemia. Neurol Res, 2013. [3] Garcia CA, et al. Edaravone reduces astrogliosis and apoptosis in young rats with kaolin-induced hydrocephalus. Childs Nerv Syst. 2016 Dec 17. [Epub ahead of print]

[4] Bai X, et al. Protective Effect of Edaravone on Glutamate-Induced Neurotoxicity in Spiral Ganglion Neurons. Neural Plast. 2016;2016:4034218. Epub 2016 Nov 10.

[1] Wu BN, et al. KMUP-1, a xanthine derivative, induces relaxation of guinea-pig isolated trachea: the role of the epithelium, cyclic nucleotides and K+ channels. Br J Pharmacol. 2004 Aug;142(7):1105-14. [2] Wei Y, et al. Angiotensin II type 2 receptor regulates ROMK-like K⁺ channel activity in the renal cortical collecting duct during high dietary K⁺ adaptation. Am J Physiol Renal Physiol. 2014 Oct 1;307(7):F833-43. [3] Hosseini A, et al. Differential metabolic effects of novel cilostamide analogs, methyl carbostiryl derivatives, on mouse and hyperglycemic rat. Iran J Basic Med Sci. 2012 Jul;15(4):916-25. [4] Crosswhite P, et al. Inhibition of phosphodiesterase-1 attenuates cold-induced pulmonary hypertension. Hypertension. 2013 Mar;61(3):585-92.

[1] Abueid L, et al. Inhibition of 5-lipoxygenase by zileuton in a rat model of myocardial infarction. Anatol J Cardiol. 2016 Nov 10. [2] Kuvibidila S, et al. Hydroxyurea and Zileuton Differentially Modulate Cell Proliferation and Interleukin-2 Secretion by Murine Spleen Cells: Possible Implication on the Immune Function and Risk of Pain Crisis in Patients with Sickle Cell Disease. Ochsner [3] Gounaris E, et al. Zileuton, 5-lipoxygenase inhibitor, acts as a chemopreventive agent in intestinal polyposis, by modulating polyp and systemic inflammation. PLoS One. 2015 Mar 6;10(3):e0121402. [1] Citron M, et al. Inhibition of amyloid beta-protein production in neural cells by the serine protease inhibitor AEBSF. Neuron. 1996 Jul;17(1):171-9. [2] Nakabo Y, et al. Lysis of leukemic cells by human macrophages: inhibition by 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF), a serine protease inhibitor. J Leukoc Biol. 1996 Sep;60(3):328-36.

[3] Buitrago-Rey R, et al. Evaluation of two inhibitors of invasion: LY311727 [3-(3-acetamide-1-benzyl-2-ethyl-indolyl-5-oxy)propane phosphonic acid] and AEBSF [4-(2-aminoethyl)-benzenesulphonyl fluoride] in acute murine toxoplasmosis. J Antimicrob Chemother. [4] Jiang YH, et al. Serine protease inhibitor 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF) inhibits the rat embryo implantation in vivo and interferes with cell adhesion in vitro. Contraception. 2011 Dec;84(6):642-8.

Metabolic En C13H11N2NaH2</s[1] Nakazawa,[1] http://w LaunchedMetabolic En C17H18N2 DMSO: ≥ 47 [1] Zhang LN,[1] http://w No Development ReportedMetabolic En C14H10BNO DMSO: ≥ 32 [1] Akama T, [1] https:// Phase 3GPCR/G ProteC10H14N4O410 mM in D [1] Schwabe U[1] http://w LaunchedMetabolic En C14H22O4 10 mM in D [1] Rae C, et [1] https:// No Development ReportedGPCR/G ProteC9H7Cl2N5 [1] Ren, C.J. [1] http://w LaunchedAutophagy; MC15H12O4 10 mM in D [1] Aida K, e [1] http://w Phase 1Metabolic En C15H12ClNO10 mM in D [1] Anguiano [1] https:// No Development ReportedMetabolic En C12H15Cl2N 10 mM in D [1] Remacle [1] http://w No Development ReportedMetabolic En C16H14N2O2DMSO: 10 m [1] Yoneda T,[1] https:// No Development ReportedAutophagy; CC18H18O2 DMSO: ≥ 37 [1] Su Young [1] http://w No Development ReportedMetabolic En C11H15KOS210 mM in D [1] Kalluri H [1] http://w No Development ReportedMetabolic En C11H15KOS210 mM in D [1] Walker K [1] http://w No Development ReportedMetabolic En C12H10F2N2DMSO: ≥ 28 [1] R.T. Sche [1] http://e No Development ReportedMetabolic En C11H16N4O410 mM in D [1] Bethge W[1] https:// LaunchedMetabolic En C15H10O5 DMSO: ≥ 34 No Development ReportedAutophagy; MC15H10O5 DMSO: ≥ 36 [1] Ciolino H [1] http://w No Development ReportedMetabolic En C9H7ClFN5ODMSO: ≥ 52 [1] http://w No Development ReportedMetabolic En C14H11NO5 10 mM in D [1] http://w LaunchedMetabolic En C16H21NO3 DMSO: ≥ 41 [1] MacKenzie[1] http://w Phase 2Metabolic En C16H21NO3 DMSO: ≥ 49 [1] Guo C, e [1] https:// Phase 1Metabolic En C16H21NO3 10 mM in D [1] Griswold, [1] http://w No Development ReportedAutophagy; MC13H18N4O3DMSO: ≥ 2.8[1] http://en [1] http://e LaunchedMetabolic En C18H22N2O 10 mM in D [1] Mario R. [1] http://c No Development ReportedMetabolic En C17H21N3O DMSO: ≥ 45 [1] Mayer N, [1] http://w No Development ReportedMetabolic En C16H12O5 DMSO: ≥ 51 [1] Thors L, [1] http://w No Development ReportedAutophagy; MC16H12O5 DMSO: ≥ 32 [1] Zhao K, e[1] http://w No Development ReportedCell Cycle/D C13H12N6O2DMSO: ≥ 27 [1] https:// No Development ReportedMetabolic En C10H12ClN5 DMSO: ≥ 30 [1] Guchelaar[1] http://w LaunchedMetabolic En C14H11ClN4 10 mM in D [1] Tsubokawa[1] http://w No Development ReportedMetabolic En C12H16O4S210 mM in D [1] Shibata T [1] http://w LaunchedMetabolic En C10H8Cl3N3 10 mM in D [1] Pescatore[1] http://w LaunchedMetabolic En C10H20N2S410 mM in D [1] https:// LaunchedMetabolic En C16H12O6 DMSO: ≥ 35 [1] Liu B, et [1] https:// No Development ReportedMetabolic En C18H20O4 10 mM in D [1] www.ncb No Development ReportedMetabolic En C20H28O2 10 mM in D [1] Thielitz, [1] http://w LaunchedCell Cycle/D C20H28O2 10 mM in D [1] Wu L, et [1] https:// LaunchedMetabolic En C17H22N2O3DMSO: ≥ 31 [1] Rath T et [1] http://w No Development ReportedAutophagy; CC19H26O3 DMSO: ≥ 36 [1] Kamath K,[1] http://w Phase 2Metabolic En C17H25N3O210 mM in D [1] Villhauer [1] http://w LaunchedMetabolic En C6H6Cl2N2ODMSO: ≥ 28 [1] Kanski, J [1] http://w LaunchedMetabolic En C14H15N3O510 mM in D [1] Piccini P [1] http://w LaunchedMetabolic En C15H14O3S210 mM in D [1] Lee M, et [1] http://w No Development Reported

DMSO：≥ 2.6 mg/mL

[1] Shieh DE,et al. Antioxidant and free radical scavenging effects of baicalein, baicalin and wogonin. Anticancer Res. 2000 Sep-Oct;20(5A):2861-5. [2] Patwardhan RS, et al. Baicalein exhibits anti-inflammatory effects via inhibition of NF-κB transactivation. Biochem Pharmacol. 2016 May 15;108:75-89. [3] Ma X, et al. Baicalein suppresses metastasis of breast cancer cells by inhibiting EMT via downregulation of SATB1 and Wnt/β-catenin pathway. Drug Des Devel Ther. 2016 Apr 18;10:1419-41. [4] Kong EK, et al. A novel anti-fibrotic agent, baicalein, for the treatment of myocardial fibrosis in spontaneously hypertensiverats. Eur J Pharmacol. 2011 May 11;658(2-3):175-81.

[1] https://www.ncbi.nlm.nih.gov/pubmed/11062694 [2] https://www.ncbi.nlm.nih.gov/pubmed/27019135 [3] https://www.ncbi.nlm.nih.gov/pubmed/27143851 [4] https://www.ncbi.nlm.nih.gov/pubmed/21371455

[1] Yue EW, et al. Discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model. J Med Chem. 2009 Dec 10;52(23):7364-7. [2] Huang X, et al. Synthesis of [(18) F] 4-amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboximidamide (IDO5L): a novel potential PET probe for imaging of IDO1 expression. J Labelled Comp Radiopharm. 2015 Apr;58(4):156-62. [1] Neil E. Paterson, Jennifer Ricciardi, Caitlin Wetzler, et al. Sub-optimal performance in the 5-choice serial reaction time task in rats was sensitive to methylphenidate, atomoxetine and d-amphetamine, but unaffected by the COMT inhibitor tolcapone. Neuroscience Research. 2011, 69(1): 41-50. [2] Saviana Di Giovanni, Simona Eleuteri, Katerina E. Paleologou, et al. Entacapone and Tolcapone, Two Catechol O-Methyltransferase Inhibitors, Block Fibril Formation of α-Synuclein and β-Amyloid and Protect against Amyloid-induced Toxicity. The Journal of Biological Chemistry, 2010, 285, 14941-14954. [3] Panos Bitsios, Panos Roussos1. Tolcapone, COMT polymorphisms and pharmacogenomic treatment of schizophrenia. Pharmacogenomics. 2001,12 (4): 559-566. [4] M.A. Vieira-Coelho, P. Soares-da-Silva. Ontogenic aspects of liver and kidney catechol-O- methyltransferase sensitivity to tolcapone. British Journal of Pharmacology.1996,117 (3):516-520. [5] J. Dingemanse, K. Jorga, G. Zurcher,et al. Pharmacokinetic-pharmacodynamic interaction between the COMT inhibitor tolcapone and single-dose levodopa. British Journal of Clinical Pharmacology 1995, 40 (3):253-262.

[1] Yoon YJ, et al. KRIBB11 inhibits HSP70 synthesis through inhibition of heat shock factor 1 function by impairing the recruitment of positive transcription elongation factor b to the hsp70 promoter. J Biol Chem. 2011 Jan 21;286(3):1737-47. [2] Samarasinghe B, et al. Heat shock factor 1 confers resistance to Hsp90 inhibitors through p62/SQSTM1 expression and promotion of autophagic flux. Biochem Pharmacol. 2014 Feb 1;87(3):445-55.

[1] Chen D, ert al. Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. Cancer Res. 2006 Nov 1;66(21):10425-33. [2] Wang W, et al. Disulfiram-mediated inhibition of NF-kappaB activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines. Int J Cancer. 2003 Apr 20;104(4):504-11. [3] Cen D, et al. Disulfiram facilitates intracellular Cu uptake and induces apoptosis in human melanoma cells. J Med Chem. 2004 Dec 30;47(27):6914-20.

[4] Brar SS, et al. Disulfiram inhibits activating transcription factor/cyclic AMP-responsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease. Mol Cancer Ther. 2004 Sep;3 [1] Chun YJ, Kim S et al. A new selective and potent inhibitor of human cytochrome P450 1B1 and its application to antimutagenesis. Cancer Res. 2001 Nov 15;61(22):8164-70. [2] Shyamala Thirunavukkarasu , Nayaab S. Khan et al. Cytochrome P450 1B1 Contributes to the Development of Angiotensin II-Induced Aortic Aneurysm in Male Apoe-/- Mice The American Journal of Pathology. 11 June 2016 [3] Maayah ZH, Althurwi HN et al. CYP1B1 inhibition attenuates doxorubicin-induced cardiotoxicity through a mid-chain HETEs-dependent mechanism..Pharmacol Res. 2016 Mar;105:28-43 [4] Tracey Einem Lindeman, Miriam C. Poirier et al. The resveratrol analogue, 2,3′,4,5′-tetramethoxystilbene, does not inhibit CYP gene expression, enzyme activity and benzo[a]pyrene-DNA adduct formation in MCF-7 cells exposed to benzo[a]pyrene. Mutagenesis 2011 Sep; 26(5): 629-635.

Metabolic En C10H11ClN2 DMSO: 11 m [1] Du ZD, et[1] https:// No Development ReportedMetabolic En C18H17N3O210 mM in D [1] http://w Phase 3Metabolic En C17H17N5O 10 mM in D [1] Dickason-[1] http://w No Development ReportedMetabolic En C16H24N2O4DMSO: 6 mg/ [1] https:// LaunchedMetabolic En C13H12FN3ODMSO: ≥ 47 [1] Lou Y, et [1] http://w No Development ReportedMetabolic En C10H23BN2ODMSO: ≥ 40 [1] https:// Phase 3Metabolic En C13H15NO6S10 mM in D [1] Khan, Ta [1] http://w No Development ReportedMetabolic En C18H19NO4 10 mM in D [1] Kumar P, [1] http://w No Development ReportedMetabolic En C18H25N3O2DMSO: ≥ 34 [1] Tahrani A[1] http://w LaunchedMetabolic En C16H16N2O310 mM in D [1] Takano Y,[1] http://w LaunchedAutophagy; CC14H15ClN6 DMSO: ≥ 45 [1] http://w Phase 2Metabolic En C15H13NO3SDMSO: ≥ 3.1[1] Ramirez, [1] http://w LaunchedMetabolic En C15H11ClFN DMSO: 20 mg/mL No Development ReportedMetabolic En C15H10Cl2N 10 mM in D [1] http://en [1] http://en Phase 3Metabolic En C15H11Cl2N DMSO: ≥ 51 [1] https:// No Development ReportedAutophagy; MC18H29ClN2 DMSO: ≥ 47 [1] Burlacu C[1] https:// LaunchedMetabolic En C18H12ClNODMSO: ≥ 29 [1] Jin YR, e [1] https:// No Development ReportedMetabolic En C21H26O3 10 mM in D [1] http://w LaunchedMetabolic En C20H24O4 [1] Gierach I [1] https:// Phase 2Cell Cycle/D C23H38O DMSO: ≥ 32 [1] Sysa-Shah[1] http://w LaunchedMetabolic En C14H16ClF2 DMSO: ≥ 31 [1] http://w Phase 2Metabolic En C19H18N4O210 mM in D [1] Kajimoto [1] http://w No Development ReportedMetabolic En C14H11NO5SDMSO: ≥150[1] Hertzel A [1] https:// No Development ReportedAutophagy; MC20H22N2O310 mM in D [1] Mor M, et [1] http://w Phase 1Metabolic En C20H25NO4 10 mM in D [1] MARY S. B[1] http://w Phase 3Metabolic En C12H6ClF3N DMSO: ≥ 36 [1] Barrett T [1] http://w No Development ReportedAutophagy; MC24H28O2 10 mM in D [1] http://w LaunchedMetabolic En C24H28O2 DMSO: 11.25[1] Pignatell [1] http://w No Development ReportedMetabolic En C22H25NO3 DMSO: 25.5 [1] Wang X, [1] https:// LaunchedAutophagy; MC22H25NO3 DMSO: ≥ 45 [1] Gianní M [1] http://w No Development ReportedMetabolic En C21H21NO2S10 mM in D [1] Talpur R, [1] https:// LaunchedMetabolic En C14H7ClFN3 DMSO: ≥ 35 [1] Xu GW, e [1] http://w No Development ReportedMetabolic En C19H16N2O5DMSO: ≥ 46 [1] Liu H, et [1] https:// Phase 3Metabolic En C19H16N2O510 mM in D [1] Chowdhury[1] https:// No Development ReportedAnti-infecti C21H20ClNO10 mM in DMSO No Development ReportedMetabolic En C16H18O9 DMSO: ≥ 32 [1] Park JJ, [1] http://w Phase 3Immunology/IC21H22O5 DMSO: ≥ 15 [1] https:// No Development ReportedMetabolic En C22H17N3O2DMSO [1] http://w No Development ReportedMetabolic En C16H14F3NO10 mM in D [1] Sestanj K [1] http://w No Development ReportedMetabolic En C18H20FN5O10 mM in D [1] Efficacy [1] http://c LaunchedAutophagy; MC15H27N5O5DMSO: ≥ 22 [1] Matsumoto[1] https:// No Development ReportedAutophagy; CC20H21ClO4 DMSO: ≥ 47 [1] Schellema[1] https:// LaunchedMetabolic En C10H17ClN2 H2</su [1] http://w Launched

[1] Yamaoka M, et al. Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys. J Steroid Biochem Mol Biol. 2012 Apr;129(3-5):115-28. [2] Kaku, Tomohiro., et al. Discovery of orteronel (TAK-700), a naphthylmethylimidazole derivative, as a highly selective 17,20-lyase inhibitor with potential utility in the treatment of prostate cancer. From Bioorganic & Medicinal Chemistry (2011), 19(21), 6 [1] Hossain A, et al. Protective effects of bestatin in the retina of streptozotocin-induced diabetic mice. Exp Eye Res. 2016 Aug;149:100-6. [2] Qian X, et al. Inhibition of p38 MAPK Phosphorylation Is Critical for Bestatin to Enhance ATRA-Induced Cell Differentiation in Acute Promyelocytic Leukemia NB4 Cells. Am J Ther. 2016 May-Jun;23(3):e680-9. [3] Lis M, et al. The effects of bestatin on humoral response to sheep erythrocytes in non-treated and cyclophosphamide-immunocompromised mice. Immunopharmacol Immunotoxicol. 2013 Feb;35(1):133-8. [4] Poloz Y, et al. Bestatin inhibits cell growth, cell division, and spore cell differentiation in Dictyostelium discoideum. Eukaryot Cell. 2012 Apr;11(4):545-57. [1] Cristillo AD, et al. HIV-1 Env vaccine comprised of electroporated DNA and protein co-administered with Talabostat. Biochem Biophys Res Commun. 2008 May 23;370(1):22-6. [2] Huang Y, et al. Fibroblast activation protein-α promotes tumor growth and invasion of breast cancer cells through non-enzymatic functions. Clin Exp Metastasis. 2011 Aug;28(6):567-79. [3] Meany H, et al. Pediatric phase I trial design using maximum target inhibition as the primary endpoint. J Natl Cancer Inst. 2010 Jun 16;102(12):909-12.

[1] Lundgren, Karen., et al. BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90. Molecular Cancer Therapeutics (2009), 8(4), 921-929. [2] Böll B, et al. Heat shock protein 90 inhibitor BIIB021 (CNF2024) depletes NF-kappaB and sensitizes Hodgkin's lymphoma cells for natural killer cell-mediated cytotoxicity. Clin Cancer Res. 2009 Aug 15;15(16):5108-16. [3] Yin X, et al. BIIB021, a novel Hsp90 inhibitor, sensitizes head and neck squamous cell carcinoma to radiotherapy. Int J Cancer. 2010 Mar 1;126(5):1216-25. [4] Zhang H, et al. BIIB021, a synthetic Hsp90 inhibitor, has broad application against tumors with acquired multidrug resistance. Int J Cancer. 2010 Mar 1;126(5):1226-34.

[1] Stachowicz A, et al. Proteomic Analysis of Mitochondria-Enriched Fraction Isolated from the Frontal Cortex and Hippocampus of Apolipoprotein E Knockout Mice Treated with Alda-1, an Activator of Mitochondrial Aldehyde Dehydrogenase (ALDH2). Int J Mol Sci. [2] Stachowicz A, et al. The impact of mitochondrial aldehyde dehydrogenase (ALDH2) activation by Alda-1 on the behavioral and biochemical disturbances in animal model of depression. Brain Behav Immun. 2016 Jan;51:144-53. [3] Ikeda T, et al. Effects of Alda-1, an Aldehyde Dehydrogenase-2 Agonist, on Hypoglycemic Neuronal Death. PLoS One. 2015 Jun 17;10(6):e0128844. [4] Gomes KM, et al. Aldehydic load and aldehyde dehydrogenase 2 profile during the progression of post-myocardial infarction cardiomyopathy: benefits of Alda-1. Int J Cardiol. 2015 Jan 20;179:129-138.

[1] Lee CS, et al. A review of acitretin, a systemic retinoid for the treatment of psoriasis. Expert Opin Pharmacother. 2005 Aug;6(10):1725-34. [2] Seng?r B, et al. Effects of acitretin on spermatogenesis of rats. J Eur Acad Dermatol Venereol. 2006 Jul;20(6):689-92. DMSO: 9.85 mg/mL (Need ultrasonic)

[1] Stanley WC, et al. Catecholamine modulatory effects of nepicastat (RS-25560-197), a novel, potent and selective inhibitor of dopamine-beta-hydroxylase. Br J Pharmacol. 1997 Aug;121(8):1803-9. [2] Stanley WC, et al. Cardiovascular effects of nepicastat (RS-25560-197), a novel dopamine beta-hydroxylase inhibitor. J Cardiovasc Pharmacol. 1998 Jun;31(6):963-70. [3] Sabbah HN, et al. Effects of dopamine beta-hydroxylase inhibition with nepicastat on the progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure. Circulation. 2000 Oct 17;102(16):1990-5. [4] Beliaev A, et al. Synthesis and biological evaluation of novel, peripherally selective chromanyl imidazolethione-based inhibitors of dopamine beta-hydroxylase. J Med Chem. 2006 Feb 9;49(3):1191-7.

[1] Vakeva L, Ranki A, Hahtola S. Ten-year experience of bexarotene therapy for cutaneous T-cell lymphoma in Finland. Acta Derm Venereol. 2012 May;92(3):258-63. doi: 10.2340/00015555-1359. [2] Zhang X, Schlaak M, Fabri M, Mauch C, Kurschat P. Successful Treatment of a Panniculitis-Like Primary Cutaneous T-Cell Lymphoma of the α/β Type with Bexarotene. Case Rep Dermatol. 2012 Jan;4(1):56-60. [3] Orendas P, Kubatka P, Kajo K, Stollarova N, Kassayova M, Bojkova B, Pec M, Nosal V, Kiskova T, Zihlavnikova K, Karsnakova R. Melatonin enhanced bexarotene efficacy in experimental mammary carcinogenesis. Neoplasma. 2012;59(4):469-74. [4] Cras A, Politis B, Balitrand N, Darsin-Bettinger D, Boelle PY, Cassinat B, Toubert ME, Chomienne C. Bexarotene via CBP/p300 induces suppression of NF-κB-dependent cell growth and invasion in thyroid cancer. Clin Cancer Res. 2012 Jan 15;18(2):442-53.

[1] Luzak B, et al. Xanthohumol from hop cones (Humulus lupulus L.) prevents ADP-induced platelet reactivity. Arch Physiol Biochem. 2016 Nov 18:1-7. [2] Arnaiz-Cot JJ, et al. Xanthohumol modulates calcium signaling in rat ventricular myocytes: Possible Antiarrhythmic properties. J Pharmacol Exp Ther. 2016 Nov 4. pii: jpet.116.236588. [3] Gallo C, et al. Hop derived flavonoid xanthohumol inhibits endothelial cell functions via AMPK activation. Oncotarget. 2016 Aug 1. [4] Chen PH, et al. The miR-204-3p-targeted IGFBP2 pathway is involved in xanthohumol-induced glioma cell apoptotic death. Neuropharmacology. 2016 Nov;110(Pt A):362-75. [1] Method for increasing HDL cholesterol levels using heteroaromatic phenylmethanes. United States Patent 6103733

[1] Rankin AJ, et al. Effects of ocular administration of ophthalmic 2% dorzolamide hydrochloride solution on aqueous humor flow rate and intraocular pressure in clinically normal cats. Am J Vet Res. 2012 Jul;73(7):1074-8. [2] Sarup V, et al. Dorzolamide and timolol saves retinal ganglion cells in glaucomatous adult rats. J Ocul Pharmacol Ther. 2005 Dec;21(6):454-62.

Autophagy; MC14H19BCl2 DMSO: ≥ 28 [1] Kupperma[1] http://w LaunchedAnti-infecti C19H21Cl2N DMSO: ≥ 3.6 [1] https:// LaunchedMetabolic En C18H18F2N2DMSO [1] Ackermann[1] https:// No Development ReportedCell Cycle/D C20H20N4O3DMSO: ≥ 32 [1] http://w Phase 3Metabolic En C16H16ClN3 10 mM in D [1] Stern A. [1] http://w LaunchedMetabolic En C17H14N6O4DMSO: ≥ 40 [1] Sanders M[1] http://w No Development ReportedAutophagy; MC20H27N5O210 mM in D [1] Schr?r K. [1] http://w LaunchedMetabolic En C17H13N3O7DMSO: ≥ 46 [1] Yang Y, e [1] http://w No Development ReportedMetabolic En C19H22ClN5 DMSO: ≥ 39 [1] Watson M,[1] http://w No Development ReportedAutophagy; MC21H24O6 10 mM in D [1] Hayashi K[1] http://w No Development ReportedMetabolic En C23H32O4 DMSO: ≥ 33 mg/mL No Development ReportedMetabolic En C23H36N2O210 mM in D [1] Weisser, [1] http://w LaunchedMetabolic En C21H17N3O410 mM in D [1] Beghyn, e[1] http://w No Development ReportedMetabolic En C20H22ClNODMSO: 6.4 mg/mL (Need ultrasonic an LaunchedMetabolic En C18H22N2O310 mM in D [1] Fenner D,[1] http://w No Development ReportedCell Cycle/D C20H18FN5ODMSO: ≥ 33 [1] McBride C[1] http://w No Development ReportedMetabolic En C21H20N2O5DMSO: ≥ 32 [1] Draheim S[1] http://w Phase 3Metabolic En C20H32N2O3DMSO: ≥ 68 [1] Abass K, [1] http://w No Development ReportedMetabolic En C25H22N2O2DMSO: ≥ 40. [1] Sherk AB,[1] http://w No Development ReportedMetabolic En C16H26Cl3N DMSO: ≥150[1] Maes MB, [1] https:// No Development ReportedMetabolic En C19H25N7O2DMSO: ≥ 36 [1] Kato N, e [1] http://w LaunchedMetabolic En C12H21N3O510 mM in D [1] DeSantis,[1] http://w LaunchedMetabolic En C20H37N3O410 mM in D [1] Li SZ, e [1] http://w No Development ReportedAutophagy; MC19H25BN4O10 mM in D [1] Adams J, [1] http://w LaunchedAutophagy; MC18H28N2O710 mM in D [1] Ceconi, C [1] http://w LaunchedMetabolic En C14H16ClN5 DMSO: 10 m [1] Fish PV, [1] https:// No Development ReportedMetabolic En C20H22ClN3 DMSO: ≥ 56 [1] Xin Z, et [1] http://w No Development ReportedMetabolic En C20H28N4O4DMSO: ≥ 47 [1] Grobelny [1] http://w No Development ReportedMetabolic En C26H32N2O DMSO: 18 m [1] Bruno RD,[1] http://w Phase 3Metabolic En C22H28O2S210 mM in D [1] Zachar Z,[1] http://w Phase 2Metabolic En C22H19N3O4DMSO: ≥ 52 [1] Blount MA[1] http://w LaunchedMetabolic En C23H35NO2S10 mM in D [1] Niesor EJ [1] http://w Phase 3Autophagy; MC23H34O5 10 mM in D [1] Sugazaki [1] http://w No Development ReportedMetabolic En C23H25N3O310 mM in D [1] Luciani G [1] http://w No Development ReportedAutophagy; MC24H29N3O210 mM in D [1] Cea M, e [1] http://w Phase 2Metabolic En C26H33NO2 10 mM in D [1] http://w LaunchedAutophagy; MC26H33NO2 10 mM in D [1] Apraiz, A [1] http://w Phase 3Metabolic En C11H13IN4ODMSO: ≥ 49 [1] Massillon [1] http://w No Development ReportedMetabolic En C24H40O4 DMSO: ≥ 3.6 [1] https:// LaunchedAutophagy; MC13H20Cl4N H2</s[1] Palayoor [1] http://w Phase 1Metabolic En C22H26N4O310 mM in D [1] Cao J, et [1] http://w No Development ReportedMetabolic En C22H26N4O310 mM in D [1] Kazi A, e [1] http://w No Development ReportedMetabolic En C21H24N4O410 mM in D [1] Dow RL, e[1] http://w Phase 1

[1] Einav S, et al. Discovery of a hepatitis C target and its pharmacological inhibitors by microfluidic affinity analysis. Nat Biotechnol. 2008 Sep;26(9):1019-27. [2] Richter JM, et al. Clemizole hydrochloride is a novel and potent inhibitor of transient receptor potential channel TRPC5. Mol Pharmacol. 2014 Nov;86(5):514-21. [3] Nishimura T, et al. Using chimeric mice with humanized livers to predict human drug metabolism and a drug-drug interaction. J Pharmacol Exp Ther. 2013 Feb;344(2):388-96. [1] Shimamura T, et al. Ganetespib (STA-9090), a Non-Geldanamycin HSP90 Inhibitor, has Potent Antitumor Activity in In Vitro and In Vivo Models of Non-Small Cell Lung Cancer. Clin Cancer Res. 2012 Jul 17. [2] Ying W, et al. Ganetespib, a unique triazolone-containing Hsp90 inhibitor, exhibits potent antitumor activity and a superior safety profile for cancer therapy. Mol Cancer Ther. 2012 Feb;11(2):475-84. [3] London CA, et al. Phase I evaluation of STA-1474, a prodrug of the novel HSP90 inhibitor ganetespib, in dogs with spontaneous cancer. PLoS One. 2011;6(11):e27018. [4] Proia DA, et al. Multifaceted intervention by the Hsp90 inhibitor ganetespib (STA-9090) in cancer cells with activated JAK/STAT signaling. PLoS One. 2011 Apr 14;6(4):e18552.

[1] Stein MN, et al. Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer. Asian J Androl. 2014 May-Jun;16(3):387-400. [2] Richards J, et al. Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Res. 2012 May 1;72(9):2176-82. [3] Li R, et al. Abiraterone inhibits 3β-hydroxysteroid dehydrogenase: a rationale for increasing drug exposure in castration-resistant prostate cancer. Clin Cancer Res. 2012 Jul 1;18(13):3571-9.

[1] Stauffer AT, et al. Chenodeoxycholic acid and deoxycholic acid inhibit 11 beta-hydroxysteroid dehydrogenase type 2 and cause cortisol-induced transcriptional activation of the mineralocorticoid receptor. J Biol Chem. 2002 Jul 19;277(29):26286-92. [2] Casaburi I, et al. Chenodeoxycholic acid through a TGR5-dependent CREB signaling activation enhances cyclin D1 expression and promotes human endometrial cancer cell proliferation. Cell Cycle. 2012 Jul 15;11(14):2699-710. [3] Kawabe Y, et al. The molecular mechanism of the induction of the low density lipoprotein receptor by chenodeoxycholic acid in cultured human cells. Biochem Biophys Res Commun. 1995 Mar 8;208(1):405-11.

[4] Ao M, et al. Chenodeoxycholic acid stimulates Cl(-) secretion via cAMP signaling and increases cystic fibrosis transmembrane conductance regulator phosphorylation in T84 cells. Am J Physiol Cell Physiol. 2013 Aug 15;305(4):C447-56. [5] Noh K, et al. Farnesoid X receptor activation by chenodeoxycholic acid induces detoxifying enzymes through AMP-activated protein kinase and extracellular signal-regulated kinase 1/2-mediated phosphorylation of CCAAT/enhancer binding protein β. Drug Metab

Anti-infecti C18H26FN3O10 mM in D [1] http://w Phase 2Metabolic En C17H14Cl2F 10 mM in D [1] Hatzelman[1] https:// LaunchedMetabolic En C24H36O5 10 mM in D [1] Alberts A [1] https:// LaunchedMetabolic En C13H9F6NO310 mM in D [1] Kumar N, [1] https:// No Development ReportedAnti-infecti C19H17F2N3DMSO: 12.67[1] Reese MJ,[1] http://w Phase 3Autophagy; MC16H15F6N510 mM in D [1] Thomas, L[1] http://w LaunchedMetabolic En C19H24N2O4DMSO: ≥ 31 [1] Fryer RM,[1] https:// No Development ReportedCell Cycle/D C24H31N3O3DMSO: ≥ 33 [1] Woodhead [1] http://w Phase 2Anti-infecti C17H19FN4O10 mM in D [1] http://w Phase 2Metabolic En C18H17ClF2 10 mM in D [1] Keith JM, [1] http://w No Development ReportedCell Cycle/D C17H20Cl2N DMSO: ≥ 40 [1] Patel PD, [1] http://w No Development ReportedMetabolic En C24H29NO5 10 mM in D [1] Ksander G[1] https:// Phase 4Metabolic En C23H33N5O2DMSO: ≥ 46 [1] Falgueyre[1] http://w Phase 2Metabolic En C28H28O3 10 mM in D [1] Ellis CN, [1] http://w LaunchedMetabolic En C21H20N2OS10 mM in D [1] Zhang Y, [1] http://w No Development ReportedMetabolic En C24H22N4O3DMSO: ≥ 46 [1] Sun X, et [1] http://w Phase 1Metabolic En C27H21N5 DMSO: ≥ 35 [1] Theriault [1] http://w No Development ReportedMetabolic En C18H17ClF3 10 mM in D [1] Adibekian[1] https:// No Development ReportedMetabolic En C23H24N6O2DMSO: ≥ 29 [1] Maxson JE[1] https:// No Development ReportedMetabolic En C23H32N2O510 mM in D [1] Raasch, W[1] http://w LaunchedMetabolic En C21H32N6O3DMSO: ≥ 28 [1] www.ncbiNo Development ReportedMetabolic En C17H27N3O7H2</s[1] Erba, F., [1] http://w LaunchedAutophagy; MC25H38O5 10 mM in D [1] http://w LaunchedMetabolic En C16H24N10O10 mM in D [1] Essayan D[1] http://w LaunchedMetabolic En C24H28N4O310 mM in D [1] Matsuda D[1] http://w No Development ReportedMetabolic En C26H44O4 DMSO: ≥ 33 [1] Fiorucci [1] http://w LaunchedMetabolic En C17H10F3N5DMSO: ≥ 28 [1] ALDOSE [1] http:// No Development ReportedAutophagy; MC23H24FN5ODMSO: 14.67[1] Monovich [1] http://w No Development ReportedCell Cycle/D C22H28ClNODMSO: 6.2 mg[1] Jones PH, [1] http://w LaunchedAutophagy; MC23H31FO6 DMSO: ≥ 45 mg/mL LaunchedMetabolic En C21H12ClF5 DMSO: ≥ 47 [1] Quinet EM[1] http://w Phase 1Metabolic En C22H25N5O4DMSO: ≥ 30 [1] Dransfiel [1] https:// No Development ReportedMetabolic En C17H12Br2ODMSO: ≥ 39 mg/mL LaunchedMetabolic En C19H15Cl2N DMSO: ≥ 47 [1] Li JJ, et [1] http://w No Development ReportedMetabolic En C19H20ClNO10 mM in D [1] Kahraman [1] http://w Phase 2Metabolic En C22H30N6OS10 mM in D [1] Fukuda-Ts[1] http://w LaunchedMetabolic En C23H17FN6O10 mM in D [1] Kunitomo [1] http://w Phase 2Metabolic En C26H24N2O410 mM in D [1] Zhao G, e[1] http://w No Development ReportedMetabolic En C21H17ClN2 DMSO: ≥300[1] Placencio [1] https:// No Development ReportedMetabolic En C24H28Ca0. DMSO: ≥ 54 [1] Ksander G[1] https:// Phase 4Metabolic En C17H10F9NO10 mM in D [1] Wang Y, [1] http://w No Development ReportedAutophagy; MC24H25FNNa10 mM in D [1] Araújo FA[1] http://w LaunchedMetabolic En C24H23N3O5DMSO: ≥ 42 [1] Long JZ, [1] http://w No Development Reported

[1] Le Pogam S, et al. Characterization of HCV quasispecies dynamics upon short term dual-therapy with the HCV NS5B nucleoside polymerase inhibitor mericitabine and the NS3/4 protease inhibitor danoprevir. Antimicrob Agents Chemother. 2012 Nov;56(11):5494-5 [2] Soriano V, et al. Directly acting antivirals against hepatitis C virus. J Antimicrob Chemother. 2011 Aug;66(8):1673-86. [3] Guedj J, et al. Hepatitis C viral kinetics with the nucleoside polymerase inhibitor mericitabine (RG7128). Hepatology. 2012 Apr;55(4):1030-7.

[1] Cotelle P.,3-Hydroxy-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-ones as new HIV-1 integrase inhibitors WO2011046873 A1.,Expert Opin Ther Pat. 2011 Nov;21(11):1799-804. [2] Al-Mawsawi LQ, Al-Safi RI, Neamati N.,Anti-infectives: clinical progress of HIV-1 integrase inhibitors.,Expert Opin Emerg Drugs. 2008 Jun;13(2):213-25. [3] Dayam R, Al-Mawsawi LQ, Neamati N.,HIV-1 integrase inhibitors: an emerging clinical reality.,Drugs R D. 2007;8(3):155-68. [4] Dicker IB, et al. Changes to the HIV long terminal repeat and to HIV integrase differentially impact HIV integrase assembly, activity, and the binding of strand transfer inhibitors. J Biol Chem. 2007 Oct 26;282(43):31186-96.

[1] Kulsum S et al. Cancer stem cell mediated acquired chemoresistance in head and neck cancer can be abrogated by Aldehydedehydrogenase 1 A1 inhibition. Mol Carcinog. 2016 Jul 6. [2] Yang SM, et al. Discovery of NCT-501, a Potent and Selective Theophylline-Based Inhibitor of Aldehyde Dehydrogenase 1A1(ALDH1A1). J Med Chem. 2015 Aug 13;58(15):5967-5978. [1] Slater, E.E., et al. Mechanism of action and biological profile of HMG CoA reductase inhibitors. A new therapeutic alternative. Drugs, 1988. 36 Suppl 3: p. 72-82. [2] Kureishi, Y., et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med, 2000. 6(9): p. 1004-10. [3] Leung BP, et al. A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol. 2003 Feb 1;170(3):1524-30. [4] Kobayashi M, et al. Preventive effect of MK-733 (simvastatin), an inhibitor of HMG-CoA reductase, on hypercholesterolemia and atherosclerosis induced by cholesterol feeding in rabbits. Jpn J Pharmacol. 1989 Jan;49(1):125-33.

[5] Ishida F, et al. Comparative effects of simvastatin (MK-733) and pravastatin (CS-514) on hypercholesterolemia induced by cholesterol feeding in rabbits. Biochim Biophys Acta. 1990 Feb 23;1042(3):365-73.

[6] Sukhova GK, et al. Statins reduce inflammation in atheroma of nonhuman primates independent of effects on serum cholesterol. Arterioscler Thromb Vasc Biol. 2002 Sep 1;22(9):1452-8.

Metabolic En C26H29NO5 DMSO: ≥ 33 [1] Naik R, e [1] https:// No Development ReportedMetabolic En C22H33N3O610 mM in D [1] Szucs, T. [1] http://w LaunchedMetabolic En C19H18ClN3 10 mM in D [1] Roehrig S[1] http://w LaunchedMetabolic En C11H13BrFN DMSO: ≥ 31 [1] Liu X, et [1] http://w Phase 3Metabolic En C25H24F2N2DMSO: 15 m [1] Flatt B, [1] http://w No Development ReportedMetabolic En C24H16F3NODMSO: ≥ 54 [1] Hennan JK No Development ReportedAutophagy; MC25H23FNO4 10 mM in D [1] http://w LaunchedAnti-infecti C20H18F2N3DMSO: ≥ 4.4[1] Kobayashi[1] http://w LaunchedMetabolic En C23H43N3O5DMSO [1] Vaclavik [1] http://w LaunchedMetabolic En C20H28ClN3 10 mM in DMSO LaunchedCell Cycle/D C22H30N6O2DMSO: ≥ 33 [1] Bao R, La[1] www.ncb Phase 1Anti-infecti C25H35NO4SDMSO: ≥ 32 [1] Yi G, De [1] http://w Phase 2Metabolic En C25H26N4O410 mM in D [1] http://w Phase 3Metabolic En C23H35NaO710 mM in D [1] McTavish [1] http://w LaunchedAnti-infecti C23H23ClFN 10 mM in D [1] Shimura K[1] https:// LaunchedMetabolic En C22H22Ca0. 10 mM in D [1] Dal Bo, L [1] http://w LaunchedAutophagy; MC29H38O4 10 mM in D [1] http://w No Development ReportedMetabolic En C19H23N3O6DMSO: ≥ 35 [1] Palsson-M[1] http://w No Development ReportedMetabolic En C23H20F3N510 mM in D [1] Johnson D[1] https:// Phase 2Metabolic En C24H23F3N410 mM in D [1] Ahn K, et [1] http://w No Development ReportedMetabolic En C25H25N5O4DMSO: 14.25 [1] https:// LaunchedMetabolic En C22H24N2O710 mM in D [1] Perez-Aso[1] https:// LaunchedMetabolic En C24H29ClN2 DMSO: ≥ 92 [1] Hou FF, e[1] http://w LaunchedMetabolic En C23H29ClN4 DMSO: ≥ 51 [1] Gilmartin [1] http://w No Development ReportedMetabolic En C25H27N5O410 mM in D [1] http://w LaunchedMetabolic En C25H23N3O4DMSO: ≥ 31 [1] Matheny [1] http://w No Development ReportedMetabolic En C27H31FN4ODMSO: ≥ 34 [1] Rohle D, [1] http://w No Development ReportedMetabolic En C24H19BFNODMSO: ≥ 39 [1] Zhang Y, [1] http://w No Development ReportedAutophagy; CC26H31N3O5DMSO: ≥ 62 [1] Best OG, [1] http://w Phase 2Cell Cycle/D C25H31N5O4DMSO: ≥100[1] Mohanan [1] Mohanan No Development ReportedMetabolic En C17H16BrFN DMSO: 19 m [1] Oballa RM[1] http://w Phase 2Metabolic En C28H36O6 DMSO: ≥ 30 [1] Okazaki M[1] https:// LaunchedMetabolic En C25H28N8O210 mM in D [1] Eckhardt [1] http://w LaunchedAutophagy; MC23H32Cl3N DMSO: ≥ 44 [1] http://w Phase 2Metabolic En C19H17F6N710 mM in D [1] Exploring [1] https://a No Development ReportedMetabolic En C21H18Br2NDMSO: ≥ 33 [1] http://w No Development ReportedMetabolic En C25H31ClN2 10 mM in D [1] Song, J.C [1] http://w LaunchedMetabolic En C22H26FN5O10 mM in D [1] Efficacy LaunchedMetabolic En C20H38N6O4 H2O: ≥ 19 mg/mL No Development ReportedMetabolic En C27H32N4O410 mM in D [1] Masood A,[1] https:// No Development ReportedMetabolic En C15H13F6N3DMSO: ≥ 39 [1] Solt LA, [1] http://w No Development ReportedMetabolic En C19H16ClN5 10 mM in D [1] Pundir S, [1] http://w No Development ReportedMetabolic En C22H21Cl2N 10 mM in D [1] Gierse J, [1] http://w No Development Reported

[1] https://www.ncbi.nlm.nih.gov/pubmed/18624980 [2] https://www.ncbi.nlm.nih.gov/pubmed/24072883 [3] https://www.ncbi.nlm.nih.gov/pubmed/15860572 [1] Mukhtar RY, et al. Pitavastatin. Int J Clin Pract. 2005 Feb;59(2):239-52. [2] Kajinami K, et al. Pitavastatin: efficacy and safety profiles of a novel synthetic HMG-CoA reductase inhibitor. Cardiovasc Drug Rev. 2003 Fall;21(3):199-215.

[1] Eikelboom JW, Weitz JI.Otamixaban in acute coronary syndromes.Lancet. 2009 Sep 5;374(9692):762-4. Epub 2009 Aug 28. [2] Sabatine MS, Antman EM, et al. Otamixaban for the treatment of patients with non-ST-elevation acute coronary syndromes (SEPIA-ACS1 TIMI 42): a randomised, double-blind, active-controlled, phase 2 trial.Lancet. 2009 Sep 5;374(9692):787-95. Epub 2009 Aug 28. [3] Guertin KR, Choi YM.The discovery of the Factor Xa inhibitor otamixaban: from lead identification to clinical development.Curr Med Chem. 2007;14(23):2471-81. [4] Cohen M, Bhatt DL, et al. SEPIA-PCI Trial Investigators.Randomized, double-blind, dose-ranging study of otamixaban, a novel, parenteral, short-acting direct factor Xa inhibitor, in percutaneous coronary intervention: the SEPIA-PCI trial.Circulation. 2007 May 22;115(20):2642-51. Epub 2007 May 14. [5] Guertin, Kevin R.; Choi, Yong-Mi.The discovery of the factor Xa inhibitor Otamixaban: from lead identification to clinical development.Current Medicinal Chemistry (2007), 14(23), 2471-2481.

[1] Yang H, et al. Celastrol, a triterpene extracted from the Chinese "Thunder of God Vine," is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice. Cancer Res. 2006 May 1;66(9):4758-65. [2] Guan Y, et al. Celastrol attenuates oxidative stress in the skeletal muscle of diabetic rats by regulating the AMPK-PGC1α-SIRT3 signaling pathway. Int J Mol Med. 2016 May;37(5):1229-38.

[1] Pinto DJ, et al. Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blo [2] Wong PC, et al. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost. 2008 May;6(5):820-9. [3] Zhang D, et al. Metabolism, pharmacokinetics and pharmacodynamics of the factor Xa inhibitor apixaban in rabbits. J Thromb Thrombolysis. 2010 Jan;29(1):70-80. [4] He K, et al. Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor. Eur J Drug Metab Pharmacokinet. 2011 Sep;36(3):129-39.

[1] Rendell M, et al. Alogliptin benzoate for the treatment of type 2 diabetes. Expert Opin Pharmacother. 2012 Mar;13(4):553-63. [2] Radha Andukuri, et al. Alogliptin: a new addition to the class of DPP-4 inhibitors. Diabetes Metab Syndr Obes. 2009; 2: 117-126. [3] Takeuchi K, et al. Pharmacological and clinical profile of alogliptin benzoate (NESINA?).Nihon Yakurigaku Zasshi. 2011 Jan;137(1):43-50. [4] Moritoh Y, et al. Chronic administration of alogliptin, a novel, potent, and highly selective dipeptidyl peptidase-4 inhibitor, improves glycemic control and beta-cell function in obese diabetic ob/ob mice. Eur J Pharmacol. 2008 Jul 7;588(2-3):325-32.

[1] Grünhagen HH, et al. Studies on the electrogenic action of acetylcholine with Torpedo marmorata electric organ. IV. Quinacrine: a fluorescent probe for the conformational transitions of the cholinergic receptor protein in its membrane-bound state. J Mol Biol. 1976 Sep 25;106(3):497-516. [2] Eriksson A, et al. Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia. Blood Cancer J. 2015 Apr 17;5:e307. [1] Pieper AA et al. Discovery of a proneurogenic, neuroprotective chemical. Cell. 2010 Jul 9;142(1):39-51. [2] Wang G et al. P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage. Cell. 2014 Sep 11;158(6):1324-34. [3] Pieper AA et al. P7C3 and an unbiased approach to drug discovery for neurodegenerative diseases. Chem Soc Rev. 2014 Oct 7;43(19):6716-26.

[1] http://clinicaltrials.gov/ct2/show/NCT00653185?term=SYR-472&rank=1 [2] http://clinicaltrials.gov/ct2/show/NCT00760344?term=SYR-472&rank=2 [3] http://clinicaltrials.gov/ct2/show/NCT01431807?term=SYR-472&rank=3 [4] http://clinicaltrials.gov/ct2/show/NCT01751360?term=SYR-472&rank=4

Metabolic En C19H18ClF3 DMSO: ≥ 46 [1] Morrell J [1] http://w No Development ReportedCell Cycle/D C21H23Cl2N DMSO: 6.2 mg[1] Massey AJ[1] http://w No Development ReportedMetabolic En C23H28O11 DMSO: ≥ 27 [1] Cao, B.Y. [1] http://w Phase 3Metabolic En C22H25ClN2 H2</s[1] Wilfried [1] http://w LaunchedMetabolic En C17H12F9NODMSO: ≥ 27 [1] Ding H et [1] https:// No Development ReportedMetabolic En C21H18F3N3DMSO: ≥ 29 [1] Wang F, e[1] http://w No Development ReportedAnti-infecti C20H20FKN610 mM in D [1] http://w LaunchedMetabolic En C25H36Cl2N H2O: ≥ 28 mg/mL LaunchedMetabolic En C23H26ClN7 10 mM in D [1] Kotera J, [1] http://w LaunchedMetabolic En C22H30ClN3 DMSO: ≥ 4.7[1] Cohen-Jon[1] http://w No Development ReportedMetabolic En C24H32N2O910 mM in D [1] Liu, Y.H. [1] http://w LaunchedMetabolic En C29H53NO5 10 mM in D [1] Zhi J, et [1] http://w LaunchedMetabolic En C32H36N2O310 mM in D [1] Lam IP, e [1] http://w No Development ReportedMetabolic En C27H29N7O310 mM in D [1] Simon Mic[1] http://p Phase 4Autophagy; MC22H27Ca0. 10 mM in D [1] Watanabe,[1] http://w LaunchedMetabolic En C24H42O7P210 mM in D [1] https:/ No Development ReportedMetabolic En C24H40N8O410 mM in D [1] Klabunde,[1] http://w LaunchedAnti-infecti C25H35N3O610 mM in D [1] Sadler B [1] http://w Phase 4Metabolic En C28H29ClN2 DMSO: ≥ 31 [1] Kirchgess[1] https:// No Development ReportedMetabolic En C32H48O5 DMSO: ≥ 5 mg/mL No Development ReportedMetabolic En C23H29ClN2 10 mM in D [1] Nakashima[1] http://w LaunchedMetabolic En C20H13Cl2F 10 mM in D [1] Giembycz [1] http://w Phase 2Metabolic En C25H36N6O4DMSO: ≥ 33 [1] Zhao, C., [1] http://w LaunchedAutophagy; MC20H23BCl2 10 mM in D [1] Liu R, et [1] https:// LaunchedMetabolic En C29H27NO8 DMSO: ≥ 31 [1] http://w No Development ReportedMetabolic En C27H26N4O5DMSO: ≥ 5.2[1] Tralau-St [1] http://w Phase 2Anti-infecti C27H45N5O5DMSO: ≥ 10 [1] Njoroge F[1] http://w LaunchedMetabolic En C27H24N2O9DMSO: ≥ 35 [1] Long JZ, [1] http://w No Development ReportedAutophagy; MC16H20F6N5H2</s[1] Thomas, L[1] http://w LaunchedMetabolic En C23H33ClN6 DMSO: ≥ 53 [1] Saenz de [1] http://w LaunchedMetabolic En C26H26F3N710 mM in D [1] Ellinghau [1] http://w No Development ReportedMetabolic En C25H27F4N3DMSO: ≥25 [1] Jacques Y[1] http://w Phase 3Metabolic En C23H38N6O610 mM in D [1] Kawada, T[1] http://w LaunchedMetabolic En C20H29N2Na10 mM in D [1] Kawabata[1] http://w LaunchedMetabolic En C27H30F6N210 mM in D [1] Lazier CB [1] http://w LaunchedMetabolic En C27H35N3O610 mM in D [1] https:// Phase 2Anti-infecti C26H28Cl2N DMSO: ≥ 5.3 [1] http://w LaunchedAutophagy; MC25H32N4O7DMSO: ≥ 50 [1] Zhou HJ, [1] http://w Phase 2Metabolic En C27H35ClN2 10 mM in D [1] Chrysant,[1] http://w LaunchedMetabolic En C27H30ClN7 DMSO: 10 m [1] Michaelis [1] https:// LaunchedMetabolic En C28H25F3N4DMSO: ≥ 34 [1] Camilleri [1] http://w Phase 2Metabolic En C21H25N5O810 mM in D [1] Ikehara S [1] http://w LaunchedMetabolic En C28H22Cl3N 10 mM in D [1] Akwabi-Am[1] http://w No Development Reported

[1] Hare, S., et al., Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc Natl Acad Sci U S A, 2010. 107(46): p. 20057-62. [2] Hicks C, et al. Raltegravir: the first HIV type 1 integrase inhibitor. Clin Infect Dis. 2009 Apr 1;48(7):931-9. [3] Moss DM, et al. Divalent metals and pH alter raltegravir disposition in vitro. Antimicrob Agents Chemother. 2012 Jun;56(6):3020-6. [4] Hare S, et al. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol. 2011 Oct;80(4):565-72. [5] Lewis, M.G., et al. Response of a simian immunodeficiency virus (SIVmac251) to raltegravir: a basis for a new treatment for simian AIDS and an animal model for studying lentiviral persistence during antiretroviral therapy. Retrovirology, 2010. 7: p. 21.

[1] Berkhout T, et al. The novel cholesterol-lowering drug SR-12813 inhibits cholesterol synthesis via an increased degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Biol Chem. 1996 Jun 14;271(24):14376-82.

[2] Jiang W, et al. Forward genetic screening for regulators involved in cholesterol synthesis using validation-based insertional mutagenesis. PLoS One. 2014 Nov 26;9(11):e112632.

[1] Uchihashi S, et al. Metabolism of the c-Fos/activator protein-1 inhibitor T-5224 by multiple human UDP-glucuronosyltransferase isoforms. Drug Metab Dispos. 2011 May;39(5):803-13. [2] Miyazaki H, et al. The effects of a selective inhibitor of c-Fos/activator protein-1 on endotoxin-induced acute kidney injury in mice. BMC Nephrol. 2012 Nov 23;13:153. [3] Izuta S, et al. T-5224, a selective inhibitor of c-Fos/activator protein-1, attenuates lipopolysaccharide-induced liver injury in mice. Biotechnol Lett. 2012 Dec;34(12):2175-82. [4] Kamide D, et al. Selective activator protein-1 inhibitor T-5224 prevents lymph node metastasis in an oral cancer model. Cancer Sci. 2016 May;107(5):666-73.

[1] Galili N, et al. Prediction of response to therapy with ezatiostat in lower risk myelodysplastic syndrome. J Hematol Oncol. 2012 May 6;5:20. [1] Seif El-Din SH, et al. Effect of ketoconazole, a cytochrome P450 inhibitor, on the efficacy of quinine and halofantrine against Schistosoma mansoni in mice. Korean J Parasitol. 2013 Apr;51(2):165-75. [2] Eil C. Ketoconazole binds to the human androgen receptor. Horm Metab Res. 1992 Aug;24(8):367-70. [3] Muindi JR et al. CYP24A1 inhibition enhances the antitumor activity of calcitriol. Endocrinology. 2010 Sep;151(9):4301-12.

Metabolic En C28H28ClN3 DMSO: ≥100[1] Izuhara Y [1] https:// No Development ReportedMetabolic En C25H22F3N5DMSO: ≥ 33 [1] Stevens T[1] http://w Phase 2Anti-infecti C27H37N3O710 mM in DMSO LaunchedMetabolic En C24H21F6NO10 mM in D [1] Chang JW,[1] http://w No Development ReportedAutophagy; MC30H53N3O610 mM in D [1] Yuji Naka [1] http://p LaunchedAutophagy; CC25H23Cl2N DMSO: ≥ 37 [1] Massey AJ[1] http://w No Development ReportedMetabolic En C31H40N4O610 mM in D [1] http://w No Development ReportedMetabolic En C16H16Cl4N DMSO: ≥ 32 [1] Narita T, [1] http://w No Development ReportedAutophagy; MC33H34Ca0. 10 mM in D [1] Santodomi[1] http://w LaunchedAutophagy; MC27H32O14 DMSO: 6.2 mg[1] Chen F, e[1] https:// No Development ReportedMetabolic En C31H40N4O7DMSO: ≥ 35 [1] Muchamuel[1] http://w No Development ReportedMetabolic En C28H22ClF3 DMSO: ≥ 39 [1] Agresta S[1] http:// No Development ReportedMetabolic En C28H22ClF3 10 mM in D [1] Agresta S[1] http:// No Development ReportedMetabolic En C30H45NNaOH2</s[1] Ondetti, [1] http://w LaunchedAutophagy; CC31H43N3O8DMSO: ≥ 55 [1] Solit DB [1] http://w Phase 3Anti-infecti C29H43N3O810 mM in D [1] Tie Y, et [1] https:// LaunchedMetabolic En C28H23Cl5N DMSO: 10 m [1] Anchoori [1] https:// No Development ReportedMetabolic En C26H25F9N210 mM in D [1] Clark RW,[1] http://w Phase 3Metabolic En C33H32Cl2F 10 mM in D [1] Mitro, Ni [1] http://w No Development ReportedCell Cycle/D C33H25F6N3DMSO: ≥ 31 [1] Ko SK et [1] https:// No Development ReportedMetabolic En C31H32BrNO10 mM in D [1] Flaveny C[1] http://w No Development ReportedMetabolic En C34H41N7O510 mM in D [1] Wienen W,[1] http://w LaunchedAnti-infecti C37H48N4O510 mM in D [1] Vishnuvar[1] http://w LaunchedMetabolic En C22H32.5N6OH2</s[1] Fukuda-Ts[1] http://w LaunchedMetabolic En C29H27F3N410 mM in D [1] Tralau-St [1] http://w Phase 2Metabolic En C30H25F10N10 mM in D [1] Niesor EJ [1] http://w Phase 3Metabolic En C31H36F6N610 mM in D [1] Cao G, et [1] http://w Phase 3Autophagy; MC27H31Br2C 10 mM in D [1] Liu M, et [1] https:// Phase 3Cell Cycle/D C32H49ClN4 DMSO: ≥ 50 [1] http://w Phase 2Anti-infecti C33H49N3O710 mM in D [1] Mondal D,[1] http://w LaunchedAutophagy; MC28H38N6O1DMSO: ≥ 29 [1] Wang Z, e[1] http://w LaunchedMetabolic En C36H38F4N410 mM in D [1] Blackie J [1] http://w Phase 3Anti-infecti C38H50N6O510 mM in D [1] Marco Don[1] http://ww LaunchedAnti-infecti C36H53N7O610 mM in D [1] Lin K, et [1] http://w LaunchedMetabolic En C34H63N5O9DMSO: ≥ 25 [1] http://w No Development ReportedAnti-infecti C36H49N5O810 mM in D [1] Stein, D. [1] http://w LaunchedAutophagy; MC40H57N5O710 mM in D [1] Kuhn DJ, [1] http://w LaunchedAnti-infecti C37H48N6O510 mM in D [1] https:// LaunchedMetabolic En C35H45N7O810 mM in D [1] Wienen W,[1] http://w LaunchedAnti-infecti C35H46FN5O10 mM in D [1] Imhof I, [1] http://w Phase 3Metabolic En C31H40ClN7 10 mM in D [1] Mendell J [1] http://w LaunchedAnti-infecti C40H50N8O6DMSO: ≥ 40 [1] Gao M, et[1] https:// LaunchedAnti-infecti C38H69NO13DMSO: ≥ 7.4[1] http://en [1] http://e Launched

[1] Ogawa M, et al. Omeprazole treatment ameliorates oxyntic atrophy induced by DMP-777. Dig Dis Sci. 2006 Mar;51(3):431-9. [2] Zagrobelny J, et al. Separation of the four stereoisomers of a potent inhibitor (L-694,458) of human leukocyte elastase and its determination in human plasma using achiral/chiral chromatography with column switching. J Pharm Biomed Anal. 1998 Sep 1;17(6-7 [3] Weis VG, et al. Maturity and age influence chief cell ability to transdifferentiate into metaplasia. Am J Physiol Gastrointest Liver Physiol. 2016 Nov 23:ajpgi.00326.2016.

[1] Ge J, et al. Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. J Med Chem. 2006 Jul 27;49(15):4606-15. [2] Hertlein E, et al. 17-DMAG targets the nuclear factor-kappaB family of proteins to induce apoptosis in chronic lymphocytic leukemia: clinical implications of HSP90 inhibition. Blood. 2010 Jul 8;116(1):45-53. [3] Henke A, et al. Reduced Contractility and Motility of Prostatic Cancer-Associated Fibroblasts after Inhibition of Heat Shock Protein 90. Cancers (Basel). 2016 Aug 24;8(9). pii: E77.

[1] Umezawa H, et al. Pepstatin, a new pepsin inhibitor produced by Actinomycetes. J Antibiot (Tokyo). 1970 May;23(5):259-62. [2] Raquel T. Lima, et al. Modulation of Autophagy by a Thioxanthone Decreases the Viability of Melanoma Cells. Molecules 2016, 21(10), 1343 [1] Eagling VA, et al. Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir. Br J Clin Pharmacol. 1997 Aug;44(2):190-4.

[2] Kumar GN, et al. Cytochrome P450-mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J Pharmacol Exp Ther. 1996 Apr;277(1):423-31.

[3] Weichold FF, et al. HIV-1 protease inhibitor ritonavir modulates susceptibility to apoptosis of uninfected T cells. J Hum Virol. 1999 Sep-Oct;2(5):261-9.

[4] Drewe J, et al. HIV protease inhibitor ritonavir: a more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833. Biochem Pharmacol. 1999 May 15;57(10):1147-52.

[5] Kumar GN, et al. Potent inhibition of the cytochrome P-450 3A-mediated human liver microsomal metabolism of a novel HIV protease inhibitor by ritonavir: A positive drug-drug interaction. Drug Metab Dispos. 1999 Aug;27(8):902-8.

Anti-infecti C38H47N5O710 mM in D [1] Lin TI, e [1] http://w LaunchedMetabolic En C36H35ClF3 DMSO: ≥ 28 [1] Tamas Ora[1] http://a LaunchedAnti-infecti C39H54N6O810 mM in D [1] http://w LaunchedMetabolic En C40H53N7O5DMSO: ≥ 29 [1] Lianhong [1] http://p LaunchedMAPK/ERK PatC41H68O14 [1] https:// No Development ReportedAnti-infecti C38H54N6O110 mM in D [1] Piliero P [1] http://w LaunchedAnti-infecti C49H54N8O8DMSO: 146.66[1] Lawitz EJ [1] https:// LaunchedAnti-infecti C49H54F2N810 mM in D [1] http://w LaunchedGPCR/G ProteC41H62N12OH2</s[1] Li P, et [1] http://w No Development ReportedMetabolic En C12H38O26SH2</su [1] http://w LaunchedAnti-infecti C52H60F2N8DMSO: ≥ 39 mg/mL Phase 4GPCR/G ProteC48H60N6Na10 mM in D [1] Huo H, et [1] https:// Launched

[1] Kaldor et al (1995) Isophthalic acid derivatives: amino acid surrogates for the inhibition of HIV-1 protease. Bioorg.Med.Chem.Lett. 5 721. [2] Yerino GA, Halabe EK, Zini E, Feleder EC. Bioequivalence study of two oral tablet formulations containing saquinavir mesylate boosted with ritonavir in healthy male subjects. Arzneimittelforschung. 2011;61(8):481-7. [3] Branham ML, Moyo T, Govender T. Preparation and solid-state characterization of ball milled saquinavir mesylate for solubility enhancement. Eur J Pharm Biopharm. 2012 Jan;80(1):194-202. [4] Brouwers J, Vermeire K, Grammen C, Schols D, Augustijns P. Early identification of availability issues for poorly water-soluble microbicide candidates in biorelevant media: a case study with saquinavir. Antiviral Res. 2011 Aug;91(2):217-23. [5] Knechten H, Lutz T, Pulik P, Martin T, Tappe A, Jaeger H. Safety and Efficacy in HIV-1-Infected Patients Treated with Ritonavir-Boosted Saquinavir Mesylate.

DMSO: ≥ 390 mg/mL (Need ultrasonic)

[1] Li M, et al. Astragaloside IV attenuates cognitive impairments induced by transient cerebral ischemia and reperfusion in mice via anti-inflammatory mechanisms. Neurosci Lett. 2016 Dec 20. pii: S0304-3940(16)30994-6 [2] He CS, et al. Astragaloside IV Enhances Cisplatin Chemosensitivity in Non-Small Cell Lung Cancer Cells Through Inhibition of B7-H3. Cell Physiol Biochem. 2016;40(5):1221-1229. Epub 2016 Dec 14.

[3] Liu L, et al. [Protective effect of astragaloside IV against acute liver failure in experimental mice]. Zhonghua Gan Zang Bing Za Zhi. 2016 Oct 20;24(10):772-777. [4] Jiang K, et al. Astragaloside IV inhibits breast cancer cell invasion by suppressing Vav3 mediated Rac1/MAPK signaling. Int Immunopharmacol. 2016 Dec 5;42:195-202 [1] Link JO, et al. Discovery of ledipasvir (GS-5885): a potent, once-daily oral NS5A inhibitor for the treatment of hepatitis C virus infection. J Med Chem. 2014 Mar 13;57(5):2033-46. [2] Hernandez D, et al. Natural prevalence of NS5A polymorphisms in subjects infected with hepatitis C virus genotype 3 and their effects on the antiviral activity of NS5A inhibitors. J Clin Virol. 2013 May;57(1):13-8. [1] Pathak MK et al. Sodium stibogluconate is a potent inhibitor of protein tyrosine phosphatases and augments cytokine responses in hemopoietic cell lines. J Immunol. 2001 Sep 15;167(6):3391-7. [2] Keke Fan et al. Sodium Stibogluconate Interacts with IL-2 in Anti-Renca Tumor Action via a T Cell-Dependent Mechanism in Connection with Induction of Tumor-Infiltrating Macrophages. The journal of immunology. 2016 Sep 27.

Research AreaInfectionCardiovascular DiseaseMetabolic DiseaseCancerCancerMetabolic DiseaseInflammation/ImmunologyCardiovascular DiseaseOthersNeurological DiseaseCancerOthersOthersCardiovascular DiseaseCancerCardiovascular DiseaseCancerOthersNeurological DiseaseInflammation/ImmunologyCancerNeurological DiseaseInflammation/ImmunologyOthersNeurological DiseaseMetabolic DiseaseCancerCardiovascular DiseaseCardiovascular DiseaseInflammation/ImmunologyCancerOthersInflammation/ImmunologyCardiovascular DiseaseOthersCancerCancerOthersInflammation/ImmunologyCancerInfectionMetabolic Disease

Cardiovascular DiseaseMetabolic DiseaseInflammation/ImmunologyInfectionCancerInflammation/ImmunologyCancerNeurological DiseaseCancerCancerOthersCancerInfectionInflammation/ImmunologyCancerCancerCancerCancerNeurological DiseaseNeurological DiseaseNeurological DiseaseInflammation/ImmunologyCardiovascular DiseaseCancerMetabolic DiseaseNeurological DiseaseCancerCancerCardiovascular DiseaseCardiovascular DiseaseCancerInflammation/ImmunologyMetabolic DiseaseCancerCancerCancerCancerCancerCancerMetabolic DiseaseNeurological DiseaseNeurological DiseaseCancer

Metabolic DiseaseCancerNeurological DiseaseCancerCancerCancerCancerMetabolic DiseaseMetabolic DiseaseMetabolic DiseaseCancerMetabolic DiseaseOthersCancerCancerOthersCardiovascular DiseaseInflammation/ImmunologyMetabolic DiseaseCancerCardiovascular DiseaseCardiovascular DiseaseMetabolic DiseaseNeurological DiseaseInflammation/ImmunologyInflammation/ImmunologyCancerCancerCancerCancerInflammation/ImmunologyCancerCancerCancerInfectionInflammation/ImmunologyCancerMetabolic DiseaseCancerMetabolic DiseaseInflammation/ImmunologyCardiovascular Diseaseothers

CancerInflammation/ImmunologyMetabolic DiseaseCancerCardiovascular DiseaseCancerCardiovascular DiseaseCancerCancerCancerEndocrinologyCancerCardiovascular DiseaseNeurological DiseaseMetabolic DiseaseCancerInflammation/ImmunologyInfectionCancerCancerMetabolic DiseaseOthersCancerCancerCardiovascular DiseaseInflammation/ImmunologyCancerCancerCancerCancerCardiovascular DiseaseCardiovascular DiseaseCancerOthersCancerCancerCancerCancerMetabolic DiseaseCancerMetabolic DiseaseCancerMetabolic Disease

InfectionInflammation/ImmunologyCardiovascular DiseaseMetabolic DiseaseInfectionCardiovascular DiseaseCardiovascular DiseaseCancerInfectionNeurological DiseaseCancerCardiovascular DiseaseInflammation/ImmunologyInflammation/ImmunologyOthersInflammation/ImmunologyCancerCancerCancerCardiovascular DiseaseCancerInflammation/ImmunologyCardiovascular DiseaseInflammation/ImmunologyMetabolic DiseaseOthersMetabolic DiseaseInflammation/ImmunologyCardiovascular DiseaseInflammation/ImmunologyMetabolic DiseaseMetabolic DiseaseMetabolic DiseaseMetabolic DiseaseCancerMetabolic DiseaseNeurological DiseaseMetabolic DiseaseCancerCardiovascular DiseaseCancerCardiovascular DiseaseNeurological Disease

CancerCardiovascular DiseaseCardiovascular DiseaseInflammation/ImmunologyMetabolic DiseaseMetabolic DiseaseMetabolic DiseaseInfectionCardiovascular DiseaseCardiovascular DiseaseCancerInfectionCardiovascular DiseaseCardiovascular DiseaseInfectionCardiovascular DiseaseInflammation/ImmunologyCancerNeurological DiseaseInflammation/ImmunologyCardiovascular DiseaseInflammation/ImmunologyCardiovascular DiseaseCancerMetabolic DiseaseCancerCancerCancerCancerNeurological DiseaseMetabolic DiseaseMetabolic DiseaseMetabolic DiseaseCancerCancerNeurological DiseaseCardiovascular DiseaseMetabolic DiseaseInflammation/ImmunologyNeurological DiseaseInflammation/ImmunologyMetabolic DiseaseInflammation/Immunology

Metabolic DiseaseCancerNeurological DiseaseInfectionCancerCancerInfectionInfectionCardiovascular DiseaseCancerCardiovascular DiseaseMetabolic DiseaseOthersCardiovascular DiseaseMetabolic DiseaseMetabolic DiseaseCardiovascular DiseaseInfectionMetabolic DiseaseCancerCardiovascular DiseaseInflammation/ImmunologyOthersCancerOthersInflammation/ImmunologyInfectionNeurological DiseaseCardiovascular DiseaseCardiovascular DiseaseCancerMetabolic DiseaseCardiovascular DiseaseOthersCancerCancerInfectionCancerCardiovascular DiseaseCardiovascular DiseaseNeurological DiseaseCardiovascular DiseaseMetabolic Disease

Cancer; Cardiovascular DInflammation/ImmunologyInfectionMetabolic DiseaseCardiovascular DiseaseCancerInflammation/ImmunologyCancerCardiovascular DiseaseInflammation/ImmunologyInflammation/ImmunologyMetabolic DiseaseMetabolic DiseaseCardiovascular DiseaseCancerInfectionCancerEndocrinologyCardiovascular DiseaseCancerCancerCardiovascular DiseaseInflammation/ImmunologyMetabolic DiseaseInflammation/ImmunologyCardiovascular DiseaseCardiovascular DiseaseCancerCancerInfectionCardiovascular DiseaseCardiovascular DiseaseInfectionInfectionOthersInflammation/ImmunologyCancerInfectionCardiovascular DiseaseInfectionCardiovascular DiseaseInfectionInfection

InfectionNeurological DiseaseInfectionInfectionCancerInfectionCancerInfectionCardiovascular DiseaseCancerInfectionCardiovascular Disease

Biological DescriptionLedipasvir D-tartrate is an inhibitor of the hepatitis C virus NS5A, with EC50 values of 34 pM against GT1a and 4 pM against GT1b replicon.

2-Deoxy-D-glucose is a glucose analog that acts as a competitive inhibitor of glucose metabolism, inhibiting glycolysis via its actions on hexokinase.

Fondaparinux sodium is an antithrombin-dependent factor Xa inhibitor. PMSF is an irreversible serine/cysteine protease inhibitor.Edaravone is a strong novel free radical scavenger, and inhibits MMP-9-related brain hemorrhage in rats treated with tissue plasminogen activator.

Theophylline is a methylated xanthine derivative; competitive nonselective phosphodiesterase inhibitor and nonselective adenosine receptor antagonist.

IBMX is a broad-spectrum phosphodiesterase (PDE) inhibitor, with IC50 of 6.5±1.2, 26.3±3.9 and 31.7±5.3 μM for PDE3, PDE4 and PDE5, respectively.

2-PMPA is a potent and selective inhibitor of glutamate carboxypeptidase II (GCPII) with an IC50 of 300 pM.

Zileuton is a potent and selective inhibitor of 5-lipoxygenase, exhibiting inflammatory activities.

AEBSF is an irreversible serine protease inhibitor, and inhibits proteases like chymotrypsin, kallikrein, plasmin, thrombin, and trypsin.

DKM 2-93 is a relatively selective inhibitor of UBA5 with an IC50 of 430 μM.

(R)-Flurbiprofen is the R-enantiomer of the racemate NSAID Flurbiprofen, (R)-Flurbiprofen inhibits the binding of [3H]9-cis-RA to RXRα LBD with IC50 of 75 μM.

HIV-1 integrase inhibitor ((Z)-4-(3-(azidomethyl)phenyl)-2-hydroxy-4-oxobut-2-enoic acid) is uesful for anti-HIV.

Aliskiren hemifumarate(CGP 60536) is a direct renin inhibitor with IC50 of 1.5 nM.IC50 value: 1.5 nM [1]Target: reninin vitro: Aliskiren hemifumarate appears to bind to both the hydrophobic S1/S3-binding pocket and to a large, distinct subpocket that extends from the S3-binding site towards the hydrophobic core of renin. Oral bioavailability of Aliskiren hemifumarate is 2.4% in rats, 16% in marmosets and about 2.5% in humans [2].in vivo: Aliskiren hemifumarate (< 10 mg/kg, oral) inhibits plasma renin activity and lowers blood pressure in sodium-depleted marmosets[3].Once-daily oral treatment with Aliskiren hemifumarate lowers blood pressure effectively, with a safety and tolerability profile, in patients with mild-to-moderate hypertension[4].

Allopurinol (Zyloprim) is a xanthine oxidase inhibitor with an IC50 of 7.82±0.12 μM.Target: XAOAllopurinol (Zyloprim, and generics) is a drug used primarily to treat hyperuricemia (excess uric acid in blood plasma) and its complications, including chronic gout. It is a xanthine oxidase inhibitor which is administered orally. A common misconception is that allopurinol is metabolized by its target, xanthine oxidase, but this action is principally carried out by Aldehyde oxidase. The active metabolite of allopurinol is oxypurinol, which is also an inhibitor of xanthine oxidase. Allopurinol is almost completely metabolized to oxypurinol within two hours of oral administration, whereas oxypurinol is slowly excreted by the kidneys over 18–30 hours. For this reason, oxypurinol is believed responsible for the majority of allopurinol's effect.Allopurinol is a purine analog; it is a structural isomer of hypoxanthine (a naturally occurring purine in the body) and is an inhibitor of the enzyme xanthine oxidase. In addition to blocking uric acid production, inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine. While xanthine cannot be converted to purine ribotides, hypoxanthine can be salvaged to the purine ribotides adenosine and guanosine monophosphates. Increased levels of these ribotides may cause feedback inhibition of amidophosphoribosyl transferase, the first and rate-limiting enzyme of purine biosynthesis. Allopurinol, therefore, decreases uric acid formation and may also inhibit purine synthesis.

3-Bromopyruvic acid is a hexokinase II inhibitor, is an effective antitumor agent on the hepatoma cells.Target: hexokinase II in vitro: 3-BrPA dissociates HK II from this complex, causing cell death, and thus, having an anti-tumor effect. In vitro treatment of cells with 3-BrPA significantly inhibited their growth, as evaluated by MTT assay and adenosine triphosphate-tumor chemosensitivity assay (ATP-TCA). [1] 3-Bromopyruvic acid (3-BP) is a glycolytic inhibitor and a promising anticancer compound, induces oxidative stress and depletes cells of glutathione (GSH). [2]in vivo: 3-BrPA treatment (50 mg/kg ip. daily, 6 days/week for three weeks) is effective in the animal model by attenuating tumor growth and causing tumor necrosis. Toxic signs were not observed. The acute toxicity study provided an LD50 of 191.7 mg/kg for 3-BrPA. [1]

Tioxolone, a metalloenzyme carbonic anhydrase I inhibitor, is an anti-acne preparation.Target: Carbonic Anhydrase Tioxolone is a metalloenzyme carbonic anhydrase I inhibitor with a Ki of 91 nM. Tioxolone lacks sulfonamide, sulfamate, or hydroxamate functional groups that are typically found in therapeutic carbonic anhydrase (CA) inhibitors, such as acetazolamide. Tioxolone is proposed to be a prodrug inhibitor that is cleaved via a CA II zinc-hydroxide mechanism known to catalyze the hydrolysis of esters. When tioxolone binds in the active site of CA II, it is cleaved and forms 4-mercaptobenzene-1,3-diol via the intermediate S-(2,4-thiophenyl) hydrogen thiocarbonate. The esterase cleavage product binds to the zinc active site via the thiol group and is therefore the active CA inhibitor, while the intermediate is located at the rim of the active-site cavity. From Wikipedia.Chlorzoxazone is a centrally acting muscle relaxant used to treat muscle spasm and the resulting pain or discomfort. It acts on the spinal cord by depressing reflexes.Chlorzoxazone is currently being used as a marker substrate in vitro/vivo studies to quantify cytochrome P450 2E1 (CYP2E1) activity in humans.

DMOG is an inhibitor of HIF prolyl hydroxylase and an antagonist of α-ketoglutarate cofactor.

Sevelamer Hcl is a phosphate binding drug used to treat hyperphosphatemia in patients with chronic kidney disease; consists of polyallylamine that is crosslinked with epichlorohydrin.Hydralazine Hydrochloride is a direct-acting vasodilator that is used as an antihypertensive agent.Target: OthersHydralazine (apresoline) is a direct-acting smooth muscle relaxant used to treat hypertension by acting as a vasodilator primarily in arteries and arterioles. By relaxing vascular smooth muscle, vasodilators act to decrease peripheral resistance, thereby lowering blood pressure and decreasing afterload. However, this only has a short term effect on blood pressure, as the system will reset to the previous, high blood pressure necessary to maintain pressure in the kidney necessary for natriuresis. The long term effect of antihypertensive drugs comes from their effects on the pressure natriuresis curve. It belongs to the hydrazinophthalazine class of drugs [1]. Hydralazine may reduce blood pressure when compared to placebo in patients with primary hypertension, however this data is based on before and after studies, not RCTs. Furthermore, its effect on clinical outcomes remains uncertain [2].

BergaptolA hydroxylated psoralen that acts as a potent inhibitors of debenzylation activity of CYP3A4 enzyme with an IC50 value of 24.92 uM. Recent studies suggest that it may have antiproliferative and anticancer properties.target: CYP3A4 [1]IC50: 24.92 [1]For in vivo enzyme activity analysis, 100 μM bergaptol was added to the cultures for an additional 24 h at 37°C. After centrifugation, the supernatant was used to measure the bergapten yield by high performance liquid chromatography (HPLC).[2]

Milrinone(Win 47203) is a PDE3 inhibitor that increases intracellular cyclic adenosine monophosphate resulting in improved ventricular function and vasodilation.IC50 Value: 2 mM( inhibiting human platelet aggregation) [3]Target: PDE3in vitro: Milrinone inhibited PDE4 in addition to PDE3 activity. In isolated rabbit cardiomyocytes, milrinone (>10 microM) caused greater elevations in intracellular cAMP and calcium than cilostazol [1]. cilostazol and milrinone were equally effective in inhibiting human platelet aggregation with a median inhibitory concentration (IC50) of 0.9 and 2 microM, respectively. In rabbit ventricular myocytes, however, cilostazol elevated cAMP levels to a significantly lesser extent (p < 0.05 vs. milrinone) [3].in vivo: Increased blood concentrations of milrinone were associated with increased inhibition of ADP and AA-induced platelet activation (P < 0.0001). Milrinone at a blood concentration of 300 ng/mL markedly impaired the platelet activation response to ADP and AA [2]. Treatment with milrinone led to improvement in biventricular myocardial function [mean right ventricular index from 0.521 (SD-0.213) to 0.385 (SD-0.215), p = 0.003; mean left ventricular index from 0.636 (SD-0.209) to 0.5 (SD-0.171), p = 0.012). No difference was found in the values of heart rate corrected right or left ventricular ejection time prior to and while on treatment with milrinone (right ventricle: mean, 1.23 (SD-0.42) and 1.14 (SD-0.48), p = 0.29; left ventricles: mean, 1.17 (SD-0.51) and 1.13 (SD-0.48), p = 0.66) [4].Clinical trial: Inhaled Milrinone in Cardiac Surgery. Phase2

PluriSln 1 is an inhibitor of stearoyl-coA desaturase (SCD), and is a pluripotent cell-specific inhibitor.Glucosamine (hydrochloride) is a natural product.IC50 value:Target:In vitro: Glucosamine hydrochloride exhibited dose-dependent DPPH antioxidant activity [1]. Short-term (4 h) glucosamine hydrochloride treatment inhibited HIF-1α at the protein level, decreased phosphorylation of p70S6K and S6, translation-related proteins [2]. In the obstructed kidneys and TGF-β1-treated renal cells, glucosamine hydrochloride significantly decreased renal expression of α-smooth muscle actin, collagen I, and fibronectin [3]. In vivo:

Memantine, an amantadine derivative with low to moderate-affinity for NMDA receptors, inhibit CYP2B6 and CYP2D6 with Ki of 0.51 nM and 94.9 μM, respectively..Target: NMDA Receptor, Memantine (Ebixa, Axura, Namenda, Akatinol) is a moderate-affinity, uncompetitive, voltage-dependent, NMDA-receptor antagonist with fast on/off kinetics that inhibits excessive calcium influx induced by chronic overstimulation of the NMDA receptor. Memantine is approved in the US and the EU for the treatment of patients with moderate to severe dementia of the Alzheimer's type [1]. Memantine has considerable therapeutic potential for the myriad of clinical entities associated with NMDA receptor-mediated neurotoxicity [2]. Memantine blocked 200 microM NMDA-evoked responses with a 50% inhibition constant (IC50) of approximately 1 microM at -60 mV and an empirical Hill coefficient of approximately 1 [3].

Methoxsalen (8-Methoxypsoralen) is a potent tricyclic furocoumarin suicide inhibitor of CYP (cytochrome P-450), is an agent used to treat psoriasis, eczema, vitiligo and some cutaneous Lymphomas in conjunction with exposing the skin to sunlight.Target: CYP (cytochrome P-450)Methoxsalen is a drug used to treat psoriasis, eczema, vitiligo, and some cutaneous lymphomas in conjunction with exposing the skin to UVA light from lamps or sunlight. Methoxsalen modifies the way skin cells receive the UVA radiation, allegedly clearing up the disease. The dosage comes in 10 mg tablets, which are taken in the amount of 30 mg 75 minutes before a PUVA (psoralen + UVA) light treatment. Chemically, methoxsalen belongs to a class of organic natural molecules known asfuranocoumarins. They consist of coumarin annulated with furan.Administration of intra peritoneal (ip) methoxsalen significantly increased nicotine's Cmax, prolonged the plasma half-life (fourfold decrease) of nicotine, and increased its area under the curve (AUC) compared with ip vehicle treatment. Methoxsalen pretreatment prolonged the duration of nicotine-induced antinociception and hypothermia (15mg/kg, po) for periods up to 6- and 24-hr postnicotine administration, respectively.

Bergapten is a natural anti-inflammatory and anti-tumor agent isolated from bergamot essential oil, other citrus essential oils and grapefruit juice. Bergapten is inhibitory towards mouse and human CYP isoforms.Captopril is a potent, competitive inhibitor of angiotensin-converting enzyme (ACE).Target: ACECaptopril has been shown to have similar morbidity and mortality benefits to those of diuretics and beta-blockers in hypertensive patients. Captopril has been shown to delay the progression of diabetic nephropathy, and enalapril and lisinopril prevent the development of nephropathy in normoalbuminuric patients with diabetes [1]. an equimolar ratio of the cis and trans states of captopril exists in solution and that the enzyme selects only the trans state of the inhibitor that presents architectural and stereoelectronic complementarity with its substrate binding groove [2].Acetazolamide is a potent carbonic anhydrase (CA) inhibitor; best-studied agent for the amelioration of acute mountain sickness (AMS).

Metyrapone is an inhibitor of cytochrome P450-mediated ω/ω-1 hydroxylase activity and CYP11B1.Target: CYP11B1Metyrapone is a drug used in the diagnosis of adrenal insufficiency and occasionally in the treatment of Cushing's syndrome (hypercortisolism). Metyrapone blocks cortisol synthesis by reversibly inhibiting steroid 11β-hydroxylase. This stimulates ACTH secretion, which in turn increases plasma 11-Deoxycortisol levels.

Oltipraz has an inhibitory effect on HIF-1α activation by insulin in a time-dependent manner, completely abrogating HIF-1α induction at ≥10 μM concentrations, the IC50 of Oltipraz for HIF-1α inhibition is 10 μM.IC50 value: 10 μMTarget: HIF-1αin vitro: Oltipraz inhibits HIF-1α activity and HIF-1α-dependent tumor growth, which may result from a decrease in HIF-1α stability through S6K1 inhibition in combination with an H2O2-scavenging effect. Oltipraz treatment also inhibits HIF-1α activation stimulated by either hypoxia or CoCl2. Oltipraz is a cancer chemopreventive agent and has an inhibitory effect on angiogenesis and tumor growth. [1] Oltipraz is also a competitive inhibitor of this cytochrome P450, with an apparent Ki of 10 μM. [2]in vivo: In wild-type mice, hepatic levels of mRNA for all of the genes analyzed were significantly increased after Oltipraz treatment, with the highest increase (treated/control) for NQO1 mRNA levels (7.6-fold). The Northern blot analyses demonstrated that the observed increases in GST and NQO1 activities by Oltipraz in wild-type mice were preceded by significant elevations in RNA expression. Interestingly, mRNA levels of Nrf2 itself were increased more than 3-fold by Oltipraz treatment. [2]

Ozagrel(OKY-046) is an antiplatelet agent working as a thromboxane A2 synthesis inhibitor.Target: Thromboxane A2 SynthaseOzagrel was selected as the best compound of highly selective inhibitors of TXA2 synthase. The inhibition of TXA2 synthase by ozagrel was more effective on human and rabbit enzymes than those of other species. Ozagrel increased 6-keto-PGF1 alpha, one of stable metabolites of PGI2, in various isolated cells and tissues perhaps via accumulated PG endoperoxides resulted by the inhibition of TXA2 synthase [1]. Ozagrel was estimated to be a reversible mixed-type inhibitor of diphenolase activity with the constants (K (S1), K (S2), K (i1), and K (i2)) determined to be 2.21, 3.89, 0.454, and 0.799 mM, repectively [2]. Infusion of OKY-046 significantly inhibited pulmonary thromboxane B2 delivery, attenuated the early increase in pulmonary vascular resistance, and blocked the increase in systemic vascular resistance. In addition, OKY-046 blunted and delayed the decrease in cardiac output and maintained end-systolic pressure-diameter relation, +dp/dt, and lung lymph flow at baseline values [3].

Bivalirudin Trifluoroacetate is a synthetic 20 residue peptide which reversibly inhibits thrombin.IC50 Value:Target: thrombinin vitro: Eptifibatide (8 mg/mL) added together with a low (70 ng/mL) concentration of bivalirudin (a direct thrombin inhibitor) effectively (approximately 90%) reduced platelet aggregation induced by thrombin (0.2 U/mL) [1]. In thrombin generation assay (TGA), bivalirudin had no effect on these parameters up to 10 μmol/l [2]. Bivalirudin-facilitated binding of MPO to BAEC resulted also in functional changes in terms of increased NO consumption as well as enhanced MPO-mediated redox modifications [3].in vivo: The use of bivalirudinprevented further increase in antiheparin/PF4 antibody IgG levels in rats [4]. Three animals in the 500-mg/kg/24 h group, and 7 animals in the 2000-mg/kg/24 h group in the toxicokinetic assessment phase of the study were found dead or euthanized in extremis (following blood sampling). Plasma concentrations of bivalirudin appeared to be linear and dose independent [5].Clinical trial: Antithrombotic Effects of Ticagrelor Versus Clopidogrel . Phase 4

Ibudilast(KC-404;AV-411;MN-166) is a relatively nonselective phosphodiesterase inhibitor which has been marketed for treating asthma.Target: PDEIbudilast (3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine) is a nonselective inhibitor of cyclic nucleotide phosphodiesterase (PDE). The inhibition of platelet aggregation and vasodilatation by ibudilast may be due to synergistic elevation of intracellular cyclic nucleotides and release of nitric oxide (NO) or prostacyclin from endothelium, rather than direct inhibition of PDE5 or PDE3. Another important property of ibudilast is its antiinflammatory activity possibly associated with potent inhibition of PDE4. Combined with its relaxing effects on bronchial smooth muscle, antiinflammatory actvity of ibudilast could favorably influence pathophysiology of asthma by antagonizing chemical mediators triggering asthmatic attacks [1, 2]. Ibudilast (AV-411) is a non-selective phosphodiesterase inhibitor that is also known to suppress glial cell activation. Preclinical data indicate that ibudilast crosses the blood-brain barrier, is well tolerated, is active on oral administration, reduces glial activation and attenuates pain symptoms in diverse rat models of neuropathic pain. In addition, it enhances acute morphine analgesia and attenuates morphine tolerance and withdrawal. Thus ibudilast may improve opioid efficacy and is a promising therapeutic candidate for neuropathic pain, with a novel mechanism of action [3].

PRT4165 is a potent inhibitor of PRC1 (Polycomb-repressive complex 1)-mediated H2A ubiquitylation. Target: PRC1in vitro: PRT4165 is a novel chromatin-remodeling compound and provide a new tool for the inhibition of ubiquitylation signaling at DNA double-strand breaks.PRT4165 inhibits histone H2A E3 ubiquitin ligase activity of RING1. PRT4165 Inhibits the E3 Ubiquitin Ligase Activity of PRC1. PRT4165 efficiently inhibits H2A ubiquitylation at lysine 119 (uH2AK119) and that this inhibition is dependent on both the concentration of PRT4165 and the incubation time with PRT4165. Treatment of cells for 60 min with 50 μm PRT4165 results in a dramatic reduction in total ubiquitylated histone H2A. PRT4165 inhibits the accumulation of all detectable ubiquitin at sites of DNA double-strand breaks (DSBs), the retention of several DNA damage response proteins in foci that form around DSBs, and the repair of the DSBs. [1]in vivo: PRT4165 inhibits the PRC1 E3 monoubiquitin ligase activity toward γ-H2AX.[1]

Methazolamide is a carbonic anhydrase inhibitor used to treat glaucoma.Target: Carbonic AnhydraseMethazolamide is a carbonic anhydrase inhibitor with Ki of 50 nM, 14 nM and 36 nM for hCA I, hCA II and bCA IV isoforms, respectively [1]. Methazolamide is of strength equal to acetazolamide, another carbonic anhydrase inhibitor used to treat irregular breathing disorders. However, methazolamide differs from acetazolamide in that it fails to activate Ca2+-dependent potassium channels in skeletal muscles. Methazolamide does not impair respiratory work performance in anesthetized rabbits [2]. Oral administration of methazolamide decreases IOPs and AHFRs in clinically normal dogs, with effectiveness diminishing in the evening [3].PD151746 is a calpain inhibitor, shows a 20-fold selectivity for u-calpain (Ki = 0.26 ± 0.03 μM) over m-calpain (Ki = 5.33 ± 0.77 μM).IC50 value: 0.26 ± 0.03 μM (Ki, for μ-calpain), 5.33 ± 0.77 μM (Ki, for m-calpain) [1]Target: calpainin vitro: The μ-calpain inhibitor PD 151746 decreases oxLDL-induced cytotoxicity. [2]

β-Lapachone(ARQ-501; beta-lapachone) is a naturally occurring quinone obtained from the bark of the lapacho tree (Tabebuia avellanedae) with cancer chemopreventive properties; potent inhibitor of IDO1(IC50=0.44 uM).IC50 value: 0.44 uM (IDO1)Target: IDO1 inhibitor; anticancer agentin vitro: β-Lapachone markedly induced cell death without caspase activation. β-Lapachone increased PI uptake and HMGB-1 release to extracellular space, which are markers of necrotic cell death. Necrostatin-1 (a RIP1 kinase inhibitor) markedly inhibited β-lapachone-induced cell death and HMGB-1 release. In addition, β-lapachone activated poly (ADP-ribosyl) polymerase-1(PARP-1) and promoted AIF release, and DPQ (a PARP-1 specific inhibitor) or AIF siRNA blocked β-lapachone-induced cell death [1]. In H9C2 cells, β-lap-mediated elevation of AMPK activity was retarded when the level of Sirt1 was reduced by transfection of siRNA against Sirt1 [2]. β-lapachone was identified as a submicromolar inhibitor of IDO1. β-lapachone represents a >10-fold gain in potency over the basic 1,2-naphthoquinone pharmacophore [4]. beta-lapachone inhibits the catalytic activity of topoisomerase I from calf thymus and human cells [5].in vivo: Oral administration of β-lap to ACS Tg mice significantly attenuated heart failure and inhibited myocardial accumulation of triacylglycerol. β-lap administration significantly increased the expression of genes associated with mitochondrial biogenesis and fatty acid metabolism that were down-regulated in ACS Tg hearts [2]. Intraocular administration of β-lapachone resulted in significant reduction in hypoxia-induced retinal neovascularization without retinal toxicity or perturbation of developmental retinal angiogenesis in mice [3].

Oxyresveratrol is neuroprotective and inhibits the apoptotic cell death in transient cerebral ischemia. It effectively scavenges H2O2, NO (IC50 = 45.3 μM), and the artificial free radical 2,2-diphenyl-l-picrylhydrazyl (IC50 = 28.9 μM) In vitro: 1)oxyresveratrol exhibited more than 50% inhibition at 100 μM on L-tyrosine oxidation by murine tyrosinase activity.2) oxyresveratrol showed an IC50 value of 52.7 μM on the enzyme activity. 3) oxyresveratrol works through reversible inhibition of tyrosinase activity rather than suppression of the expression and synthesis of the enzyme.[2] In vivo: 1) Oxyresveratrol (10 or 20 mg/kg) significantly reduced the brain infarct volume by approximately 54% and 63%, respectively, when compared to vehicle-treated MCAO rats.2) oxyresveratrol treatment diminished cytochrome c release and decreasedcaspase-3 activation in MCAO rats. [3]KNK437, dose-dependently inhibited the acquisition of thermotolerance and the induction of various HSPs including HSP105, HSP70, and HSP40 in COLO 320DM (human colon carcinoma) cells. It also inhibit mRNA levels with IC 50: 17 umol/L.[1] This compound also inhibited the acquisition of thermotolerance as developed by sodium arsenite. However, it did not increase thermosensitivity in nontolerant cells. [2]Topiroxostat(FYX-051) is a novel and potent xanthine oxidoreductase (XOR) inhibitor with IC50 value of 5.3 nM.IC50 value: 5.3 nM [1]Target: xanthine oxidoreductasein vitro: Steady-state kinetics study showed that FYX-051 initially behaved as a competitive-type inhibitor with a K(i) value of 5.7 × 10(-9) M, then after a few minutes it formed a tight complex with XOR via a Mo-oxygen-carbon atom covalent linkage, as reported previously [3].in vivo: FYX-051 exhibited a weak CYP3A4-inhibitory activity (18.6%); its Cmax and bioavailability were as high as 4.62 μg/mL (3 mg/kg) and 69.6%, respectively. Moreover, the t1/2 value of 39 was greater (19.7 h) than that of compound 2 (0.97 h) [1]. In the mechanistic study by 52-week oral treatment with topiroxostat at 3 mg/kg to F344 male rats, with and without citrate, simple and papillary transitional cell hyperplasias of the urinary bladder epithelium were observed in 5/17 in the topiroxostat-alone treatment group, along with xanthine-induced nephropathy, in contrast to neither xanthine crystals nor lesions in urinary organs by co-treatment group with citrate [2].

AN-2728 is a potent inhibitor of PDE4 and cytokine release; inhibit PDE4 with an IC50 of 0.49 μM.

C75 trans is an enantiomer of C75. C75 is a synthetic fatty-acid synthase (FASN) inhibitor; inhibits prostate cancer cells PC3 with an IC50 of 35 μM.

Isoliquiritigenin is an anti-tumor flavonoid from the root of Glycyrrhiza glabra, which inhibits aldose reductase with an IC50 of 320 nM.

D609 is a selective competitive inhibitor of phosphatidyl choline-specific phospholipase C (PC-PLC), with Ki of 6.4 μM, used for antiviral and antitumor research.

Pentostatin is an irreversible inhibitor of adenosine deaminase with Ki of 2.5 pM.Baicalein (5,6,7-Trihydroxyflavone) is a xanthine oxidase inhibitor with an IC50 value of 3.12 mM.

NLG919 is a potent IDO (indoleamine-(2,3)-dioxygenase) pathway inhibitor with Ki/EC50 of 7 nM/75 nM.

KRIBB11 is an inhibitor of Heat shock factor (HSF), with IC50 of 1.2 μM.

Diosmetin is a natural flavonoid which inhibits human CYP1A enzyme activity with an IC50 of 40 μM in HepG2 cell.

Ozagrel(OKY-046) sodium salt is an antiplatelet agent working as a thromboxane A2 synthesis inhibitor.Target: Thromboxane A2 SynthaseOzagrel was selected as the best compound of highly selective inhibitors of TXA2 synthase. The inhibition of TXA2 synthase by ozagrel was more effective on human and rabbit enzymes than those of other species. Ozagrel increased 6-keto-PGF1 alpha, one of stable metabolites of PGI2, in various isolated cells and tissues perhaps via accumulated PG endoperoxides resulted by the inhibition of TXA2 synthase [1]. Ozagrel was estimated to be a reversible mixed-type inhibitor of diphenolase activity with the constants (K (S1), K (S2), K (i1), and K (i2)) determined to be 2.21, 3.89, 0.454, and 0.799 mM, repectively [2]. Infusion of OKY-046 significantly inhibited pulmonary thromboxane B2 delivery, attenuated the early increase in pulmonary vascular resistance, and blocked the increase in systemic vascular resistance. In addition, OKY-046 blunted and delayed the decrease in cardiac output and maintained end-systolic pressure-diameter relation, +dp/dt, and lung lymph flow at baseline values [3].

ZLN005 is a novel transcriptional regulator of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α).IC50 value:Target: PGC-1αin vitro: ZLN005 increases expression of the PGC-1α gene in L6 myotubes. ZLN005 increased PGC-1α mRNA levels in a dose-dependent manner; 20 μmol/L ZLN005 caused a threefold increase over the control after 24 h. At 10 μmol/L, the PGC-1α mRNA levels were increased to almost the same extent at 16 to 48 h [1]. ZLN005 did not increase the expression of the PGC-1α gene in rat primary hepatocytes. AMP-activated protein kinase is involved in the mechanism inducing PGC-1α in L6 myotubes [1]in vivo: An insulin tolerance test revealed that treatment with ZLN005 significantly decreased insulin resistance in db/db mice, as evidenced by the approximately 18% decrease in the AUC. A PTT also was performed in db/db mice, and ZLN005 improved pyruvate tolerance, as evidenced by the 16% decrease in the AUC. In db/db mice, plasma NEFA and triglyceride levels were decreased by 20% and 37%, respectively, and cholesterol was decreased by 10% with ZLN005 treatment. Plasma insulin and β-hydroxybutyrate content, liver/bodyweight index and adipose composition, and muscle and liver triglyceride levels, however, were not ameliorated by treatment with ZLN005 or metformin [1].

Dyphylline acts as an adenosine receptor antagonist and phosphodiesterase inhibitor, which is used in the treatment of respiratory disorders.Target: Adenosine Receptor; PDEDyphylline (trade names Dilor, Lufyllin), also known as diprophylline, is a xanthine derivative with bronchodilator and vasodilator effects. It is used in the treatment of respiratory disorders like asthma, cardiac dyspnea, and bronchitis. It acts as an adenosine receptor antagonist and phosphodiesterase inhibitor.Irsogladine is a PDE4 inhibitor and muscarinic acetylcholine receptor binder.Target: PDE4; mACHRIrsogladine treatment (300 and 500 mg/kg/day) resulted in a dose-dependent reduction of angiogenesis in wild-type mice by 21 and 45.3% (P < 0.02, P < 0.001), in tPA-deficient mice by 42.6 and 46% (P < 0.001, P < 0.001), and in uPA-deficient mice by 27.2 and 46% (P < 0.05, p < 0.001), respectively. Irsogladine inhibits bFGF-induced angiogenesis in wild-type, tPA-knockout, and uPA-knockout mice [1]. Irsogladine up-regulates GJIC between PC cells via regulation of the PKA pathway. It also suggests a useful adjuvant of Irsogladine to pancreatic cancer therapy [2]. irsogladine produces the increase of intracellular cAMP content via non-selective inhibition of PDE isozymes, which may be a key mechanism involved in its gastroprotective actions [3].AR7 is a retinoic acid receptor α (RARα) antagonist.NSC-405020 is a novel small molecule inhibitor of MT1-MMP that specifically targets PEX domain rather than the catalytic domain of MT1-MMP with IC50 >100 μM and does not inhibit the catalytic activity of MT1-MMP or MMP-2. IC50 value: > 100 uM [1]Target: MT1-MMP PEX inhibitorNSC-405020 directly interacts with and binds to PEX in a vicinity of Met-328, Arg-330, Asp-376, Met-22 and Ser-470 of the druggable pocket in the full-length MT1-MMP structure, which affects the conformation and flexibility of blades I to IV of the β-propeller resulting in the decrease of the PEX-dependent homodimerization of cellular MT1-MMP. NSC-405020 dose not affect the ability of MT1-MMP to activate MMP-2 but its ability to degrade COL-I.

RG13022 is a tyrosine kinase inhibitor; inhibits the autophosphorylation reaction of the EGF receptor with an IC50 of 4 μM.Magnolol, the main polyphenol compound of the bark of Magnolia officinalis, has a variety of pharmacological activities.

SPK-601(LMV-601) is a potent phosphatidylcholine-specific phospholipase C (PC-PLC) inhibitor; SPK-601 is useful antimicrobial agent.IC50 value:Target: PC-PLC

Zardaverine is a newly developed dual-selective PDE3/4 inhibitor with IC50 values of 0.5 uM and 0.8 uM respectively. IC50 value: 0.5 uM (PDE3); 0.8 uM (PDE4)Target: PDE3; PDE4Zardaverine inhibited the cyclic GMP-inhibitable PDE III from human platelets and the rolipram-inhibitable PDE IV from canine trachea and human polymorphonuclear (PMN) cells with IC50-values of 0.58, 0.79 and 0.17 μM, respectively. The pyridazinone derivative affected the calmodulin-stimulated PDE I, the cyclic GMP-stimulated PDE II and the cyclic GMP-specific PDE V only marginally at concentrations up to 100μM. Zardaverine inhibits the ADP-induced aggregation of human platelets with an IC50 of 1.6 μM. This inhibition was synergistically increased by activators of adenylate cyclase such as PGE1 and forskolin. In human PMN cells, Zardaverine inhibited the zymosan-induced superoxide anion generation with an IC50 of 0.40 μM. Again, this effect was increased by activators of adenylate cyclase. Zardaverine acted in synergy with the adenylate cyclase activators prostaglandin E2 and CG 4203, a prostacyclin analog, and super-additive effects of combinations were observed. Zardaverine and dexamethasone prevent bronchial eosinophilia and neutrophilia with similar dosage of 30 microM/kg orally, suggesting that this PDE III/IV inhibitor may be useful for both, bronchorelaxation and reduction of inflammation in asthma therapy.Galangin is an agonist/antagonist of the arylhydrocarbon receptor, and also shows inhibition of CYP1A1 activity.IDO-IN-2 is a potent IDO1 inhibitor with IC50 of 19 nM in Hela cell assay.Tolcapone(Ro 40-7592) is an orally active selective, potent catechol-O-methyltransferase (COMT) inhibitor. IC50 value:Target: COMTTolcapone inhibits both central and peripheral COMT. Tolcapone caused a rapid and reversible inhibition of COMT activity in erythrocytes in parallel with a dose-dependent decrease in the formation of 3-OMD. Tolcapone increased the area under the concentration-time curve and elimination half-life of levodopa. Tolcapone crosses the blood-brain barrier, and has been used for L-DOPA adjunct therapy in the treatment of Parkinson's disease.

Rolipram is a selective inhibitor of phosphodiesterases PDE4 with IC50 of 3 nM, 130 nM and 240 nM for PDE4A, PDE4B, and PDE4D, respectively.

(R)-(-)-Rolipram is the R-enantiomer of Rolipram. Rolipram is a selective inhibitor of phosphodiesterases PDE4 with IC50 of 3 nM, 130 nM and 240 nM for PDE4A, PDE4B, and PDE4D, respectively.

(S)-(+)-Rolipram is a PDE4-inhibitor and an anti-inflammatory agent, less potent than its R enantiomer.Target: PDE4B; PDE4DRolipram, a selective inhibitor of the cyclic AMP-specific phosphodiesterase (PDE IV). Rolipram did not inhibit 5-lipoxygenase activity but did inhibit human monocyte production of leukotriene B4 (LTB4, IC50 3.5 microM). Rolipram inhibited arachidonic acid-induced inflammation in the mouse, while the low Km-cyclic-GMP PDE inhibitor. Rolipram had a modest effect on LTB4 production in the mouse, but markedly reduced LTB4-induced PMN infiltration [1]. In humans and animals rolipram produces thereby a variety of biological effects. These effects include attenuation of endogenous depression and inflammation in the central nervous system (CNS), both effects are of potential clinical relevance [2].

Pentoxifylline is a competitive nonselective phosphodiesterase inhibitor.Target: PDEPentoxifylline is a competitive nonselective phosphodiesterase inhibitor which raises intracellular cAMP, activates PKA, inhibits TNF and leukotriene synthesis, and reduces inflammation and innate immunity. In addition, pentoxifylline improves red blood cell deformability, reduces blood viscosity and decreases the potential for platelet aggregation and thrombus formation. Pentoxifylline is also an antagonist at adenosine 2 receptors [1]. Pentoxifylline is generally well tolerated. Based on the totality of the available evidence, it is possible that pentoxifylline could have a place in the treatment of IC as a means of improving walking distance and as a complimentary treatment assuming all other essential measures such as lifestyle change, exercise and treatment for secondary prevention have been taken into account [2]. Pentoxifylline reduce AST and ALT levels and may improve liver histological scores in patients with NALFD/NASH, but did not appear to affect cytokines. Large, prospective, and well-designed randomized, controlled studies are needed to address this issue [3].Atglistatin is a selective adipose triglyceride lipase (ATGL) inhibitor with IC50 of 0.7 μM for lipolysis in vitro.Biochanin A is a naturally occurring fatty acid amide hydrolase (FAAH) inhibitor, which inhibits FAAH with IC50s of 1.8, 1.4 and 2.4 μM for mouse, rat, and human FAAH, respectively. Oroxylin A is a natural active flavonoid with strong anticancer effects.IC50 value:Target:In vitro: Oroxylin A suppressed the MDM2-mediated degradation of p53 via downregulating MDM2 transcription in wt-p53 cancer cells [1]. Oroxylin A remarkably reduced the generation of lactate and glucose uptake under hypoxia in HepG2 cells, inhibited HIF-1α expression and its stability [2]. Oroxylin A promotes superoxide dismutase (SOD2) gene expression through SIRT3-regulated DNA-binding activity of FOXO3a and increases the activity of SOD2 by promoting SIRT3-mediated deacetylation [3]. In vivo: Oroxylin A inhibited the tumor growth of nude mice-inoculated MCF-7 or HCT116 cells. The expression of MDM2 protein in tumor tissue was downregulated by oroxylin A as well [1].

Cladribine is an adenosine deaminase inhibitor used to treat hairy cell leukemia and multiple sclerosis. Target: Adenosine DeaminaseCladribine possesses concentration-dependent apoptosis-inducing potential in the HSB2 cells. Cladribine inhibits growth of primary mast cell (MC) and the MC line HMC-1 in a dose-dependent manner, with lower IC50 values recorded in HMC-1.2 cells harboring KIT D816V compared to HMC-1.1 cells lacking KIT D816V. Cladribine (0.7-3.5 mM) and/or diltiazem (2.4 mM), is injected intraperitoneally into adult zebrafish and red blood cell (RBC) lysates are assayed by HPLC for levels of purine nucleotides (e.g. ATP), potential biomarkers of cardiovascular health. Diltiazem increased RBC ATP concentrations, which are inhibited by co-injection of cladribine.

Olprinone Hcl(Loprinone Hcl) is a selective phosphodiesterase 3 (PDE3) inhibitor. IC50 value:Target: PDE3Olprinone is used as cardiotonic agent with positive inotropic and vasodilating effects. Olprinone has been reported to improve microcirculation and attenuate inflammation. Olprinone is often used to increase cardiac output after cardiopulmonary bypass (CPB). Olprinone was infused at a rate of 0.2 μg/kg/min when weaning from CPB was started. Olprinone has also shown potent antioxidative and anti-inflammatory effects in the meconium-induced oxidative lung injury.

Malotilate is a liver protein metabolism improved compound, which selectively inhibit the 5-lipoxygenase. IC50 Value:Target: 5-lipoxygenasein vitro: In an in vitro invasion assay using rat lung endothelial (RLE) cells, invasion of tumor cells which had been treated with MT (10 ng/ml, 24 h) was not affected; however, when RLE cells had been treated with MT, invasion was significantly inhibited in three cell lines (SAS, Ca9-22 and HSC-4) and a tendency to inhibition was also observed in other cell lines [1].in vivo: The improvement rates for choline esterase activity were significantly greater in the malotilate group than in the control group. Serum albumin levels significantly increased in the malotilate group but not in the control group [2]. In the rats treated with MT for 19 days after i.v. inoculation of c-SST-2 cells, lung metastasis was also significantly suppressed [3]. Malotilate prevented increases in serum markers of type III and IV collagen synthesis as well as accumulation of the collagens, laminin and fibronectin in the liver [4].Toxicity: Malotilate cytotoxicity to PBMCs, assessed by trypan blue dye exclusion and lactate dehydrogenase (LDH) release into the culture media, was found to be markedly increased by the addition of the NADPH generating system, indicating that metabolites play a significant role in toxicity [5].

Anagrelide Hydrochloride(BL4162A) is a drug used for the treatment of essential thrombocytosis.Target: PDEAnagrelide hydrochloride is an oral imidazoquinazoline agent that has been shown to reduce elevated platelet counts and the risk of thrombosis in patients with thrombocythaemia in various myeloproliferative disorders (MPD). It is currently approved by the FDA as oral treatment for essential thrombocythaemia (ET) and thrombocythaemia associated with polycythaemia vera (PV). Anagrelide is known to inhibit platelet cyclic adenosine monophosphate (cAMP) phosphodiesterase at concentrations that exceed those achieved at doses used to treat ET. Anagrelide is extensively metabolised in the liver and its metabolites are primarily excreted in the urine [1]. Anagrelide is an established platelet-reducing drug. Studies have also investigated the effects of anagrelide on platelets, indicating that platelet function is as important as platelet counts in ET [2].Disulfiram is a specific inhibitor of aldehyde-dehydrogenase (ALDH1), used for the treatment of chronic alcoholism by producing an acute sensitivity to alcohol.TMS is a very selective and potent competitive inhibitor of P450 1B1 (CYP1A1). It has strong selectivity among P450 family 1 enzymes. TMS exhibits 50-fold selectivity for P450 1B1 over P4501A1 and 500-fold selectivity for P450 1B1 over P450 1A2.IC50:6 nM[1]Target: P450 1B1(CYP1A1)in vitro: Twenty-four hours after incubation with the 10 μM DOX in the presence and absence of 0.5 μM TMS, approximately 1.5 × 106 cells per six-well culture plate were collected in 100 μl lysis buffer (50 mM HEPES, 0.5 M sodium chloride, 1.5 mM magnesium chloride, 1 mM EDTA, 10% glycerol (v/v), 1% Triton X-100, and 5 μl/ml of protease inhibitor cocktail). [3]in vivo: Mice were administered 300 μg/kg of selective inhibitor of P450 1B1, TMS or its vehicle (dimethyl sulfoxide), i.p. every third day for the duration of the experimental period

Isotretinoin(13-cis-Retinoic acid) is a medication used for the treatment of severe acne. It was first developed to be used as a chemotherapy medication for the treatment of brain cancer, pancreatic cancer and more.Target: RAR/RXRIsotretinoin has been the most effective and long-lasting drug for the treatment of severe acne for more than 30 years and can achieve long-term remission in 70-80% of patients after a single course. The new evidence-based European S3-guideline recommends the use of Isotretinoin as a first-line medication for the treatment of severe papulopustular or conglobate acne, especially when prognostically unfavorable factors are present: family history of acne, early onset, marked seborrhea, localization on the trunk, scarring, psychosocial disability or persistent/late-type acne [1]. Five patients with pityriasis rubra pilaris were treated with isotretinoin from September 1982 through 1985. Isotretinoin at an average dose of 1.16 mg/kg/day for 16 to 24 weeks caused complete or almost complete clearing in four of the five patients [2]. isotretinoin produces significant anti-inflammatory effects by inhibition of monocyte and neutrophil chemotaxis across intact biologic barriers in vivo [3]. Isotretinoin 5 mg/day is effective in reducing the number of acne lesions, and improving patients dermatologic quality of life, with minimal adverse effects [4]. Clinical indications: Acne Toxicity: Isotretinoin is teratogenic. It also causes mucocutaneous side effects suck as cheilitis, dry skin, and dry eyes.

Retinoic acid is a natural agonist of RAR/RXR nuclear receptors. Retinoic acid also bind to PPARβ/δ, with Kd of 17 nM. CL-82198 is a selective inhibitor of MMP-13.In vitro: In the presence of 10 and 20 μM of the specific MMP-13 inhibitor, CL-82198, migration of the LS174 cells was significantly reduced by 55 and 52%, respectively. . CL-82198 binds to the S1' pocket of MMP-13 leading to 89% enzyme inhibition at a concentration of 10 μg/ml. The addition of the specific MMP-13 inhibitor CL-82198 at a concentration of 10 μM resulted in a 45±5.6% reduction in the migration of LS174 cells.2-Methoxyestradiol is a microtubule and HIF-1 inhibitor, binds to tubulin at or near the colchicine site and inhibits the polymerization of tubulin in vitro, works by interfering with normal microtubule function.

Vildagliptin (LAF-237; NVP-LAF 237) inhibits DPP-4 with IC50 of 2.3 nM.IC50 Value: 2.3 nM[1]Target: DPP-4in vitro: Vildagliptin is an N-substituted glycyl-2-cyanopyrrolidine (figure 2). It is a potent competitive and reversible inhibitor of human and rodent DPP-4 in vitro, with a median inhibitory concentration (IC50) ~2-3 nmol/L. Importantly, vildagliptin inhibits DPP-4 with high specificity relative to other similar peptidases where its IC50 exceeds 200 mol/L [1].in vivo: Compared to age-, gender-, BMI-matched subjects with normal renal function, the mean AUC of vildagliptin after 14 days in patients with mild, moderate, and severe RI increased by 40%, 71%, and 100%, respectively [2]. The treatment was effective in modulating stress in pancreatic tissue, both by reducing levels of stress markers as well as by increasing activity of SOD and catalase. After analyzing the pancreatic histology, we found that vildagliptin was also able to preserve islets and pancreatic β-cells, especially at the concentration of 5 mg/kg [3].Clinical trial: FDA approved drug.

Dichlorphenamide(Diclofenamide) is a carbonic anhydrase inhibitor that is used in the treatment of glaucoma. Target: Carbonic AnhydraseDichlorphenamide is a sulfonamide and a carbonic anhydrase inhibitor of the meta-Disulfamoylbenzene class. This drug has the same side-effects as acetazolamide, for which it is a useful substitute, except for a lesser tendency to cause dermatitis, renal calculi and metabolic acidosis. It may induce a more pronounced renal loss of potassium [1]. An average daily dose of 33 mg of diclofenamide, a carbonic-anhydrase inhibitor, was added to the anti-epileptic medication already employed in 105 cases of severe epilepsy which had shown insufficient clinical improvement. A favourable action on seizures, often accompanied by an improvement in the EEG tracing, was observed in 83 cases. The effect was of long duration in 47 cases in that it lasted for more than a year. It persisted for one to twelve months in a further 17 cases, while in 19 patients, who had reacted favourably to the treatment, medication had to be suspended because of intolerance [2].

Entacapone is a specific, potent, peripherally acting catechol-O-methyltransferase (COMT) inhibitor with IC50 of 151 nM for PD treatment.IC50 Value: 151 nMTarget: COMTin vitro: Entacapone inhibits catechol-O-methyltransferase(COMT) with similar IC50 in different tissues including live, duodenum, kidney and lung, but entacapone is more active than tolcapone in those tissues. Entacapone (< 100 μM) is a potent inhibitor of α-syn and β-amyloid (Aβ) oligomerization and fibrillogenesis, and also protects against extracellular toxicity induced by the aggregation of both proteins in PC12 cells.in vivo: Levodopa/carbidopa/entacapone has been shown to improve the pharmacokinetic profile of levodopa and provide superior symptomatic control compared with conventional levodopa/dopa decarboxylase inhibitor therapy. We report four case histories describing clinical experience of using levodopa/carbidopa/entacapone 200/50/200 mg, one of the latest doses of this formulation, in a range of patients with Parkinson's disease. These cases illustrate that levodopa/carbidopa/entacapone 200/50/200 mg provides improvements in symptomatic control.Clinical trial: The combination product carbidopa/levodopa/entacapone (CLE) was approved in 2003 for the treatment of PD patients.

SB-3CT is a potent and selective inhibitor of matrix metalloproteinase (MMP)-2 and -9.

TCS 401 is a selective inhibitor of protein tyrosine phosphatase 1B (PTP1B).

Bestatin is an inhibitor of CD13 (Aminopeptidase N)/APN and leukotriene A4 hydrolase, used for cancer treatment.

Carboxypeptidase G2 (CPG2) Inhibitor is a novel Carboxypeptidase G2 (CPG2) Inhibitor, Antitumor agents.CPA inhibitor is a potent inhibitor for carboxypeptidase A (CPA).

BIIB021 is an orally available, fully synthetic inhibitor of HSP90 with Ki and EC50 of 1.7 nM and 38 nM, respectively.

FAAH-IN-2 is a potent FAAH(fatty acid amide hydrolase) inhibitor extracted from Patent WO/2008/100977A2.

Alda-1 is a potent ALDH2 agonist, which significantly improves ALDH2 activity.Levobupivacaine Hcl is a local anaesthetic compound belonging to the amino amide group; long-acting local anesthetic.NQ301 is an antithrombotic agent; inhibits collagen-challenged rabbit platelet aggregation with an IC50 of 10 mg/mL.

Sobetirome is a thyroid hormone receptor β (TRβ)-specific agonist, GC-1 is designed to bind selectively to TRβ-1 with EC50 of 0.16 μM.

HTS01037 is an inhibitor of fatty acid binding; and a competitive antagonist of protein-protein interactions mediated by AFABP/aP2 with a Ki of 0.67 μM.

Tamibarotene is an agonist for retinoic acid receptor α/β, and used for cancer treatment.AM580 is a stable retinobenzoic derivative, and originally synthesized as a RARα agonist.Tazarotene is a selective retinoic acid receptor (RAR) agonist for the treatment of plaque psoriasis and acne vulgaris.

HIV-1 integrase inhibitor, in the treatment of human immunodeficiency virus (HIV) infection.

Xanthohumol is one of the principal flavonoids isolated from hops, the inhibitor of diacylglycerol acetyltransferase (DGAT), COX-1 and COX-2, and shows anti-cancer and anti-angiogenic activities. CDD3505 is used for elevating high density lipoprotein cholesterol (HDL) by inducing hepatic cytochrome P450IIIA (CYP3A) activity.Tolrestat is a potent, orally active aldose reductase inhibitor with IC50 of 35 nM.

E-64 is a potent irreversible inhibitor against general cysteine proteases with IC50 of 9 nM for papain.

Orteronel is a highly selective inhibitor of human 17,20-lyase with IC50 of 38 nM, and exhibits >1000-fold selectivity over other CYPs such as 11-hydroxylase and CYP3A4.LY2183240 is a novel and highly potent blocker of anandamide uptake (IC50 = 270 pM). LY2183240 inhibits fatty acid amide hydrolase (FAAH) activity (IC50 = 12.4 nM). IC50: 270 pM (anandamide uptake); 12.4 nM (FAAH)Target: FAAH; Anandamide uptakeFollowing i.p. administration in rats, LY2183240 increases brain anandamide concentration and exerts antinociceptive effects in formalin model of pain.

U-104 is a potent carbonic anhydrase (CA) inhibitor for CA IX and CA XII with Ki of 45.1 nM and 4.5 nM; low inhibition for CA I and CA II.IC50 value: 45.1 nM/4.5 nM(Ki, CA IX/CA XII) [1]Target: Carbonic anhydrase inhibitorin vitro: U-104 (50 μM) blocks the mesenchymal phenotype in the cancer stem cells population in hypoxia condition of 4T1 cells. U-104 (<50 μM) significantly reduces migration in a dose-dependent manner in metastatic MDA-MB-231 LM2-4Luc+ cells , with cells growing as compact colonies similar to parental MDA-MB-231 cells [2]. in vivo: U-104 (38 mg/kg) inhibits primary tumor growth in the mice implanted orthotopically with MDA-MB-231 LM2-4Luc+ cells. U-104 (19 mg/kg) inhibits metastases formation in the 4T1 experimental metastasis mice model [1]. U-104 (38 mg/kg) significantly delay primary tumor growth and reduces cancer stem cell population in NOD/SCID mice orthotopically implanted with MDA-MB-231 LM2-4Luc+ cells. U-104 (5 mg/mL, oral gavage) shows a significant delay in tumor growth in Balb/c mice orthotopically implanted with 4T1 cells [2].

Talabostat (mesylate) is an orally active, specific inhibitor of dipeptidyl peptidases with IC50 of 1 nM for DPP4, including tumor-associated fibroblast activation protein.Saxagliptin(BMS477118) is a selective and reversible DPP4 inhibitor with IC50 of 26 nM and Ki of 1.3 nM.IC50 value: 26 nM [1]Target: DPP4in vitro: Saxagliptin has an inhibition constant Ki of 1.3 nM for DPP4 inhibition, which is 10-fold more potent than either vildagliptin or sitagliptin (another two DPP4 inhibitors) with Ki of 13 and 18 nM. In addition, Saxagliptin demonstrates greater specificity for DPP4 than for either the DPP8 or DPP9 enzymes (400- and 75- fold, respectively). The active metablite of saxagliptin is two-fold less potent than the parent. Both Saxagliptin and its metabolite are highly selective (>4000-fold) for the prevention of DPP4 compared with a range of other proteases (selectivity of sitagliptin and vildagliptin for DPP4 is >2600 and <250-fold, respectively, compared with DPP8 and DPP9) [2]. Saxagliptin reduces the degradation of the incretin hormone glucagon-like peptide-1, thereby enhancing its actions, and is associated with improved β-cell function and suppression of glucagon secretion.in vivo: Saxagliptin is highly effective at eliciting marked dose-dependent enhancements in glucose clearance in the dose range 0.13-1.3 mg/kg in ob/ob mice relative to controls. Saxagliptin dose-dependently elevate plasma insulin significantly at 15 min post-oGTT, with concomitant improvement in the glucose clearance curves at 60 min post-oGTT [4].

Febuxostat(TEI 6720;TMX 67 ) is selective xanthine oxidase inhibitor with Ki of 0.6 nM.IC50 value: 0.6 nM (Ki) [1]Target: xanthine oxidasein vitro: Febuxostat displays potent mixed-type inhibition of the activity of purified bovine milk xanthine oxidase, with Ki and Ki' values of 0.6 nM and 3.1 nM respectively, indicating inhibition of both the oxidized and reduced forms of xanthine oxidase [1]. in vivo: Febuxostat (5–6 mg/kg/day) combined with fructose significantly lowers blood pressure, UA, triglycerides, and insulin in rats compared with fructose alone. Febuxostat (5–6 mg/kg/day) combined with fructose also reduces glomerular pressure, renal vasoconstriction, and afferent arteriolar area in rats compared with fructose alone [2]. Febuxostat prevents hyperuricemia in 5/6 nephrectomy (5/6 Nx)+oxonic acid (OA)+Febuxostat(Fx) rats and ameliorates proteinuria, preserves renal function and prevents glomerular hypertension in both 5/6 nephrectomy (5/6 Nx)+vehicle (V)+Febuxostat(Fx) and 5/6 nephrectomy (5/6 Nx)+oxonic acid (OA)+Febuxostat(Fx) groups [3]. Febuxostat (5 mg/kg/d by gavage for 8 days) treatment after transverse aortic constriction (TAC) attenuates the TAC-induced left ventricular (LV) hypertrophy and dysfunction. Febuxostat blunts the TAC-induced increases in nitrotyrosine (indicating reduced myocardial oxidative stress), p-Erk(Thr202/Tyr204), and p-mTOR(Ser2488), with no effect on total Erk or total mTOR [4].

Epalrestat is an aldose reductase inhibitor for the treatment of diabetic neuropathy.Target: Aldose ReductaseEpalrestat may affect or delay progression of the underlying disease process. Data from six clinical trials were evaluated, and it was determined that epalrestat 50 mg 3 times/day may improve motor and sensory nerve conduction velocity and subjective neuropathy symptoms as compared with baseline and placebo. Epalrestat may serve as a new therapeutic option to prevent or slow the progression of diabetic neuropathy [1]. Epalrestat significantly increased the amplitude of 3 cpm waves on EGG and improved the spectral analytical parameters of heart rate variability. These findings suggest that epalrestat is useful for the treatment of diabetic gastroparesis [2]. Epalrestat is a highly effective and safe agent for the treatment of diabetic neuropathy [3].

Lonidamine is an orally administered small molecule hexokinase inactivator.Target: OthersLonidamine is a derivative of indazole-3-carboxylic acid, which for a long time, has been known to inhibit aerobic glycolysis in cancer cells. It seems to enhance aerobic glycolysis in normal cells, but suppress glycolysis in cancer cells. This is most likely through the inhibition of the mitochondrially bound hexokinase. Later studies in Ehrlich ascites tumor cells showed that lonidamine inhibits both respiration and glycolysis leading to a decrease in cellular ATP. Clinical trials of lonidamine in combination with other anticancer agents for a variety of cancers has begun. Lonidamine has been used in the treatment of brain tumours in combination with radiotherapy and temozolomide. Results showed that a combination of temozolomide and lonidamine at clinically achievable, low plasma concentrations, could inhibit tumour growth, and lonidamine could reduce the dose of temozolomide required for radiosensitization of brain tumours. From Wikipedia.

Acitretin(Ro 10-1670) is a second-generation, systemic retinoid that has been used in the treatment of psoriasis.Target: RAR/RXRAcitretin is a second-generation, systemic retinoid that has been approved for the treatment of psoriasis since 1997. It can be considered one of the treatments of choice for pustular and erythrodermic psoriasis. However, the efficacy of acitretin as a monotherapy for plaque psoriasis is less, although it is often used in combination therapy with other systemic psoriasis therapies, especially ultraviolet B or psoralen plus ultraviolet A phototherapy, to increase efficacy. Such combination treatments may potentially minimise toxicity by using lower doses of each of the two agent [1].Thirty-nine male adult Wistar albino rats were divided into 3 groups as two experimental groups and one control group. The first group consisting 14 rats were applied orally standard dose (0.75 mg/kg/day) acitretin and the second group consisting 16 rats were applied high dose (1.5 mg/kg/day) acitretin.Acitretin was given within dimetil sulphoxide (DMSO), which was diluted with saline solution as a ratio of 1/10, in order to increase its solubility. The control group consisting 9 rats were given only saline solution including DMSO for 8 weeks. After 8 weeks of the administration, half of the rats in the first and second groups and the entire control group were sacrificed under deep ether anaesthesia and bilateral orchiectomy was made. The remainingrats were compared with the control group using a similar method at the end of 8 weeks of wash-off period. The orchiectomy materials were histopathologically evaluated under the light microscope for spermatogenesis according to parameters including spermatogenetic activity, spermatogenetic organization, seminiferous tubular diameter, interstitial Leydig cells and fibroblasts. In our study it was concluded that the standard and high doses of acitretin do not have any effect on the spermatogenesis of threats [2].Clinical indications: PsoriasisFDA Approved Date: Toxicity: nausea; headache; itching; red or flaky skin; dry or red eyes; dry mouth; depression; 0cystitis acne or hair loss

Teprenone(Geranylgeranylacetone; GGA)is commonly utilized to protect the gastric mucosa in peptic ulcer disease; has been shown to protect the myocardium from ischemia/reperfusion by activating heat shock proteins.IC50 value:Target: Hsp 70 activatorin vitro: GGA reduced doxorubicin cardiac toxicity, preserved cardiac function, prevented TUNEL-positive cardiac cell death, and reduced doxorubicin-induced oxidant production in a nitric oxide synthase-dependent and independent manner. GGA also reduced heart doxorubicin-induced ROCK1 cleavage [1]. GGA suppressed the cell injury and apoptosis caused by cerebral I/R. Moreover, the protective effect of GGA was found to involve heat shock protein 90 (HSP90) and phosphorylated endothelial nitric oxide synthase (eNOS) expression and activity. Both the HSP90 and eNOS inhibitor abolished the effect of GGA [2].in vivo: In xenograft-implanted mice, combined GGA/doxorubicin treatment decreased tumor growth more effectively than doxorubicin treatment alone. As evidence of antitumor effect, GGA inhibited LPA-induced motility and invasion by MDA-MB-231 cells [1]. Geranylgeranylacetone treatment from the 2nd to 8th week after myocardial infarction attenuated the reduction in mitochondrial HSPB1 and HSPB8 contents. Furthermore, the mitochondrial energy-producing ability and cardiac pump function were preserved by orally administered geranylgeranylacetone during the development of heart failure [3]. GGA treatment reversed stress-induced alterations in locomotor activity and target levels of MAO-A and caspase-3. In addition, GGA treatment induced heat shock protein 70 (Hsp70) expression in the hippocampus [4].

Nepicastat Hcl(SYN117 Hcl; RS-25560-197 Hcl) is a dopamine beta-hydroxylase inhibitor with IC50 of 8.5 ± 0.8 and 9.0 ± 0.8 nM for bovine and human, respectively. IC50 value: 8.5/9.0 nM(bovine/human dopamine beta-hydroxylase)Dopamine beta-hydroxylase is an enzyme that catalyzes the conversion of dopamine to norepinephrine. Nepicastat (SYN117; RS-25560-197) has been studied as a possible treatment for congestive heart failure, and appears to be well tolerated as such.

Pimobendan is a selective inhibitor of PDE3 with IC50 of 0.32 μM.Target: PDE3Pimobendan exhibits selective inhibition of PDE III isolated from guinea pig cardiac muscle with IC50 of 0.32 uM compared to the inhibition of PDE I and PDE II (IC50s >30 μM). In human atrial cells, 100 μM pimobendan significantly increases the L-type calcium current (ICa(L)) (evoked by depolarization to +10 mV from a holding potential of -40 mV) by 250.4% with the half-maximal stimulation (EC50) of 1.13 μM. In rabbit atrial cells, Pimobendan increases ICa(L) at +10 mV by 67.4.%, which is significantly lower than that obtained in human atrial cells Pimobendan shows a beneficial effect on survival in the murine model of EMC virus-induced myocarditis. Administration of Pimobendan significantly increases the final survival rate from 33.6% (control) to 53.3% (0.1 mg/kg) or 66.7% (1 mg/kg). Pimobendan (1 mg/kg) also significantly reduces myocardial cellular infiltration, the level of intracardiac tumor necrosis factor (TNF)-α and interleukin (IL)-1β compared with the control group, which shows no effect on myocardial necrosis, heart weight and body weight. Pimobendan suppresses expression of the intracardiac iNOS gene , causing reduction of intracardiac NO production.

URB597 is a potent, orally bioavailable FAAH inhibitor with IC50 of 4.6 nM, with no activity on other cannabinoid-related targets.IC50 value: 4.6 nM [1]Target: FAAH in vitro: URB597 binds in the hydrophobic pocket and catalytic core of FAAH that connects the active site residues to the membrane surface of FAAH [1]. URB597 reduces the expression of the LPS-induced enzymes cyclo-oxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS; NOS2) in primary rat microglial cell, with a concomitant reduction in the release of the inflammatory mediators prostaglandin E2 (PGE2) and (NO) nitric oxide [2]. in vivo: URB597 inhibits [3H]anandamide hydrolysis in rat brain membranes with a parallel increase in brain anandamide, OEA, and PEA content by inhibition of FAAH. URB597 enhances the hypothermia effect induced by ethanolamide by inhibiting FAAH [3]. When delivered intraperitonealy (0.3 mg/kg) URB597 reduces allodynia and hyperalgesia through cannabinoid CB1 and CB2 receptor-mediated analgesia in rats with inflammatory pain [4].

Cilomilast(SB 207499; Ariflo) is a potent PDE4 inhibitor with IC50 of about 110 nM, has anti-inflammatory activity and low central nervous system activity.IC50 value: 110 nMTarget: PDE 4Cilomilast (SB-207499) inhibits HPDE4 and LPDE4 catalytic activity with equal potency (Ki ≈100 nM). SB-207499 and rolipram are equipotent against LPDE4, but Cilomilast (Ariflo, SB-207499) is 100-fold less potent against HPDE4. This profile suggests that Cilomilast (Ariflo, SB-207499) retain the anti-inflammatory activity of rolipram yet have a decreased tendency to produce side effects.JNJ-42041935 is a potent, competitive and selective inhibitor of prolyl hydroxylase PHD; inhibits PHD1, PHD2, and PHD3 with pKi values of 7.91±0.04, 7.29 ±0.05, and 7.65±0.09, respectively.Bexarotene (Targretin) is a selective RXR agonist approved for the treatment of CTCL.IC50 value:Target: retinoid X receptorExposure of NSCLC cell lines to bexarotene as a single agent had modest growth inhibitory effects (at > 1 μM). However, exposure of several NSCLC lines to bexarotene (1–3 μM) produced significant decreases in the expression of EGFR, Her-2 and TGF mRNA and protein. EGF levels were also decreased to a much lesser degree.

TTNPB is a highly potent RAR agonist. Competitive binding assays using human RARs yield IC50s of α=5.1 nM, β= 4.5 nM, and γ=9.3 nM, respectively.�

PYZD-4409 is a novel small molecule inhibitor of Ubiquitin-activating enzyme UBA1/E1 enzyme with an IC50 of 20 uM (cell-free enzymatic assay).IC50 Value: 20 uM (cell-free enzymatic assay) [1]Target: E1 enzyme (Ubiquitin-activating enzyme)in vitro: PYZD-4409 inhibited the ATP-dependent activation of ubiquitin and subsequent transfer of the activated ubiquitin from the E1 to the common human E2 enzyme UBE2E2 in a gel-based assay. The IC50 of inhibition was estimated to be 20μM in a cell-free enzymatic assay. Suggesting specificity of PYZD-4409 for the E1 enzyme, the compound had no effect on unrelated enzymes such as α-Mannosidase II glycosylation enzyme or Luciferase at concentrations up to 100μM (data not shown). It also did not inhibit the summo E1, Uba2, at concentrations up to 100μM. In 5 of 8 leukemia and myeloma cell lines, PYZD-4409 induced cell death with a LD50 less than 10μM. Myeloma cell lines were particularly sensitive to E1 inhibition because PYZD-4409 induced cell death with 3 of 4 myeloma cell lines (ie, LP1, KMS11, and U226) having an LD50 of 3μM or less. In contrast, solid tumor cell lines were less sensitive with an LD50 of approximately 15 to 20μM [1]. in vivo: SCID mice were injected subcutaneously with MDAY-D2 murine leukemia cells and then treated with PYZD-4409 (10 mg/kg) or buffer control intraperitoneally daily on alternate days over 8 days. Sixteen days after tumor implantation, the mice were killed, and the tumors excised and weighed. Compared with control-treated mice, treatment with PYZD-4409 delayed tumor growth and decreased tumor weight without untoward toxicity. Inhibition of the E1 can achieve an antitumor effect in vivo [1].

FG-4592 is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, currently used for the treatment of anemia. IOX2 is a specific prolyl hydroxylase-2 (PHD2) inhibitor with IC50 of 22 nM. Chlorogenic acid(NSC-407296; 3-O-Caffeoylquinic acid) is one of the most abundant polyphenols in the human diet, has been reported to inhibit cancer cell growth and a major anti-inflammatory constituent of lonicerae flos extract.IC50 value:Target: in vitro: CGA significantly decreases the hypoxia-induced HIF-1α protein level in A549 cells, without changing its mRNA level. CGA was, however, found to suppress the transcriptional activity of HIF-1α under hypoxic conditions, leading to a decrease in the expression of its downstream target VEGF [1]. CGA inhibited various TLR agonist-, IL-1α-, or high-mobility group box-1-stimulated autophosphorylation (activation) of IRAK4 in peritoneal macrophages from C57BL/6 or C3H/HeJ mice via directly affecting the kinase activity of IRAK4, a proximal signal transducer in the MyD88-mediated innate immunity that enhances transcriptional activity of NF-κB or AP-1 [2].in vivo: CGA can block hypoxia-stimulated angiogenesis in vitro and VEGF-stimulated angiogenesis in vivo using HUVEC cells in a mouse model [1]. CGA consequently attenuated protein or mRNA levels of NF-κB/AP-1 target genes encoding TNF-α, IL-1α, IL-6, and high-mobility group box-1 in vivo under endotoxemia or ALI [2]. CGA (10, 30 and 100 mg/kg) and omeprazole (positive control, 10 mg/kg) were administered orally 48 h after the RE operation for 12 days. CGA reduced the severity of esophageal lesions, and this beneficial effect was confirmed by histopathological observations. CGA reduced esophageal lipid peroxidation and increased the reduced glutathione/oxidized glutathione ratio. CGA attenuated increases in the serum level of tumor necrosis factor-α, and expressions of inducible nitric oxide synthase and cyclooxygenase-2 protein [3].

Trelagliptin(SYR-472) is a long acting dipeptidyl peptidase-4 (DPP-4) inhibitor that is being developed for the treatment of type 2 diabetes (T2D). IC50 value:Target: DPP4Two Phase II clinical studies have been completed with Efficacy and Safety of SYR-472 in Subjects With Type 2 Diabetes Mellitus. Phase III clinical studies with trelagliptin in Japan to evaluate its safety and efficacy in a once-weekly oral treatment regimen. Currently, all available DPP-4 inhibitors are dosed once-daily. A once-weekly treatment, such as trelagliptin, would provide patients with a convenient treatment alternative and has the potential to improve treatment compliance.Fenofibrate is a relatively potent inhibitor of CYP2C19 (IC50=0.2 μM) and CYP2B6 (IC50=0.7 μM). Fenofibrate is also a well-known PPARα agonist (EC50=30 μM).

Dorzolamide Hcl(L671152 Hcl; MK507 Hcl) is an anti-glaucoma agent, which is a carbonic anhydrase inhibitor.Target: carbonic anhydrase (CA)Dorzolamide hydrochloride is a carbonic anhydrase inhibitor. It is an anti-glaucoma agent, and acts by decreasing the production of aqueous humour [1]. Glaucoma was induced in the right eye of adult Wistar rats by episcleral venous occlusion. One experimental group was administered dorzolamide hydrochloride 2%-timolol 0.5% combination eye drops, while the other experimental group was administered dorzolamide hydrochloride2% eye drops. Control groups had surgery without drug administration. Drug application was initiated either 2 weeks before surgery (Group A), from the day of surgery (Group B), 2 weeks after surgery (Group C), or 4 weeks after surgery (Group D). RGCs were labeled by intratectal Fluorogold injections and counted from flat-mount preparations, and IOP was measured using Tonopen. Both dorzolamide-timolol combination and dorzolamide hydrochloride, when applied topically, significantly reduced IOP and improved RGC densities in experimental eyes when compared to control eyes. Earlier initiation, as well as longer duration of drug application, resulted in higher RGC densities [2].Clinical indications: Glaucoma; Ocular hypertensionFDA Approved Date: 1995Toxicity: Dizziness, headache, shortness of breath, slow heartbeat, severe asthma, cardiac arrest

EMD638683 is a highly selective SGK1 inhibitor with IC50 of 3 μM.Ganetespib is a unique non-geldanamycin heat shock protein 90 (HSP90) inhibitor, with IC50 of 4 nM in OSA 8 cells.

PYR-41 is a specific and cell permeable inhibitor of ubiquitin-activating enzyme E1 with an IC50 of < 10 μM, with no or little activity at E2.

Deoxycorticosterone acetate is a steroid hormone produced by the adrenal gland that possesses mineralocorticoid activity and acts as a precursor to aldosterone.

Carbosulfan inhibited relatively potently CYP3A4 and moderately CYP1A1/2 and CYP2C19 in pooled HLM (human livers). Carbosulfan activation is predominantly catalyzed in humans by CYP3A4.GSK 650394 is a novel SGK inhibitor with IC50 of 62 nM and 103 nM for SGK1 and SGK2 in the SPA assay respectively. UAMC00039 dihydrochloride is a potent, reversible and competitive dipeptidyl peptidase II inhibitor with an IC50 of 0.48 nM.

UK-371804 is a urokinase-type plasminogen activator (uPA) inhibitor with a Ki of 10 nM.A939572 is a potent, and orally bioavailable SCD1 inhibitor with IC50 values of <4 nM and 37 nM for mSCD1 and hSCD1, respectively.

CPI-613 is an E1α pyruvate dehydrogenase (PDH) modulator that prevents cancer cells from metabolizing glucose for energy. CPI-613 has been granted orphan drug status by the US FDA for pancreatic cancer.

FK866 is an effective inhibitor of nicotinamide phosphoribosyltransferase (NMPRTase) with IC50 of 0.09 nM.Abiraterone acetate is an oral, potent, selective, and irreversible inhibitor of CYP17.

5-Iodotubercidin is a potent adenosine kinase inhibitor with IC50 of 26 nM.Chenodeoxycholic Acid is a hydrophobic primary bile acid that activates nuclear receptors (FXR) involved in cholesterol metabolism.PX-478 is an inhibitor of hypoxia-inducible factor-1α (HIF-1α), and is cytotoxic to a variety of cancer cell lines under normoxia and hypoxia in vitro with IC50 of 20-30 μM.

MLN2238 is a selective, potent, and reversible proteasome inhibitor, which inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with an IC50 value of 3.4 nM (Ki of 0.93 nM). Clemizole hydrochloride is an H1 histamine receptor antagonist, is found to substantially inhibit HCV replication. The IC50 of Clemizole for RNA binding by NS4B is 24±1 nM, whereas its EC50 for viral replication is 8 µM. Metolazone(Zaroxolyn) is primarily used to treat congestive heart failure and high blood pressure.Target: OthersMetolazone is a thiazide-like diuretic marketed under the brand names Zytanix from Zydus Cadila, Zaroxolyn, and Mykrox. It is primarily used to treat congestive heart failure and high blood pressure. Metolazone indirectly decreases the amount of water reabsorbed into the bloodstream by the kidney, so that blood volume decreases and urine volume increases. This lowers blood pressure and prevents excess fluid accumulation in heart failure. Metolazone is sometimes used together with loop diuretics such as furosemide or bumetanide, but these highly effective combinations can lead to dehydration and electrolyte abnormalities.Metolazone and the other thiazide diuretics inhibit the function of the sodium-chloride symporter, preventing sodium and chloride, and therefore water too, from leaving the lumen to enter the tubule cell. As a result, water remains in the lumen and is excreted as urine, instead of being reabsorbed into the bloodstream. Since most of the sodium in the lumen has already been reabsorbed by the time the filtrate reaches the distal convoluted tubule, thiazide diuretics have limited effects on water balance and on electrolyte levels. Nevertheless, they can be associated with low sodium levels, volume depletion, and low blood pressure, among other adverse effects.

TZ9 is a novel inhibitor of Rad6 ubiquitin conjugating enzyme(E2 enzyme); inhibits MDA-MB-231 cell proliferation with IC50 of ~6 uM.IC50 value: 6 uM [1]Target: Rad6 inhibitorThe bulk of MDA-MB-231 cells treated with 10 μmol/L or more SMI #9 displayed a round morphology compared with controls and less than 5 μmol/L doses of SMI #9. Simultaneous comparison of SMIs #8 and 9 confirmed SMI #9 inhibits Matrigel-induced migration of MDA-MB-231 cells in a dose-dependent manner compared with SMI #8. 5 μmol/L SMI #9 treatment triggered morphologic changes consistent with apoptosis in a time-dependent manner. 5 μmol/L SMI #9 treatment of MDA-MB-231 cells for 24 hours increased the proportion of G2–M-arrested cells by 2-fold and was accompanied by a proportional decrease in S-phase cells. SMIs #8 or 9 treatments dramatically reduced β-catenin staining as visualized by reduced merged Rad6/β-catenin yellow fluorescence.

Cilostazol(OPC 13013; OPC 21) is a potent inhibitor of PDE3A, the isoform of PDE 3 in the cardiovascular system (IC50=0.2 uM).IC50 Value: 0.2 uM [1]Target: PDE3Ain vitro: Cilostazol caused a concentration-dependent increase in the cAMP level in rabbit and human platelets with similar potency. Furthermore, cilostazol and milrinone were equally effective in inhibiting human platelet aggregation with a median inhibitory concentration (IC50) of 0.9 and 2 microM, respectively. In rabbit ventricular myocytes, however, cilostazol elevated cAMP levels to a significantly lesser extent (p < 0.05 vs. milrinone) [2]. Cilostazol inhibited SIPA dose-dependently in vitro. The IC50 value of cilostazol for inhibition of SIPA was 15 +/- 2.6 microM (m +/- SE, n=5), which was very similar to that (12.5 +/- 2.1 microM) for inhibition of ADP-induced platelet aggregation. Cilostazolpotentiates the inhibition of SIPA by PGE1 and enhances its ability to increase cAMP concentrations [3].in vivo: A single oral adminstration of 100 mgcilostazol to healthy volunteers produced a significant inhibition of SIPA [3]. Male C57BL/6J mice were assigned to five groups: mice fed a normal diet (groups 1 and 2); 0.1% or 0.3% cilostazol-containing diet (groups 3 and 4, respectively); and 0.125% clopidogrel-containing diet (group 5). Two weeks after feeding, groups 2-5 were intraperitoneally administered carbon tetrachloride (CCl4 ) twice a week for 6 weeks, while group 1 was treated with the vehicle alone [4].Toxicity: Cilostazol in addition to dual antiplatelet therapy appears to be effective in reducing the risk of restenosis and repeat revascularization after PCI without any significant benefits for mortality or stent thrombosis [5].

GMX1778(CHS-828) is a potent inhibitor of NAD+ biosynthesis enzyme NAMPT with IC50 <25 nM.IC50 value: < 25 nM [1]Target: NAMPT inhibitorin vitro: The phosphoribosyltransferase activity of recombinant NAMPT was sensitive to inhibition by GMX1778 (IC50 < 25 nM) whereas the adenyltransferase activity of recombinant NMNAT1 was not. The Kd of recombinant NAMPT for GMX1778 labeled with a fluorescent tag (GMX1778-Alexa Fluor) was 120 nM. Overexpression of wild-type NAMPT was able to maintain a certain level of NAD+ under conditions of challenge with 3 nM GMX1778, but this effect was lost when cells were exposed to 300 nM GMX1778 [1]. GMX1778 increases intracellular ROS in cancer cells by elevating the superoxide level while decreasing the intracellular NAD(+) level. Notably, GMX1778 treatment does not induce ROS in normal cells. GMX1778-induced ROS can be diminished by adding nicotinic acid (NA) in a NA phosphoribosyltransferase 1 (NAPRT1)-dependent manner [2].in vivo: A 4-h iv infusion of NA (120 mg/kg of body weight) did not adversely affect the antitumor activity of a 24-h iv infusion of GMX1777 at a dose of 150 mg/kg or 650 mg/kg in the NAPRT1-deficient xenograft experiments. GMX1777 at 650 mg/kg is above the maximum tolerated dose. The administration of NA as a 4-h iv infusion immediately following treatment with 750 mg/kg GMX1777 reduced the mortality associated with toxic doses of GMX1777 [1].

Arctigenin is a lignan found in certain plants of the Asteraceae; it has shown antiviral and anticancer effects in glass; it is the aglycone of arctiin.IC50 value: Target: anticancer agentArctiin and its aglucone, arctigenin from the fruits of Arctium lappa L. showed potent in vitro antiviral activities against influenza A virus (A/NWS/33, H1N1) (IFV). Based on the data from time-of-addition experiments and on release tests of progeny viruses, arctigenin was assumed to interfere with early event(s) of viral replication after viral penetration into cells, and to suppress the release of progeny viruses from the host cells [1]. arctigenin treatment reduced viability of bladder cancer T24 cells in a dose- and time-dependent manner after treatment with arctigenin (10, 20, 40, 80, and 100 μmol/L) for 24 hr and 48 hr. Arctigenin treatment clearly arrested tumor cells in the G1 phase of the cell cycle. At the molecular level, arctigenin treatment decreased cyclin D1 expression, whereas CDK4 and CDK6 expression levels were unaffected. Moreover, arctigenin selectively altered the phosphorylation of members of the MAPK superfamily, decreasing phosphorylation of ERK1/2 and activated phosphorylation of p38 significantly in a dose-dependent manner [2]. The use of arctigenin has been shown to be effective in a mouse model of Japanese encephalitis [3].

Finasteride is an orally active testosterone 5-alpha-reductase inhibitor (Ki= 10 nM). Target: 5-alpha ReductaseApproved: 1992Finasteride, a synthetic 4-azasteroid antiandrogen compound, is a specific inhibitor of steroid Type II 5α-reductase, an intracellular enzyme that converts the androgen testosterone into 5α-dihydrotestosterone (DHT). Finasteride is used in the treatment of prostate cancer, benign prostatic hyperplasia, and androgenetic alopecia (male pattern baldness). In benign prostatic hyperplasia, finasteride inhibits 5alpha-reductase activity in epithelium for Ki of 10 nM, significantly lower than in stroma (Ki = 33nM) [1].

Nortadalafil is demethyl Tadalafil, which is a PDE5 inhibitor, currently marketed in pill form for treating erectile dysfunction (ED) under the name Cialis; and under the name Adcirca for the treatment of pulmonary arterial hypertension.IC50 value:Target:Papaverine hydrochloride is a selective phosphodiesterase inhibitor for the PDE10A subtype found mainly in the striatum of the brain.Target: PDEin vitro: Papaverine is an opium alkaloid antispasmodic drug, used primarily in the treatment of visceral spasm, vasospasm (especially those involving the heart and the brain).in vivo: When administered chronically to mice, Papaverine produces motor and cognitive deficits and increased anxiety, but conversely may produce an antipsychotic effect.

Ro 28-1675 (Ro 0281675) is a potent allosteric GK activator with a SC1.5 value of 0.24± 0.0019 uM. IC50 value: 0.24± 0.0019 uM (SC1.5) [1]Target: Glucokinase activatorThe R stereoisomer Ro 28-1675 activated GK with a SC1.5 of 0.24 uM, while the S isomer did not activated GK up to 10 uM. Oral administration of Ro 28-1675 (50 mg/Kg) to male C57B1/6J mice caused a statistically significant reduction in fasting glucose levels and improvement in glucose tolerance relative to the vehicle treated animals [1]. Comparison of rat PK parameters indicated that Ro 28-1675 displayed lower clearance and higher oral bioavailability compared to 9a. Following a single oral dose, Ro 28-1675 reduced fasting and postprandial glucose levels following an OGTT, was well tolerated, and displayed no adverse effects related to drug administration other than hypoglycemia at the maximum dose (400 mg). [1]

NVP-HSP990(HSP990) is an orally bioavailable inhibitor of Hsp90(IC50=13 nM; Hsp90α) with potential antineoplastic activity.IC50 value: 13 nM(Hsp90α) [1]Target: Hsp90 inhibitorin vitro: NVP-HSP990 triggered apoptosis in a panel of human multiple myeloma cells, induced cell-cycle arrest, PARP cleavage, downregulation of client proteins, the inability to reactivate phospho-STAT3 following exogenous IL-6 stimulation, and it synergized with azacytidine and bortezomib in cell lines and primary multiple myeloma samples [2]. Exposure of MM cells to a combination of NVP-HSP990 and either melphalan or histone deacetylase (HDAC) inhibitors caused synergistic inhibition of viability, increased induction of apoptosis, and was able to overcome the primary resistance of the cell line RPMI-8226 to HSP90 inhibition [3]. in vivo: HSP990 was given to control mice every 3 days for 14 days at close to the maximum tolerated dose, which was most likely to reveal any effect on phototransduction machinery biogenesis. HSP990-treated retinae showed a significant reduction in GRK1 levels, compared with vehicle-treated control. Moreover, HSP990-treated retinae exhibited retinal morphology that was indistinguishable from age-matched vehicle-treated animals, with rhodopsin localized in the OS [4].

LY315920 (Varespladib) is a potent and selective human non-pancreatic secretory phospholipase A2 (sPLA) inhibitor with IC50 of 7 nM.IC50 value: 7 nMTarget: sPLA2in vitro: LY315920 exhibits the significant inhibitory effect on sPLA2 activity in serum from various species including rat, rabbit, guinea pig and human with IC50 of 8.1 nM, 5.0 nM, 3.2 nM and 6.2 nM, respectively. [2] In BAL cells challenged with human sPLA2, LY315920 at doses ranging from 0.1 μM–3 μM reduces the formation of thromboxane mediated by human sPLA2 in a concentration-dependent manner with an IC50 of approximately 0.8 μM. [2] In human conjunctival epithelial cell line (HCjE), LY315920 (10 μM) significantly inhibits all-trans-retinoic acid (RA) -induced membrane-associated mucin MUC16 expression by 100% at 24 hours and 99% at 48 hours. [3]in vivo: Ex vivo, LY315920 at doses ranging from 3 mg/kg to 30 mg/kg via i.v. inhibits human sPLA2-induced release of thromboxane from guinea pig BAL cells with ED50 of 16.1 mg/kg. [2] In Transgenic Mice Expressing Human sPLA2, both oral and i.v. administration of LY315920 (0.3 mg/kg–3 mg/kg) abolishes serum sPLA2 activity in a dose and time dependent manner. [2]

Anagliptin is a potent and selective DPP-4 inhibitor(IC50= 3.8 nM); > 10 fold less potent for DPP-8 and DPP-9.IC50 value: 3.8 nM [1]Target: DPP-4 inhibitorin vitro: In THP-1 cells, anagliptin reduced lipopolysaccharide-induced TNF-α production with inhibiting ERK phosphorylation and nuclear translocation of nuclear factor-κB [2]. lipopolysaccharide (LPS)- or palmitate-induced elevations of inflammatory cytokine mRNA expressions in RAW264.7 macrophages were shown to be significantly suppressed by co-incubation with a DPP-4 inhibitor, anagliptin (10μM), despite low DPP-4 expression in the RAW264.7 cells. Anagliptin also acted on 3T3-L1 adipocytes, weakly suppressing the inflammatory cytokine expressions induced by LPS and TNF-α. When 3T3-L1 and RAW cells were co-cultured and stimulated with LPS, the effects of anagliptin on the suppression of cytokine expressions in 3T3-L1 adipocytes were more marked, and became evident at the 10μM concentration [3].in vivo: Treatment with anagliptin for 16 wk significantly reduced accumulation of monocytes and macrophages in the vascular wall, SMC content in plaque areas, and oil red O-stained area around the aortic valve without affecting glucose tolerance or body weight. Quantitative analysis also showed that anagliptin reduced the area of atherosclerotic lesion in apoE-deficient mice [2]. Anti-inflammatory effects of anagliptin were also observed in vivo on the elevated hepatic and adipose expressions and serum concentrations of inflammatory cytokines in association with the suppression of hepatic NF-κB transcriptional activity, in LPS-infused mice [3].

Brinzolamide(AL 4862) is a potent carbonic anhydrase II inhibitor with IC50 of 3.19 nM.Target: carbonic anhydrase IIBrinzolamide (< 1 mg) ophthalmic suspension lowers intraocular pressure in Dutch-belted pigmented rabbits in a dose-dependent manner with an onset within 0.5 hour and a peak response by 1-2 hours. Brinzolamide (0.6 mg) ophthalmic suspension lowers intraocular pressure in laser-treated glaucomatous cynomolgus monkeys in a dose-dependent manner with an onset within 1 hour and a peak response by 3 hours. Brinzolamide dosages of 30 mg/kg, produces a 44% reduction in intestinal charcoal meal progression, but 1 and 10 mg/kg produced 8% and 18% decreases, respectively, in male CD-1 mice. Brinzolamide of 1 mg/kg, 10 mg/kg, and 30 mg/kg prolongs barbiturate sleep time by 57%, 15%, and 35%, respectively, in male CD-1 mice [1]. Brinzolamide (< 3%) produces significantly greater mean percent intraocular pressure reductions and mean intraocular pressure reductions compared with placebo in patients with primary, open-angle glaucoma or ocular hypertension. The optimal intraocular pressure-lowering concentration of brinzolamide is 1%, brinzolamide 1% is well tolerated by patients with primary open-angle glaucoma or ocular hypertension when administered twice daily [2].

MG-101 is a potent inhibitor of cysteine proteases including calpain I (Ki = 190 nM), calpain II (Ki = 220 nM), cathepsin B (Ki = 150 nM), and cathepsin L (Ki = 500 pM).IC50 value: 150 nM (Ki)Target: cysteine proteasein vitro: MG-101 is a calpain inhibitor (IC50 = 0.09 μM) that activates p53-dependent apoptosis in tumor cell lines. At 10-100 μM MG-101 dose-dependently prevents the degradation of IκBα and IκBβ by the ubiquitin-proteasome complex, which blocks activation of NFκB and the production of TNF and IL-1β, suggesting a potential therapeutic effect for inflammatory diseases.2 At 10 μM, MG-101 can inhibit nitric oxide production by activated macrophages by interfering with transcription of the inducible nitric oxide synthase gene. In HCT116 cells, MG-101 decreases cell viability and tumor growth, and induces apoptosis response through Bax translocation from cytosol to mitochondria. [1] in vivo: In mice bearing HCT116 xenografts, MG-101 (10 mg/kg i.p.) inhibits colon tumor formation. [1]

Bortezomib is a potent 20S proteasome inhibitor with Ki of 0.6 nM.Enalaprilat is an angiotensin-converting enzyme (ACE) inhibitor with IC50 of 1.94 nM.Target: ACEEnalaprilat has high affinity for human endothelial ACE with IC50 of 1.94 nM in vitro binding assay by displacing a saturating concentration of [125I]351A, a radiolabeled lisinopril analogue from ACE binding sites, and shows bradykinin/angiotensin I selectivity ratio of 1.00 calculated from double displacement experiments [1]. Enalaprilat attenuates the IGF-I induced neonatal rat cardiac fibroblast growth (30% reduction) in a concentration-dependent fashion, with IC50 of 90 mM [2].Administration of Enalaprilat induces a significant reduction of MAP at 70 minutes compared with the placebo group during haemorrhagic shock in rats, and results in a 50% reduction of CO, a general tendency of EB extravasation which is significant in the kidney and lungs, and a significant increase in ileal EB extravasation (53%) [3]. GM6001 is a broad spectrum matrix metalloprotease (MMP) inhibitor, with Ki of 0.4 nM, 0.5 nM, 27 nM, 3.7 nM, 0.1 nM, 0.2 nM, 3.6 nM, 13.4 nM, 0.36 nM for MMP-1/2/3/7/8/9/12/14/26, respectively.

TOK-001 is a multifunctional antiandrogen and CYP17 inhibitor (IC50=47 nM) in castration resistant prostate cancer (CRPC). Tadalafil is a PDE5 inhibitor with an IC50 value of 1.8 nM.IC50 Value: 1.8±0.4nM [1]Target: PDE 5Tadalafil is marketed in pill form for treating erectile dysfunction(ED) under the name Cialis, and under the name Adcirca for the treatment of pulmonary arterial hypertension. Tadalafil can elevate the level of cGMP in the corpus cavernosum and effectively improve ED of various causes and degrees.in vitro: Biochemical potencies (affinities) of these compounds for PDE5 determined by IC(50), K(D) (isotherm), K(D) (dissociation rate), and K(D) ((1/2) EC(50)), respectively, were the following: sildenafil (3.7 +/- 1.4, 4.8 +/- 0.80, 3.7 +/- 0.29, and 11.7 +/- 0.70 nM), tadalafil (1.8 +/- 0.40, 2.4 +/- 0.60, 1.9 +/- 0.37, and 2.7 +/- 0.25 nM); and vardenafil (0.091 +/- 0.031, 0.38 +/- 0.07, 0.27 +/- 0.01, and 0.42 +/- 0.10 nM). Thus, absolute potency values were similar for each inhibitor, and relative potencies were vardenafil >> tadalafil > sildenafil [1]. 0.5 ml tadalafil solutions with different concentrations were added (0.2, 0.1, 0.05 and 0.025 μg ml-1, respectively) into semen samples. In both groups, samples treated with 0.2 μg ml-1 tadalafil had significant increase in sperm motility after 2 h incubation [2].in vivo: The Tadalafil-treated group showed enhanced erectile function (intracavernosal pressure/mean arterial pressure) at 0.3, 0.5, 1, 3, and 5 Hz compared with diabetic group values at the respective frequencies (P <.05) that approached control values [3]. oral administration of tadalafil (20 mg) or sildenafil (100 mg) was given. In both groups, computer-assisted semen analysis parameters showed no significant difference. After the administration of tadalafil (2 h) and sildenafil (1 h), there was no significant difference observed in premature acrosome reaction incidence rate [2].Clinical trial: Study the Safety and Effectiveness of Tadalafil in Men With Problems Getting or Maintaining an Erection When Taken Prior to Desiring an Erection. Phase 3

Dalcetrapib (JTT-705; RO-4607381) is a rhCETP inhibitor with IC50 of 0.2 μM that increases the plasma HDL cholesterol. IC50 value: 0.2 uM [1]Target: CETPin vitro: Dalcetrapib modulates CETP activity. Dalcetrapib induces a conformational change in CETP, when added to human plasma. CETP-induced pre-β-HDL formation in human plasma is unchanged by Dalcetrapib ≤3 μM and increased at 10 μM. Dalcetrapib statistically and significantly increases pre-β-HDL formation [1]. Dalcetrapib achieves 50% inhibition of CETP activity in human plasma at a concentration of 9 μM [2]. Dalcetrapib inhibits the CETP activity of media in HepG2 in a dose-dependent manner [3].in vivo: Treatment with Dalcetrapib leads to significant increases in HDL-C levels. In hamsters injected with [3H]cholesterol-labeled autologous macrophages Dalcetrapib significantly increases fecal elimination of both [3H]neutral sterols and [3H]bile acids. Dalcetrapib increases plasma HDL-[3H]cholesterol [1]. Dalcetrapib has 95% inhibition of CETP activity in male Japanese white rabbits at an oral dose of 30 mg/kg. Dalcetrapib increases the plasma HDL cholesterol level by 27% and 54%, respectively, when given at oral doses of 30 mg/kg or 100 mg/kg once a day for 3 days to male Japanese white rabbits [2].

Mevastatin (Compactin; ML236B) inhibits HMGCR (HMG-CoA reductase) (Ki for acid form is 1 nM) which in turn inhibits isoprenoid biosynthesis and therefore blocks protein isoprenylation and reduces plasma cholesterol levels in humans. IC50 value: 1 nM (Ki)Target: HMGCRMevastatin induces apoptosis, arrests cancer cells in G1 phase and downregulates cdk 2, 4, and 6, cyclin D1 and E1, p21 and p27. Mevastatin suppresses TNF-induced NF-κB activation (IC50 = ~17 uM), which potentiates apoptosis in human myeloid leukemia cells and thus, may be useful in treating cancer.

Dafadine-A, an analog of dafadine, is a novel inhibitor of DAF-9 cytochrome P450 in the nematode Caenorhabditis elegans; also inhibits the mammalian ortholog of DAF-9(CYP27A1). IC50 value:Target: DAF-9(CYP27A1) inhibitorThe DAF-9 cytochrome P450 is a key regulator of dauer formation, developmental timing and longevity in the nematodeCaenorhabditis elegans. Here we describe the first identified chemical inhibitor of DAF-9 and the first reported small-molecule tool that robustly induces dauer formation in typical culture conditions. This molecule (called dafadine) also inhibits the mammalian ortholog of DAF-9(CYP27A1), suggesting that dafadine can be used to interrogate developmental control and longevity in other animals.Fenretinide is a synthetic retinoid deriverative, binding to the retinoic acid receptors (RAR) at concentrations necessary to induce cell death.

T-863(DGAT-1 inhibitor) is an orally active, selective and potent DGAT1 (Acyl-CoA:diacylglycerol acyltransferase 1) inhibitor that interacts with the acyl-CoA binding site of DGAT1, and inhibits triacylglycerol synthesis in cells.IC50 value:Target: DGAT1T863 causes weight loss, reduction in serum and liver triglycerides, and improved insulin sensitivity in obese mice.

PI-1840 is a potent and selective inhibitor for chymotrypsin-like (CT-L) (IC50 value = 27 ± 0.14 nM) over trypsin-like and peptidylglutamyl peptide hydrolyzing (IC50 values >100 μM) activities of the proteasome. IC50 value: 27 nM(CT-L activities of the proteasome) [1]Target: CT-L inhibitorin vitro: PI-1840 is over 100-fold more selective for the constitutive proteasome over the immunoproteasome. Mass spectrometry and dialysis studies demonstrate that PI-1840 is a noncovalent and rapidly reversible CT-L inhibitor. In intact cancer cells, PI-1840 inhibits CT-L activity, induces the accumulation of proteasome substrates p27, Bax, and IκB-α, inhibits survival pathways and viability, and induces apoptosis. Furthermore, PI-1840 sensitizes human cancer cells to the mdm2/p53 disruptor, nutlin, and to the pan-Bcl-2 antagonist BH3-M6 [1].in vivo: PI-1840 but not bortezomib suppresses the growth in nude mice of human breast tumor xenografts [1].

PF-04620110 is an orally active, selective and potent diglyceride acyltransferase-1 (DGAT1) inhibitor with IC50 of 19 nM.IC50 value: 19 nM [1]Target: DGAT1PF-04620110 and imipramine (internal standard) were separated using a Hypersil Gold C18 column, with a mixture of acetonitrile and 10 mm ammonium formate (90:10, v/v) as the mobile phase. The ion transitions monitored in positive-ion mode [M + H](+) of multiple-reaction monitoring were m/z 397.0 -260.2 for PF-04620110 and m/z 280.8 - 86.0 for imipramine. The detector response was specific and linear for PF-04620110 at concentrations within the range 0.05-50 μg/mL and the signal-to-noise ratios for the samples were ≥10 [2].

R-7128 is a nucleoside inhibitor of the HCV NS5B polymerase that acts as an RNA chain terminator and prevents elongation of RNA transcripts during replication.

Lovastatin, a HMG-CoA reductase inhibitor, is a cholesterol-lowering drug.SR3335 is a selective RORα synthetic ligand, directly binds to RORα (Ki 220 nM) but not other RORs, and functions as a selective partial inverse agonist of RORα in cell-based assays.

Sitagliptin is a potent inhibitor of DPP4 with IC50 of 19 nM in Caco-2 cell extracts.Omapatrilat is a dual inhibitor of the metalloproteases ACE and NEP with Ki values of 0.64 and 0.45 nM, respectively.

AHU-377 is a potent NEP inhibitor with an IC50 of 5 nM. AHU-377 is a component of the heart failure medicine LCZ696.

N6022 is a potent, selective, reversible, and efficacious S-Nitrosoglutathione reductase(GSNOR) inhibitor with IC50 of 8 nM.

XMD16-5 is a potent TNK2 inhibitor with IC50 values of 16 and 77 nM for the D163E and R806Q mutations, respectively.

Simvastatin is a competitive inhibitor of HMG-CoA reductase with Kd of 0.1-0.2 nM.

INT-747 is a potent and selective FXR agonist (EC50=99 nM) endowed with anticholestatic activity.

FIPI is a derivative of halopemide which potently inhibits both PLD1 and PLD2 with IC50s of 25 nM and 20 nM, respectively.

AM-2394 is a structurally distinct glucokinase activator (GKA). AM-2394 activates glucokinase (GK) with an EC50 of 60 nM.

BMS-303141 is a potent, cell-permeable ATP-citrate lyase (ACL) inhibitor with an IC50 value of 0.13 μM.CTS-1027 is a potent small molecule inhibitor of MMPs, with IC50s of 0.3 nM, 0.5 nM for MMP2, MMP13, respectively, and has > 1,000 fold selectivity over MMP1.

TM5441 is a plasminogen activator inhibitor-1 (PAI-1); inhibits several tumor cell lines with IC50 values between 9.7 and 60.3 μM.AHU-377 hemicalcium salt is a potent NEP inhibitor with an IC50 of 5 nM. AHU-377 is a component of the heart failure medicine LCZ696.

Roflumilast is a selective PDE4 inhibitor with IC50s of 0.7, 0.9, 0.7, and 0.2 nM for PDE4A1, A4, B1, and B2, respectively, without affecting PDE1, 2, 3 or 5 isoenzymes from various cells.

Cabotegravir is a potent HIV integrase inhibitor as an oral lead-in tablet and long-acting injectable for the treatment and prevention of HIV infection. Cabotegravir is an inhibitor of OAT1 (IC50 0.81 μM) and OAT3 (IC50 0.41 μM).IC50 value: 0.81 μM (OAT1), 0.41 μM (OAT3) [1]Target: OAT1, OAT3Cabotegravir is a potent HIV integrase inhibitor in clinical development as an oral lead-in tablet and long-acting injectable for the treatment and prevention of HIV infection.[2] Cabotegravir is an HIV-1 integrase inhibitor under development as a tablet for both oral lead-in therapy and long-acting (LA) injectable for intramuscular dosing.[3]

AT13387 is a selective potent Hsp90 inhibitor with IC50 of 18 nM in A375 cells, displays a long duration of anti-tumor activity.IC50 Value: 18 nM Target: Hsp90in vitro: AT13387 is a synthetic, orally bioavailable, small-molecule inhibitor of heat shock protein 90 (Hsp90) with potential antineoplastic activity. Hsp90 inhibitor AT13387 selectively binds to Hsp90, thereby inhibiting its chaperone function and promoting the degradation of oncogenic signaling proteins involved in tumor cell proliferation and survival. Hsp90, a chaperone protein upregulated in a variety of tumor cells, regulates the folding, stability and degradation of many oncogenic signaling proteins. AT13387 is a selective potent heat shock protein 90 (Hsp90) inhibitor with IC50 of 18 nM in A375 cells. The Kd for AT13387 binding is 0.7 nM.in vivo: AT13387 could be tolerated at doses of up to 70 mg/kg twice weekly or 90 mg/kg once weekly. Body weight loss in mice does not exceed 20% before recovering in all cases except one, and loss is highest following the second dose. Tumor growth inhibition is similar in NCI-H1975 for both dosing regimens. The maintenance of antitumor effects with such a prolonged off-treatment period is consistent with the extended pharmacodynamic action of AT13387 observed for mutant EGFR and other biomarkers in vitro and in vivo and the extended retention of AT13387 in tumors.

BMS-707035 is an HIV-1 integrase (IN) inhibitor with an IC50 value of 15 nM. IC50 Value: 15 nMTarget: HIV IntegraseBMS-707035 was scheduled to be evaluated in a Phase II study to assess the antiretroviral activity, safety, pharmacodynamics, and pharmacokinetics in 50 HIV-infected subjects using a 10-day randomized, double-blind, placebo-controlled, ascending multiple-dose study design.

JNJ-42165279 is a FAAH inhibitor with IC50 of 70 ± 8 nM and 313 ± 28 nM for hFAAH and rFAAH, respectively.IC50 value: 70 ± 8 nM (for hFAAH), 313 ± 28 nM (for rFAAH )Target：FAAHJNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channels, transporters, and receptors. JNJ-42165279 exhibits high selectivity against a panel of 50 receptors, enzymes, transporters, and ion-channels at 10 μM, at which concentration it does not produce >50% inhibition of binding to any of the targets. Fortunately, JNJ-42165279 also does not inhibit CYPS (1A2, 2C8, 2C9, 2C19, 2D6, 3A4) or hERG when tested at a 10 μM compound concentration. [1]in vivo: JNJ-42165279 exhibits excellent ADME and pharmacodynamic properties as evidenced by its ability to block FAAH in the brain and periphery of rats and thereby cause an elevation of the concentrations of anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA). The compound was also efficacious in the spinal nerve ligation (SNL) model of neuropathic pain. JNJ-42165279 exhibits relatively rapid clearance in the course of rat pharmacokinetic experiments, manifesting as a low AUC and Cmax; however, sufficiently high exposures were obtainable to support preclinical animal models. In a subsequent higher dose (20 mg/kg) oral PK experiment, compound concentrations were determined both in the plasma and brain of rats. [1]

PU-WS13 is a potent, Grp94-specific Hsp90 inhibitor of the purine scaffold class. Target: Hsp90PU-WS13 has been shown to reduce the viability of breast cancer cells that express high levels of cell surface HER2 and the viability of human multiple myeloma cells in vitro.Balicatib(AAE-581) is a potent and selective inhibitor of cathepsin K; 10-100 fold more potent in cell-based enzyme occupancy assays than against cathepsin B, L, and S.IC50 value:Target: cathepsin KThe cathepsin K inhibitor AAE-581 (balicatib) as the most advanced of them passed Phase II clinical trials in 2005. Eighty adult female Macaca fascicularis underwent bilateral ovariectomies and were dosed twice daily by oral gavage with balicatib at 0, 3, 10, and 50 mg/kg for 18 months (groups O, L, M, H, respectively). Approximately 1 month after treatment initiation, the 50 mg/kg dose was decreased to 30 mg/kg. Twenty animals underwent sham-ovariectomies (group S). Bone mass was measured at 3-6 month intervals. At 18 months, vertebra and femur were collected for histomorphometry.

Adapalene(CD-271; Differin), a synthetic retinoid, is a retinoic acid receptor agonist (RAR).Target: Retinoic acid receptor agonist (RAR)Adapalene is a third-generation topical retinoid primarily used in the treatment of mild-moderate acne and is also used (off-label) to treat keratosis pilaris as well as other skin conditions. Adapalene is possibly more effective than tretinoin 0.025% gel in the treatment of acne vulgaris [1].Thirty-six rats of either sex were divided into six groups (two control groups, and an etodolac, indomethacin, tretinoin and adapalene group) of six animals each. Each group was given different drugs or chemicals. The inhibitory activities of the drugs were determined on carrageenan-induced rat-paw oedema. The inhibition rate (53.48%) in the tretinoin group was found to be higher thanadapalene and controls (P < 0.05). Adapalene was found to have an inhibition rate of 10.28%, and when compared with the other groups, was found to have no statistically significant anti-inflammatory activity [2].

SW033291 is a small-molecule inhibitor of 15-PGDH (Ki=0.1 nM) that increases prostaglandin PGE2 levels in bone marrow and other tissues.IC50 value: 0.1 nM(Ki) [1]Target: 15-PGDHin vitro: SW033291 inhibition of 15-PGDH was noncompetitive versus PGE2 over concentrations up to 40 μM PGE2. SW033291 also demonstrated selective high-affinity interaction with 15-PGDH in thermal denaturation assays. Treatment of A549 cells with SW033291 increased PGE2 levels by 3.5-fold at 500 nM, with 50% of maximal stimulation (EC50) at ~75 nM [1].in vivo: mice injected with SW033291 closely phenocopied 15-PGDH knockout mice, with 10 mg per kg of weight (mg/kg) SW033291 inducing a twofold increase in PGE2 levels in bone marrow, colon, lung, and liver. Mice injected with SW033291 at 20 mg/kg daily for 7 days showed equivalent daily weights and activity as mice injected with vehicle-control and showed no adverse changes in blood counts or serum chemistry [1].

ML228(CID-46742353) is an activator of the Hypoxia Inducible Factor (HIF) pathway; potently activate HIF in vitro as well as its downstream target VEGF.IC50 value: 1 uM (EC50) [1]Target: HIF activatorML228 represents a novel chemotype available to the research community for the study of HIF activation and its therapeutic potential. Not only is the compound substantially different in structure from known HIF activators, ML228 lacks the acidic functional group almost universally present in PHD inhibitors, which may be important for certain disease applications.ML348 is a selective and reversible lysophospholipase 1 (LYPLA1) inhibitor (IC50 = 210 nM), Exhibits 14-fold selectivity for LYPLA1 over LYPLA2, Also selective over a panel of ~30 other serine hydrolases.target: LYPLA1 [1]IC 50： 210 nM [1]

Ramipril is an angiotensin-converting enzyme (ACE) inhibitor with IC50 of 5 nM.Target: ACERamipril is an angiotensin-converting enzyme (ACE) inhibitor with IC50 of 5 nM [1]. Ramipril enhances the activity of ACE-associated CK2 and the phosphorylation of ACE Ser1270 in cultured endothelial cells, but is unable to activate JNK or stimulate the nuclear accumulation of c-Jun in endothelial cells expressing a S1270A ACE mutant or in ACE-deficient cells. Prolonged Ramipril treatment increases ACE expression in primary cultures of human endothelial cells and in vivo (mouse lung), which can be prevented by pretreatment with the JNK inhibitor SP600125 [2].Chronic in vivo administration of Ramipril to rats at a dosage that has similar hypotensive effects in vitro HUVECs significantly reduces the rate of LPS-induced apoptosis compared to the other ACE inhibitors, which contrasts with the apoptosis effect in vitro [3]. Ramipril inhibits systolic blood pressure (SBP) with IC50 of 1.97 mg/kg in spontaneously hypertensive rats (SHR). When in combination with AT1-receptor blockade by candesartan-cilexetil increases SBP reduction synergistically rather than additively [4].

NCT-501 is a potent and selective theophylline-based inhibitor of aldehyde dehydrogenase 1A1 (ALDH1A1), inhibits hALDH1A1 with IC50 of 40 nM, typically shows better selectivity over other ALDH isozymes and other dehydrogenases (hALDH1B1, hALDH3A1, and hALDH2, IC50 >57 μM).IC50 value: 40 nMTarget: hALDH1A11) NCT-501 is well absorbed and distributed but rapidly metabolized and/or excreted. NCT-501 does penetrate the blood-brain barrier.2) NCT-501(ALDH1A1 inhibitor) inhibited functional properties, such as self-renewal property, migratory potential and induced sell sensitivity in cisplatin resistant cells. In all, NCT-501 in combination with Cisplatin showed a significant decrease in proliferating cells as compared to individual treatment.You can use NCT-501 (20nM)+ Cisplatin (5 M) to investigate the functional properties.[2]

Gabexate Mesylate is a Factor X inhibitor; serine protease inhibitor .Target: Factor XGabexate mesylate is a non-antigenic synthetic inhibitor of trypsin-like serine proteinases that is therapeutically used in the treatment of pancreatitis and disseminated intravascular coagulation and as a regional anticoagulant for hemodialysis. Values of the inhibition constant (K(i)) for gabexate mesylate binding to human and bovine tryptase were 3.4 x 10(-9) M and 1.8 x 10(-7) M (at pH 7.4 and 37.0 degrees ), respectively. Gabexate mesylate inhibited the fibrinogenolytic activity of human tryptase [1]. Gabexate Mesylate decreased the TNFalpha production of LPS-stimulated monocytes as shown by the inhibition of mRNA expression and increased the IL-10 production of LPS-stimulated monocytes. Gabexate Mesylate also suppressed the NFkappaB activity of LPS-stimulated monocytes. Inhibitory effect of Gabexate Mesylate on the TNFalpha production of activated human monocytes is mediated by the suppression of NFkappaB activation [2]. Gabexate mesylate inhibits competitively constitutive and inducible NO synthase (cNOS and iNOS, respectively), with Kivalues of 1.0×10 4M and 5.0×10 3M, respectively, at pH 7.4 and 37.0°C. gabexate mesylate increases iNOS mRNA expression in rat C6 glioma cells, as induced byE. colilipopolysaccharide plus interferon-γ. Gabexate mesylate inhibits dose-dependently nitrite production (i.e. NO release) in rat C6 glioma cells, as induced byE. colilipopolysaccharide plus interferon-γ [3].

Aminophylline is a competitive nonselective phosphodiesterase inhibitor that is used to treat airway obstruction from asthma or COPD.Target: PhosphodiesteraseAminophylline is a compound of the bronchodilator theophylline with ethylenediamine in 2:1 ratio. The ethylenediamine improves solubility, and the aminophylline is usually found as a dihydrate. Aminophylline is less potent and shorter-acting than theophylline. Its most common use is in the treatment of airway obstruction from asthma or COPD. It is used off-label as a reversal agent during nuclear stress testing. Aminophylline is a nonselective adenosine receptor antagonist and phosphodiesterase inhibitor.Adenosine is an endogenous extracellular messenger that can regulate myocardial oxygen needs. It acts through cellular surface receptors which effect intracellular signalling pathways to increase coronary artery blood flow, slow heart rate, block atrioventricular node conduction, suppress cardiac automaticity, and decrease β-adrenergic effects on contractility. Adenosine also antagonizes chronotropic and ionotropic effects of circulating catecholamines. Overall, adenosine decreases the heart's rate and force of contraction, which increases blood supply to the cardiac muscle. Given specific circumstances this mechanism (which is intended to protect the heart) may cause atropine-resistant refractory bradyasystole. Adenosine's effects are concentration-dependent. Adenosine's receptors are competitively antagonized by methylxanthines such as aminophylline. Aminophylline competitively antagonizes the cardiac actions of adenosine at the cell surface receptors. Thus, it increases heart rate and contractility.

DGAT-1 inhibitor 2 is an effective inhibitor of DGAT-1;antiobesity agents.IC50 value:Target: DGAT-1Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is one of two known DGAT enzymes that catalyze the final step in triglyceride synthesis. Findings from genetically modified mice as well as pharmacological studies suggest that inhibition of DGAT1 is a promising strategy for the treatment of obesity and type 2 diabetes.Aldose reductase-IN-1 is a inhibitor of aldose reductase with IC50 of 28.9 pM.IC50 value: 28.9 pMTarget: aldose reductaseDetailed information please refer to WO2014113380 A1 and US20130225592.Choline Fenofibrate (ABT-335) is the choline salt of fenofibric acid under clinical development as a combination therapy with rosuvastatin for the management of dyslipidemia. IC50 value:Target:Several clinical trials have been developed with Choline Fenofibrate on Reverse Cholesterol Transport, Macular Edema and Hypertriglyceridemia.Fludrocortisone Acetate is a synthetic mineralocorticoid, used to control the amount of sodium and fluids in your body. It is used to treat Addison's disease by decreasing the amount of sodium that is lost (excreted) in your urine，also used to increase blood pressure.

WAY-252623 (LXR-623) is a highly selective and orally bioavailable synthetic modulator of LXR.IC50 Value:Target: LXRin vitro: In nonhuman primates with normal lipid levels, WAY-252623 significantly reduced total (50-55%) and LDL-cholesterol (LDLc) (70-77%) in a time- and dose-dependent manner as well as increased expression of the target genes ABCA1/G1 in peripheral blood cells [1].in vivo: LXR-623 was absorbed rapidly with peak concentrations (C(max)) achieved at approximately 2 hours. The C(max) and area under the concentration-time curve increased in a dose-proportional manner. The mean terminal disposition half-life was between 41 and 43 hours independently of dose. LXR activation resulted in a dose-dependent increase in ABCA1 and ABCG1 expression [2]. Twelve cynomolgous monkeys maintained on normal chow were orally dosed with 0, 15 and 50 mg/kg/day of LXR-623 (n = 4 per dose group). Blood was collected prior to the first dose (day 0) to serve as a baseline and again on day 7. RNA prepared from whole blood was used for gene expression analysis of ABCA1 and ABCG1 by qPCR. In contrast to rodents, ABCG1 changed with much greater magnitude in primate blood cells than ABCA1 in response to LXR-623 at all doses tested [3].Benzbromarone is a highly effective and well tolerated non-competitive inhibitor of xanthine oxidase, used as an uricosuric agent, used in the treatment of gout.

Teneligliptin is a potent chemotype prolylthiazolidine-based DPP-4 inhibitor, which competitively inhibits human plasma, rat plasma, and human recombinant DPP-4 in vitro, with IC50s of approximately 1 nM.

TAK-063 is a highly potent, selective and orally active PDE10A inhibitor with IC50 of 0.30 nM; >15000-fold selectivity over other PDEs.IC50 value: 0.3 nM [1]Target: PDE10A inhibitorTAK-063 has potent inhibitory activity (IC50 = 0.30 nM), excellent selectivity (>15000-fold selectivity over other PDEs), and favorable pharmacokinetics, including high brain penetration, in mice. Oral administration of TAK-063 to mice elevated striatal 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) levels at 0.3 mg/kg and showed potent suppression of phencyclidine (PCP)-induced hyperlocomotion at a minimum effective dose (MED) of 0.3 mg/kg [1]. TAK-063 at 0.3 and 1 mg/kg, p.o., increased cAMP and cGMP levels in the rodent striatum and upregulated phosphorylation levels of key substrates of cAMP-dependent and cGMP-dependent protein kinases. TAK-063 at 0.3 and 1 mg/kg, p.o., strongly suppressed MK-801-induced hyperlocomotion that is often used as a predictive model for antipsychotic-like activity in rodents. TAK-063 did not affect plasma prolactin or glucose levels at doses up to 3 mg/kg, p.o. TAK-063 at 3 mg/kg, p.o., elicited a weak cataleptic response compared with haloperidol and olanzapine [2].

coein vivo: Zucker fatty rats and diet-induced dyslipidemic hamsters were dosed orally with A-922500 (0.03, 0.3, and 3-mg/kg), a potent and selective DGAT-1 inhibitor, for 14 days. Serum triglycerides were significantly reduced by the 3 mg/kg dose of the DGAT-1 inhibitor in both the Zucker fatty rat (39%) and hyperlipidemic hamster (53%) [1]. A 922500 confers weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depletes serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice [2]. The potent and selective DGAT-1 inhibitorA-922500 (0.03, 0.3 and 3 mg/kg, p.o.), dose-dependently attenuated the maximal postprandial rise in serum triglyceride concentrations in all species tested. At the highest dose of DGAT-1 inhibitor, the postprandial triglyceride response was abolished [3].Clinical trial: SR1078 is an agonist of retinoic acid receptor-related orphan receptor (ROR)α/γ.Fluvastatin sodium is a competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase (HMGCR), used to treat hypercholesterolemia and to prevent cardiovascular disease.Target: HMGCR Fluvastatin is a competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase (HMGCR), the enzyme that catalyzes the conversion of HMG-CoA to mevalonic acid, the rate-limiting step in cholesterol biosynthesis. Human hepatocellular carcinoma cell (HCC) studies indicate that Fluvastatin induces G2/M phase arrest. In the presence of Fluvastatin, HCC cells show a decrease of Bcl-2 and procaspase-9 expression, and an increase in Bax, cleaved caspase-3, and cytochrome c. Fluvastatin is antilipemic and is used to reduce plasma cholesterol levels and prevent cardiovascular disease.

JZL195 is a selective and efficacious dual FAAH/MAGL inhibitor with IC50 of 13 nM and 19 nM for mouse brain FAAH and MAGL respectively.IC50 value: 13 nM/19 nM (mouse brain FAAH/MAGL) [1]Target: dual FAAH/MAGL inhibitorin vitro: JZL195 shows only modest and incomplete inhibitory activity against NTE (IC50 >5 uM). At higher concentrations, JZL195 inhibited ABHD6 but not any of the other brain serine hydrolases detected in our competitive ABPP assays. JZL195 also inhibited rat and human FAAH and MAGL enzymes with IC50 values in the range of 10–100 nM based on competitive ABPP assays [1].in vivo: A time course analysis of mice given one administration ofJZL195 (20 mg/kg, i.p.) revealed that blockade of FAAH andMAGL lasted at least 10 h as judged by gel-based ABPP or AEAand 2-AG hydrolysis assays [1]. The effect of systemic injections of a range of doses of JZL195 and the pan-cannabinoid receptor agonist WIN55212 were performed 1 day following intraplantar injection of CFA in C57BL/6 mice. JZL195 and WIN55212 both reduced mechanical allodynia and thermal hyperalgesia, and produced catalepsy and sedation in a dose dependent manner. Unlike WIN55212, JZL195 reduced allodynia at doses below those at which side-effects were observed [2].

LW6 is a novel HIF-1 inhibitor with an IC50 of 4.4 μM.

INCB 024360 is a potent and selective IDO1 inhibitor with IC50 of 71.8 nM±17.5 nM.WAY-362450 is a potent, selective, and orally bioavailable FXR agonist with EC50 of 4 nM.

Apixaban is a highly selective, reversible inhibitor of Factor Xa with Ki of 0.08 nM and 0.17 nM in human and rabbit, respectively.

AGI-5198 is a novel R132H-IDH1 inhibitor, used for cancer treatment.

TRC051384 is a heat shock protein 70 (HSP70) inducer.

Clinofibrate (S-8527) is a hypelipidemic agent and a HMG-CoA reductase inhibitor.Linagliptin is a highly potent, selective DPP-4 inhibitor with IC50 of 1 nM.

SR1001 is a selective RORα and RORγ inverse agonist; inhibits TH17 cell differentiation and function.

Cilazapril Monohydrate is a angiotensin-converting enzyme (ACE) inhibitor used for the treatment of hypertension and congestive heart failure.Target: ACECilazapril is a new nonthiol group containing angiotensin converting enzyme (ACE) inhibitor. Cilazapril has been investigated in more than 4000 patients with all degrees of hypertension, as well as in the special patient groups such as the elderly, renally impaired, and patients with concomitant diseases, such as congestive cardiac failure or chronic obstructive pulmonary disease [1]. Cilazapril is a very potent and highly effective converting enzyme inhibitor. Doses well below 5 mg/day will probably suffice for therapeutic efficacy [2].Rivaroxaban is a highly potent and selective, direct Factor Xa (FXa) inhibitor, achieving a strong gain in anti-FXa potency (IC50 0.7 nM; Ki 0.4 nM).

Tiplaxtinin is a selective and orally efficacious inhibitor of plasminogen activator inhibitor-1 (PAI-1) with IC50 of 2.7 μM. Pitavastatin Calcium is a competitive inhibitor of the enzyme HMGCR (HMG-CoA reductase) results in a reduction in LDL cholesterol synthesisTarget: HMG-CoA reductasePitavastatin (usually as a calcium salt) is a member of the blood cholesterol lowering medication class of statins, marketed in the United States under the trade name Livalo. Like other statins, it is an inhibitor of HMG-CoA reductase, the enzyme that catalyses the first step of cholesterolsynthesis. It has been available in Japan since 2003, and is being marketed under licence in South Korea and in India. It is likely that pitavastatin will be approved for use in hypercholesterolaemia (elevated levels of cholesterol in the blood) and for the prevention of cardiovascular disease outside South and Southeast Asia as well. In the US, it received FDA approval in 2009. Most statins are metabolised in part by one or more hepatic cytochrome P450 enzymes, leading to an increased potential for drug interactions and problems with certain foods (such as grapefruit juice). Pitavastatin appears to be a substrate of CYP2C9, and not CYP3A4 (which is a common source of interactions in other statins). As a result, pitavastatin is less likely to interact with drugs that are metabolized via CYP3A4, which might be important for elderly patients who need to take multiple medicines.

Dolutegravir sodium is an inhibitor of HIV-1 integrase-catalyzed strand transfer with IC50 of 2.7 nM.

Perindopril erbumine is a potent ACE inhibitor of which is used to treat high blood pressure, heart failure or stable coronary artery disease.Target: ACEPerindopril is a long-acting ACE inhibitor. It is used to treat high blood pressure, heart failure or stable coronary artery disease in form of perindopril arginine (trade names include Coversyl, Coversum) or perindopril erbumine (trade name Aceon). According to the Australian government's Pharmaceutical Benefits Scheme website, based on data provided to the Australian Department of Health and Aging by the manufacturer, perindopril arginine and perindopril erbumine are therapeutically equivalent and may be interchanged without differences in clinical effect. However the dose prescribed to achieve the same effect will differ due to different molecular weights for the two forms. Perindopril is one of the most prescribed inhibitors of angiotensin converting enzyme, has a large evidence base, which allows to use it in patients with hypertension, diabetes mellitus type 2, coronary heart disease and chronic heart failure. In this review, the author focused on the evidence of organoprotecting properties of perindopril that lie outside lowering blood pressure.

Imidapril Hydrochloride is the hydrochloride salt of Imidapril, an angiotensin-converting enzyme (ACE) inhibitor with antihypertensive activity. Target: ACEAs a prodrug, Imidapril is converted by hydrolysis in the liver into its active form imidaprilat. Imidaprilat competitively binds to and inhibits ACE, thereby blocking the conversion of angiotensin I to angiotensin II. This prevents the potent vasoconstrictive actions of angiotensin II and results in vasodilation. Imidaprilat also decreases angiotensin II-induced aldosterone secretion by the adrenal cortex, which leads to an increase in sodium excretion and subsequently increases water outflow.

Debio 0932 ( CUDC-305 ) is a novel heat shock protein 90 (HSP90) inhibitor trong affinity for HSP90 alpha/beta, high oral bioavailability and potent anti-proliferative activity against a broad range of cancer cell lines (with a mean IC50 of 220 nmol/L) [1].target: HSP90 [1]IC50: 220 nmol/L [1]in vitro: H1993 and H1975 NSCLC cells were incubated with 1 μmol/L CUDC-305 for 7 hours and then cultured in compound-free medium for an additional 0, 17, or 24 hours, respectively, before being analyzed by Western blot [1]in vivo: CUDC-305 was delivered through oral gavage on an every-other-day (once every two days) dosing schedule at various doses up to 160 mg/kg-its maximum tolerated dose in nude mice. In survival studies in Balb/C nude mice, the highest dose was reduced to 120 mg/kg as a result of the compromised animal condition due to lung and brain tumor implantation surgeries. [1]

VX-222 (VCH-222) is a novel, potent and selective inhibitor of HCV polymerase with IC50 of 0.94-1.2 μM, 15.3-fold less effective for mutant M423T, and 108-fold less effective for mutant I482L.IC50 Value: 0.94 μM (HCV NS5B 1a); 1.2 μM (HCV NS5B 1b)Target: HCVVX-222 is a small molecule non-nucleoside inhibitor of HCV NS5B polymerase that is being investigated for the treatment of hepatitis C virus infection. VX-222 exhibits non-competitive and selective inhibition in HCV NS5B of genotype 1a and 1b, with IC50 of 0.94 and 1.2 μM, respectively. VX-222 selectively inhibits the replication of subgenomic HCV genotype 1a and 1b with an EC50 of 22.3 and 11.2 nM, respectively. [1] Similarly, a recent study shows that VX-222 inhibits the 1b/Con1 HCV subgenomic replicon, with an EC50 of 5 nM. In rats and dogs, VCH-222 displays fine pharmacokinetic pro le, including low total body clearance and excellent oral bioavailability (greater than 30%) and good ADME properties. VCH-222 is biotransformed by several enzymes (CYP1A1, 2A6, 2B6, 2C8, CYP 3A4, UGT1A3) and is predicted to be actively transported in liver and excreted mainly intact in bile or as glucuronide adducts.

Otamixaban(FXV673) is a potent (Ki = 0.5 nM), selective, rapid acting, competitive and reversible fXa inhibitor that effectively inhibits both free and prothrombinase-bound fXa.IC50 value:Target: Factor Xa Otamixaban is a potent (Ki = 0.5 nM), selective, rapid acting, competitive and reversible fXa inhibitor that effectively inhibits both free and prothrombinase-bound fXa. In vivo experiments have demonstrated that Otamixaban is highly efficacious in rodent, canine and porcine models of thrombosis. In addition, recent clinical findings indicate that Otamixaban is efficacious, safe and well tolerated in humans and therefore has considerable potential for the treatment of acute coronary syndrome. This review article chronicles the discovery and pre-clinical data surrounding the fXa inhibitor Otamixaban as well as the recent clinical findings in humans.

Pravastatin sodium is an HMG-CoA reductase inhibitor against sterol synthesis with IC50 of 5.6 μM.Target: HMG-CoA reductasePravastatin (marketed as Pravachol or Selektine) is a member of the drug class of statins, used in combination with diet, exercise, and weight-loss for lowering cholesterol and preventing cardiovascular disease.Pravastatin is primarily used for the treatment of dyslipidemia and the prevention of cardiovascular disease. It is recommended to be used only after other measures such as diet, exercise, and weight reduction have not improved cholesterol levels.The evidence for the use of pravastatin is generally weaker than for other statins. The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT), failed to demonstrate a difference in all-cause mortality or nonfatal myocardial infarction/fatal coronary heart disease rates between patients receiving pravastatin 40mg daily (a common starting dose) and those receiving usual care.

Elvitegravir is an HIV integrase inhibitor for HIV-1IIIB, HIV-2EHO and HIV-2ROD with IC50 of 0.7 nM, 2.8 nM and 1.4 nM, respectively.

Zofenopril Calcium(SQ26991) is an antioxidant that acts as an angiotensin-converting enzyme inhibitor.Target: ACEZofenopril is a pro-drug designed to undergo metabolic hydrolysis yielding the active free sulfhydryl compound zofenoprilat, which is an angiotensin converting enzyme (ACE) inhibitor [1]. Zofenopril promotes the regeneration of peripheral nerve injuries in rat models [2]. Zofenopril increases SR calcium cycling and stimulates active calcium uptake into the SR [3].Celastrol is a proteasome inhibitor, potently and preferentially inhibits the chymotrypsin-like activity of a purified 20S proteasome (IC50=2.5 μM). DASA-58 is a highly specific small molecule PKM2 activator. DASA-58 inhibits LPS-induced Hif-1a and IL-1b, as well as the expression of a range of other Hif-1a-dependent genes.Target: HifDASA-58 enhances PKM2 activity by inducing the tetramer formation.PF-04457845 is a highly efficacious and selective FAAH inhibitor with IC50 values is 7.2±0.63 nM and 7.4±0.62 nM for hFAAH and rFAAH, respectively.PF-3845 is a selective fatty acid amide hydrolase (FAAH) inhibitor (Ki = 0.23 μM); showing negligible activity against FAAH2.IC50 value: 0.23 uMTarget: FAAHPF-3845 selectively inhibits FAAH by carbamylating FAAH's serine nucleophile [1]. PF-3845 treated mice (10 mg/kg, i.p.) shows rapid and complete inactivation of FAAH in the brain, as judged by competitive activity-based protein profiling (ABPP) with the serine hydrolase-directed probe fluorophosphonate (FP)-rhodamine. PF-3845 shows a long duration of action up to 24 hour. PF-3845-treated mice also shows dramatic (>10-fold) elevation in brain levels of AEA and other NAEs (N-pamitoyl ethanolamine [PEA] and N-oleoyl ethanolamine [OEA]). FAAH is AEA-degrading enzyme fatty acid amide hydrolase. PF-3845 (1–30 mg/kg, oral administration [p.o.]) causes a dose dependent inhibition of mechanical allodynia with a minimum effective dose (MED) of 3 mg/kg (rats are analyzed at 4 hour post dosing with PF-3845). At higher doses (10 and 30 mg/kg), PF-3845 inhibits pain responses to an equivalent, if not greater, degree than the nonsteroidal anti-inflammatory drug naproxen (10mg/kg, p.o.) [1]. PF-3845 (10 mg/kg, i.p.) significantly reverses LPS-induced tactile allodynia, but doesn't modify paw withdrawal thresholds in the saline-injected paw [2].

Apremilast is a novel phosphodiesterase 4 (PDE4) inhibitor, regulates inflammation through multiple cAMP downstream effectorsApremilast inhibits PDE4 with an IC50 of 74 nM using 1 μM cAMP as substrate.

Benazepril hydrochloride, an angiotensin converting enzyme inhibitor, which is a medication used to treat high blood pressure.Target: angiotensin converting enzyme (ACE)Benazepril hydrochloride is a medication used to treat high blood pressure (hypertension), congestive heart failure, and chronic renal failure. Upon cleavage of its ester group by the liver, benazepril hydrochloride is converted into its active form benazeprilat, a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor [1].Animals were randomly divided into 4 groups: sham STNx group (control), STNx group, morning benazepril hydrochloride group (MB) and evening benazepril hydrochloride group (EB).Benazepril hydrochloride was intragastrically administered at a dose of 10 mg/kg/day at 07:00 and 19:00 in the MB group and EB group respectively for 12 weeks. All the animals were synchronized to the light:dark cycle of 12:12 for 12 weeks. Systolic blood pressure (SBP), 24-h urinary protein excretion and renal function were measured at 11 weeks. Blood samples and kidneys were collected every 4 h throughout a day to detect the expression pattern of renin activity (RA), angiotensin II (AngII) and aldosterone (Ald) by radioimmunoassay (RIA) and the mRNA expression profile of clock genes (bmal1, dbp and per2) by real-time PCR at 12 weeks. Our results showed that no significant differences were noted in the SBP, 24-h urine protein excretion and renal function between the MB and EB groups. There were no significant differences in average Ald and RA content of a day between the MB group and EB group. The expression peak of bmal1 mRNA was phase-delayed by 4 to 8 h, and the diurnal variation of per2 and dbp mRNA diminished in the MB and EB groups compared with the control and STNx groups. It was concluded when the similar SBP reduction, RAAS inhibition and clock gene profile were achieved with optimal dose of benazepril hydrochloride, morning versus evening dosing of benazepril hydrochloride has the same renoprotection effects [2].Clinical indications: Congestive heart failure; End stage renal disease; HypertensionFDA Approved Date: Toxicity: headaches; cough; Anaphylaxis; angioedema; hyperkalemia

GSK 2830371 is a highly selective Wip1 phosphatase inhibitor with IC50 of 6 nM.Alogliptin benzoate(SYR 322) is a potent, selective inhibitor of DPP-4 with IC50 of <10 nM, exhibits greater than 10,000-fold selectivity over DPP-8 and DPP-9.IC50 value: <10 nMTarget: DPP4Alogliptin is an orally administered, anti-diabetic drug in the DPP-4 inhibitor class. A randomized clinical trial reporting in 2011 aimed to determine the efficacy and safety of alogliptin versus placebo and voglibose among newly diagnosed Type 2 diabetes patients in Japan. The main outcome indicated that alogliptin was statistically superior to both comparitors. A randomized clinical trial reporting in 2012 aimed to demonstrate that alogliptin was "non-inferior" to a "very low fat/calorie traditional Japanese diet" among newly diagnosed Type 2 diabetes patients in Japan. The outcome indicated that both the drug and dietary treatments comparably impacted indicators of the diabetic condition, such as HbA1c levels and glycemic efficacy. The drug treatment had its impact without changing body mass index (BMI), but the dietary treatment was accompanied by a significant reduction in the BMI…

STF-118804 is a highly specific NAMPT inhibitor; reduces the viability of most B-ALL cell lines with IC50 <10 nM.IC50 value:Target: NAMPT inhibitorin vitro: improves survival in an orthotopic xenotransplant model of high-risk acute lymphoblastic leukemia, and targets leukemia stem cells. STF-118804 displays distinctive cytotoxicity by inducing apoptosis without causing a phase-specific cell cycle arrest. Over-expression of NAMPT rendered 293T cells more resistant to STF-118804 resulting in a higher IC50 (106 nM, 95% CI 74–151 nM) compared to control cells (17 nM, 95% CI 13–23 nM), further confirming that NAMPT protein levels dictate sensitivity to STF-118804 [1].in vivo: STF-118804 displayed high efficacy in a xenograft model of ALL. Mice treated with STF-118804 over a 20-day period survived an average of 34 days longer than vehicle-treated animals. During treatment, bioimaging showed regression of tumor followed by suppression of disease. STF-118804 was tolerated in the efficacious dose range, and the absence of adverse physical or pathological effects indicated that toxicity was not limiting in a 20-day study of mock transplanted mice [1].

HA130 is a selective ATX (autotaxin) inhibitor with IC50 of 28 nM. IC50 value: 28 nM [2]Target: ATXin vitro: HA130 completely blocks the ability of ATX to promote TEM (transendothelial migration). HA130 at 0.3 μM completely ablates the activity of ATX on TK1 uropod formation. [1]in vivo: HA130 instantaneously lowers plasma levels of LPA in mice after intravenous administration. HA130 is an inhibitor of the enzymatic activity of ATX, slows T cell migration across lymph node HEVs. HA130 decreased the "outside HEVs/inside HEVs" ratio by 3-4-fold, compared to vehicle-treated animals vehicle (p < 0.01 for both PLNs and MLNs). [1]NVP-AUY922 is a highly potent HSP90 inhibitor with IC50 of 13 nM/21 nM for for HSP90α/β, respectively, and has weaker potency against the HSP90 family members GRP94 and TRAP-1.

MK-8245 is a liver-targeting inhibitor of stearoyl-CoA desaturase (SCD) with IC50 of 1 nM for human SCD1 and 3 nM for both rat SCD1 and mouse SCD1, with anti-diabetic and anti-dyslipidemic efficacy.IC50 value: 1 nM (hSCD1) [1]Target: SCD1in vitro: MK-8245, a phenoxy piperidine isoxazole derivative, has been identified as a potent and liver-specific SCD inhibitor. It contains a tetrazole acetic acid moiety, which is the key molecule for OATPs recognition and liver-targeting. MK-8245 displays similar potencies against human, rat and mouse SCD1 with IC50 values of 1 nM for human SCD1 and 3 nM for both rat SCD1 and mouse SCD1. MK-8245 exhibits a significant SCD inhibition in the rat hepatocyte assay which contains functional, active OATPs with IC50 of 68 nM, while being only weakly active in the HepG2 cell assay which is devoid of active OATPs with IC50 of ~1 μM. MK-8245 displays highly selective activity for the Δ-5 and Δ-6 desaturases (i.e., >100000 μM vs rat and human Δ5D and Δ6D as assessed in the HepG assay [1].in vivo: Administration of MK-8245 at 10 mg/kg in mice exhibits a tissue distribution profile concentrated in the liver. It shows a liver-to-Harderian gland ratio of 21, suggesting a high degree of liver-targeting compared to a systemically distributed compound with liver-to-Harderian gland ratio of 1.5. Oral dosing of MK-8245 in mice, rats, dogs, and rhesus monkeys demonstrates that MK-8245 is distributed mainly to the liver, with low exposure in tissues associated with potential adverse events. The liver-to-skin ratios are >30:1 in all four species. Administration of MK-8245 to eDIO mice before the glucose challenge improves glucose clearance in a dose-dependent manner with ED50 of 7 mg/kg.

Quinacrine is a fluorescent probe for the conformational transitions of the cholinergic receptor protein. Quinacrine shows activity in the low μM range with a mean IC50 of 2.30 μM In the patient AML cells.IC50 value: 2.30 μM (for AML cells)Target:in vitro: Quinacrine is a fluorescent probe for the conformational transitions of the cholinergic receptor protein in its membrane-bound state.[1] In the patient AML samples, Quinacrine showed activity in the low μM range with a mean IC50 of 2.30 μM, statistically significantly lower than that of normal PBMCs; 3.54 μM (P=0.0327; Student's t-test). Samples from patients with chronic lymphocytic, acute myeloid and lymphocytic leukemias as well as peripheral blood mononuclear cells (PBMC) were tested in response to 1266 compounds from the LOPAC1280 library. 25 compounds were defined as hits with activity in all leukemia subgroups (<50% cell survival compared with control) at 10 μM drug concentration. Only Quinacrine showed concurrent high activity in all leukemia subgroups and low activity in normal PBMCs and was, therefore, selected for further preclinical evaluation. Quinacrine also induced early inhibition of both DNA and protein synthesis. Quinacrine have repositioning potential for treatment of acute myeloid leukemia by targeting of ribosomal biogenesis.[2]

Enasidenib is a first-in-class, oral, potent, reversible, selective inhibitor of the IDH2 mutant enzymes. P7C3 is a NAMPT activator. P7C3 can enhance learning and memory in aged rats. Protects newborn neurons in the dentate gyrus by mitigating cell death. In vitro: Administration of active P7C3 chemicals to cells treated with doxorubicin, which induces NAD depletion, led to a rebound in intracellular levels of NAD and concomitant protection from doxorubicin-mediated toxicity. In vivo: P7C3 is orally bioavailable, crosses the blood-brain barrier, and is non-toxic at doses several fold higher than the efficacious dose.An easily administered pro-neurogenic compound. The administration of P7C3 is 10mg/ kg( IP) in rats. Administration of P7C3 to normal mice, as well as npas3-/- mice, enhance survival of neurons subsequent to their birth in the SGZ.

Quinapril is a prodrug that belongs to the angiotensin-converting enzyme (ACE) inhibitor class of medications.Target: ACEQuinapril is an angiotensin-converting enzyme inhibitor (ACE inhibitor) used in the treatment of hypertension and congestive heart failure. Quinapril is rapidly de-esterified after absorption to quinaprilat (the active diacid metabolite), a potent angiotensin converting enzyme (ACE) inhibitor. Quinapril is now firmly established as an effective and well tolerated ACE inhibitor for the treatment of patients with hypertension and congestive heart failure. Quinapril 40 mg/day also significantly reduced the incidence of ischaemic events in patients undergoing CABG in one study [1, 2]. An overview of 32 clinical trials of ACE inhibitors in heart failure showed that no significant heterogeneity in mortality was found among enalapril, ramipril, quinapril, captopril, lisinopril, benazepril, perindopril and cilazapril. Initiation of therapy with captopril, ramipril, and trandolapril at least 3 days after an acute MI resulted in all-cause mortality risk reductions of 18 to 27% [3].

Trelagliptin(SYR-472) is a long acting dipeptidyl peptidase-4 (DPP-4) inhibitor that is being developed for the treatment of type 2 diabetes (T2D). IC50 value:Target: DPP4Two Phase II clinical studies have been completed with Efficacy and Safety of SYR-472 in Subjects With Type 2 Diabetes Mellitus. Phase III clinical studies with trelagliptin in Japan to evaluate its safety and efficacy in a once-weekly oral treatment regimen. Currently, all available DPP-4 inhibitors are dosed once-daily. A once-weekly treatment, such as trelagliptin, would provide patients with a convenient treatment alternative and has the potential to improve treatment compliance.Leupeptin hemisulfate is a reversible, competitive serine/cysteine protease inhibitor, which has been shown to inhibit cathepsins B, H, L, and S, calpain, and trypsin. Leupeptin hemisulfate is an orally active, antioxidant and anti-inflammatory agent.Bay 60-7550 is a selective inhibitor of PDE2 with Ki of 3.8±0.2 nM, also is a modulator of NO.VR23 is a small molecule that potently inhibited the activities of trypsin-like proteasomes (IC50 = 1 nM), chymotrypsin-like proteasomes (IC50 = 50-100 nM), and caspase-like proteasomes (IC50 = 3 μM).IC50 value: 1 nM (trypsin-like proteasome), 50-100 nM(chymotrypsin-like proteasome), 3 μM (caspase-like proteasome)Target: proteasomein vitro: VR23 is a novel proteasome inhibitor targeting β2 of the 20S proteasome subunit. VR23 produces a synergistic effect in killing multiple myeloma cells, including those that were resistant to bortezomib. VR23 as a structurally novel proteasome inhibitor with desirable properties as an anticancer agent.in vivo: VR23 shows effective antitumor and antiangiogenic activities in mice.

PF-8380 is a potent autotaxin inhibitor with an IC50 of 2.8 nM in isolated enzyme assay and 101 nM in human whole blood.

Doxycycline (hyclate) is a tetracycline antibiotic and broad-spectrum metalloproteinase (MMP) inhibitor.

Raltegravir (potassium salt) is a potent integrase (IN) inhibitor, used to treat HIV infection.Tilorone dihydrochloride is the first recognized synthetic, small molecular weight compound that is an orally active interferon inducer, used as an antiviral drug.

SR12813 is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, with an IC50 value of 0.85 μM.

BMS-779788 is a LXR partial agonist with IC50 values of 68 nM for LXRα and 14 nM for LXRβ.

T-5224 is a selective inhibitor of c-Fos/activator protein (AP)-1 for rheumatoid arthritis therapy, and inhibits MMP activity with IC50s of 10 nM for both MMP-3 and MMP-13.

Sitagliptin phosphate monohydrate is a potent inhibitor of DPP4 with IC50 of 19 nM in Caco-2 cell extracts

BAY 87-2243 is a highly potent and selective hypoxia-inducible factor-1 (HIF-1) inhibitor.

Ezatiostat is a glutathione analog inhibitor of glutathione S-transferase P1-1 (GSTP1-1).

Dabigatran ethyl ester hydrochloride is a potent inhibitor of ribosyldihydronicotinamide dehydrogenase (NQO2) with an IC50 value of 0.8 μM and a thrombin inhibitor.LX-1031 is a potent, orally available tryptophan 5-hydroxylase (TPH) inhibitor that reduces serotonin (5-HT) synthesis peripherally.

GW 4064 is a potent FXR agonist with EC50 of 65 nM.

AZD7545 is a novel, selective small-molecule inhibitor of PDHK2 (PDH kinase2) with an IC50 of 36.8 nM and 6.4 nM for PDHK1 and PDHK2 respectively.IC50 Value: 36.8 nM (PDHK1); 6.4 nM (PDHK2) [1]Target: PDHK1/2in vitro: The IC50 values for inhibition of PDHK2 and PDHK1 by AZD7545 were 6.4 ± 2.2 nM (n = 6) and 36.8 ± 18 nM (n = 3) respectively. Other compounds in this series inhibited both PDHK1 and PDHK2 and a consistent trend of reduced potency (5-15-fold) towards PDHK1, as compared with PDHK2, was observed. In contrast, AZD7545 and related compounds failed to inhibit PDHK4 and paradoxically, at higher concentrations (>10 nM), AZD7545 stimulated PDHK4 activity [1]. In the presence of PDHK2, AZD7545 increased PDH activity with an EC(50) value of 5.2 nM. In rat hepatocytes, the rate of pyruvate oxidation was stimulated 2-fold (EC(50) 105 nM) [2].in vivo: A single dose of AZD7545 to Wistar rats increased the proportion of liver PDH in its active, dephosphorylated form in a dose-related manner from 24.7 to 70.3% at 30 mg/kg; and in skeletal muscle from 21.1 to 53.3%. A single dose of 10 mg/kg also significantly elevated muscle PDH activity in obese Zucker (fa/fa) rats. Obese, insulin-resistant, Zucker rats show elevated postprandial glucose levels compared with their lean counterparts (8.7 versus 6.1 mM at 12 weeks old). AZD7545 (10 mg/kg) twice daily for 7 days markedly improved the 24-h glucose profile, by eliminating the postprandial elevation in blood glucose [2]. An interestingobservation is that administration of maximally effective doses of AZD7545 and related compounds to rats results in the near-complete activation of PDH activity in liver, where PDHK2 is the major isoenzyme, while only partial activation of PDH activity is achieved in skeletal muscle and heart, tissues which express high levels of PDHK4. For example, following administration of a maximally effective dose of compound K (30 mg/kg) the percentage of PDH present in the active (dephosphorylated) state in liver is elevated from 35.3 ± 4.0% to 90.2 ± 2.2% while in skeletal muscle and heart PDH activity plateaus at 64.3 ± 2.3% and 61.8 ± 4.3% respectively. Further evidence for a link between in vitro isoenzyme selectivity and in vivo activity comes from the observation that in fasted rats the ability of AZD7545 toelevate PDH activity in liver is intact, while the activation of skeletal muscle PDH activity in response to the compound is severely blunted [1].

NVP-BEP800(VER82576) is a novel, fully synthetic, oral Hsp90 inhibitor with an IC50 of 0.058 ± 0.006 μM.

IC50 Value: 58 nMTarget: HSP90in vitro: NVP-BEP800 is an ATP-competitive inhibitor of Hsp90β with an IC50 of 58 nM, exhibiting >70-fold selectivity against Hsp90 family members Grp94 and Trap-1 with IC50 values of 4.1 μM and 5.5 μM, respectively. NVP-BEP800 displays no inhibitory activity against the closely related GHKL ATPase, topoisomerase II, and the structurally unrelated ATPase, Hsp70 at the concentration of 10 μM. NVP-BEP800 potently inhibits the proliferation of various tumor cell lines with GI50 values ranging from 38 nM in A375 to 1.05 μM in PC3, and primary human tumors with the mean IC50 of 0.75 μM and IC70 of 1.8 μM. NVP-BEP800 treatment at the concentration of five times the GI50 increases the percentage of G2-M phase in A2058 and A549 cells and sub-G1 phase in BT-474, HCT116, A2058 and A549 cells by 29.5%, 33.6%, 42.7%, 12.1%, 5.9% and 7.1%, respectively. in vivo: Oral administration of NVP-BEP800 at 15 or 30 mg/kg/day for 15 days causes a dose-dependent reduction in B-Raf and Akt phosphorylation levels, and displays significant dose-dependent antitumor efficacy in the A375 melanoma xenograft model with the T/C values of 53% and 6% at the dose of 15 and 30 mg/kg/day, respectively, suggesting almost complete tumor inhibition at 30 mg/kg/day. Administration of NVP-BEP800 induces dose-dependent increase of Hsp90-p23 complex dissociation and reductions in the levels of steady-state ErbB2, phospho-Akt and phospho-S6, in BT-474 breast cancer xenografts, and exhibits significant antitumor activity with 38% tumor regression at dose of 30 mg/kg/day and a T/C of 36% at dose of 15 mg/kg/day.

Paeoniflorin is a herbal constituent extracted from the root of Paeonia albiflora Pall.Target: OthersPaeoniflorin (PF) is the principal bioactive component of Radix Paeo- niae alba, which is widely used in Traditional Chinese Medicine for the treatment of neurodegenerative disorders such as Parkinson's disease(PD) [1]. Paeoniflorin, a compound found in white peony that inhibited the production of testosterone and promoted the activity of aromatase, which converts testosterone into estrogen [2]. Treatment of cells with paeoniflorin but not glycyrrhizin resulted in enhanced phosphorylation and acquisition of the deoxyribonucleic acid-binding ability of heat shock transcription factor 1 (HSF1), as well as the formation of characteristic HSF1 granules in the nucleus, suggesting that the induction of HSPs by paeoniflorin is mediated by the activation of HSF1. Also, thermotolerance was induced by treatment with paeoniflorin but not glycyrrhizin. Paeoniflorin had no toxic effect at concentrations as high as 80 microg/ mL (166.4 microM). To our knowledge, this is the first report on the induction of HSPs by herbal medicines [3].

T0901317 is a potent and selective agonist for both LXR and FXR, with EC50 of ~50 nM and 5 μM, respectively, inhibits nuclear factor/κB (NF/κB)target: LXR, FXR;IC 50: 50 nM and 5 μM.In vitro: upregulates the expression and activity of TM, T0901317 treatment inhibits nuclear factor κB (NF/κB) signaling and the secretion of high glucose induced proinflammatory mediators, including tumor necrosis factor α and interleukin 1β in GECs. [1]T0901317 enhances the interaction between LXR α and the transcriptional coactivator, p300, in GEC extracts. [1]In vivo: The reference dose is 10mg/kg/d. You can dilute the product in 0.5% carboxymethylcellulose. Administration of T0901317 does not lead to severe myocardial lipid accumulation in rats despite of its high plasma availability. [1] Administration of T0901317 to high-fat fed rats augments diet-induced hyperlipidemia. T0901317 completely restores glucose transporter 4 expression and insulin-stimulats Akt substrate of 160 kDa phosphorylation in all investigated muscles.[2]

AGI-6780 that potently and selectively inhibits the tumor-associated mutant IDH2R140Q with IC50 of 23±1.7 nM. AGI-6780 is less potent against IDH2WT with IC50 of 190±8.1 nM.

Avanafil(TA-1790) is a potent and highly selective phosphodiesterase-5(PDE-5) inhibitor(IC50=5.2 nM) for erectile dysfunction; lower selectivity against PDE1, PDE6, and PDE11.IC50 value: 5.2 nM [1]Target: PDE5Avanafil is highly selective toward PDE5 and against all other PDE isozymes tested. Lower selectivity against PDE1, PDE6, and PDE11 is consistent with results from randomized, placebo-controlled, phase 3 trials in which musculoskeletal and hemodynamic adverse events were reported in <2% of patients and no color vision-related abnormalities were reported with avanafil doses up to 200mg once daily [2]. Intraduodenal doses of avanafil or sildenafil (0.1 and 1 mg/kg) potentiated the AUC of nitroglycerin induced hypotension. However, the potentiating effect of avanafil at 1 mg/kg was significantly weaker than that of sildenafil (p <0.05) [3].

FTI-277 Hcl is an inhibitor of farnesyl transferase (FTase); a highly potent Ras CAAX peptidomimetic which antagonizes both H- and K-Ras oncogenic signaling.IC50 value:Target: FTase inhibitorin vitro: Treatment with FTI-277 (20 microM) for 48 h prior to irradiation led to a significant decrease in survival of radioresistant cells expressing the 24-kDa isoform (HeLa 3A) but had no effect on the survival of control cells (HeLa PINA). The radiosensitizing effect of FTI-277 is accompanied by a stimulation of postmitotic cell death in HeLa 3A cells and by a reduction in G(2)/M-phase arrest in both cell types [1]. Treatment of PC-3 cells with GGTI-298 and FTI-277 inhibited migration and invasion in a time- and dose-dependent manner [3].in vivo: FTI-277 treatment prevented increased PTP-1B and PTEN protein expression in burned mice as compared with vehicle alone. In contrast, FTI-277 did not significantly alter protein expression of PTP-1B and PTEN in sham-burned mice [2].

Enalapril Maleate, the active metabolite of enalapril, is an angiotensin-converting enzyme (ACE) inhibitor.Target: ACEEnalapril is a prodrug that belongs to the angiotensin-converting enzyme (ACE) inhibitor class of medications. It is rapidly metabolized in the liver to enalaprilat following oral administration. Enalaprilat is a potent, competitive inhibitor of ACE, the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATII). ATII regulates blood pressure and is a key component of the renin-angiotensin-aldosterone system (RAAS). Enalapril may be used to treat essential or renovascular hypertension and symptomatic congestive heart failure [1].

Orlistat is a general lipase inhibitor with IC50 of 122 ng/ml for PL from human duodenal juice.Target: lipase inhibitorOrlistat (also known as tetrahydrolipstatin) is a drug designed to treat obesity. It is marketed as a prescription drug under the trade name Xenical by Roche in most countries, and is sold over-the-counter as Alli by GlaxoSmithKline in the United Kingdom and the United States. Its primary function is preventing the absorption of fats from the human diet by acting as a lipase inhibitor, thereby reducing caloric intake. It is intended for use in conjunction with a healthcare provider-supervised reduced-calorie diet.Orlistat is the saturated derivative of lipstatin, a potent natural inhibitor of pancreatic lipases isolated from the bacterium Streptomyces toxytricini. However, due to its relative simplicity and stability, orlistat was chosen over lipstatin for development as an anti-obesity drug. The effectiveness of orlistat in promoting weight loss is definite, though modest. Pooled data from clinical trials suggest that people given orlistat in addition to lifestyle modifications, such as diet and exercise, lose about 2–3 kilograms (4.4–6.6 lb) more than those not taking the drug over the course of a year.

Fexaramine is a small molecule farnesoid X receptor (FXR) agonist with 100-fold increased affinity relative to natural compounds. IC50 value:Target:in vitro: In vitro treatment of CDCA or fexaramine elevated the SHP transcript level and occupancy on secretin promoter [1]. Fexaramine significantly enhanced osteoblastic differentiation through the upregulation of Runx2 and enhanced extracellular signal-regulated kinase (ERK) and β-catenin signaling [2]. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver [3].

ethyl ester of Dabigatran, which is an emerging oral anticoagulant which is a direct inhibitor of thrombin activity. IC50 value:Target: thrombinDabigatran provides a stable anticoagulation effect without any need to perform periodical laboratory controls. Of note, there is a growing amount of clinical evidence which shows its safety and efficacy. For these reasons, Dabigatran may suppose a revolution in oral anticoagulation. Dabigatran etexilate was rapidly converted to Dabigatran, with peak plasma dabigatran concentrations being attained after approximately 1.5 h; the bioavailability of Dabigatran after p.o. administration of Dabigatran etexilate was 7.2%.

Rosuvastatin Calcium is a competitive inhibitor of HMG-CoA reductase with IC50 of 11 nM. IC50 Value: 11 nM [1]Target: HMG-CoA reductasein vitro: Rosuvastatin is relatively hydrophilic and is highly selective for hepatic cells; its uptake is mediated by the liver-specific organic anion transporter OATP-C. Rosuvastatin is a high-affinity substrate for OATP-C with apparent association constant of 8.5 μM [2]. Rosuvastatin inhibits cholesterol biosynthesis in rat liver isolated hepatocytes with IC50 of 1.12 nM. Rosuvastatin causes approximately 10 times greater increase of mRNA of LDL receptors than pravastatin [1]. Rosuvastatin (100 μM) decreases the extent of U937 adhesion to TNF-α-stimulated HUVEC. Rosuvastatin inhibits the expressions of ICAM-1, MCP-1, IL-8, IL-6, and COX-2 mRNA and protein levels through inhibition of c-Jun N-terminal kinase and nuclear factor-kB in endothelial cells [3].in vivo: Rosuvastatin (3 mg/kg) daily administration for 14 days decreases plasma cholesterol levels by 26% in male beagle dogs with normal cholesterol levels. In cynomolgus monkeys, Rosuvastatin decreases plasma cholesterol levels by 22% [1]. Rosuvastatin (20 mg/kg/day) administration for 2 weeks, significantly reduces very low-density lipoproteins (VLDL) in diabetes mellitus rats induced by Streptozocin [4]. Rosuvastatin shows antiatherothromhotic effects in vivo. Rosuvastatin (1.25 mg/kg) significantly inhibits thrombin-induced transmigration of monocvtes across mesenteric venules via inhibition of the endothelial cell surface expression of P-selectin, and increases the basal rate of nitric oxide in aortic segments by 2-fold times [5].

Dipyridamole (Persantine) is a phosphodiesterase inhibitor that blocks uptake and metabolism of adenosine by erythrocytes and vascular endothelial cells.Target: Phosphodiesterase (PDE)Dipyridamole concentrations of 1 nmol/ml blood caused 90% inhibition of adenosine metabolism. Dipyridamole at therapeutic concentrations causes significant inhibition of adenosine metabolism in whole blood [1]. Dipyridamole has a dose-dependent inhibitory effect on thromboxane synthesis which was independent of aggregation. Dipyridamole also inhibited malonyldialdehyde production in response to both thrombin and arachidonic acid [2]. Dipyridamole enhances platelet inhibition by amplifying the signaling of the NO donor sodium nitroprusside. These data support the concept that enhancement of endothelium-dependent NO/cGMP-mediated signaling may be an important in vivo component of dipyridamole action [3].

Amprenavir (Agenerase) is a HIV protease inhibitor(Ki=0.6 nM) used to treat HIV infection.IC50 Value: 0.6 nM (Ki); Against wild-type clinical HIV isolates:14.6 +/- 12.5 ng/mL (mean +/- SD) [1].Target: HIV proteasein vitro: Amprenavir has an enzyme inhibition constant (Ki = 0.6 nM) that falls within the Ki range of the other protease inhibitors. Amprenavir's in vitro 50% inhibitory concentration (IC50) against wild-type clinical HIV isolates is 14.6 +/- 12.5 ng/mL (mean +/- SD) [1]. Amprenavir had direct inhibitory effects on invasion of Huh-7 hepatocarcinoma cell lines, inhibiting MMP proteolytic activation [2].in vivo: Amprenavir was able to promote regression of hepatocarcinoma growth in vivo by anti-angiogenetic and overall anti-tumor activities, independently by PI3K/AKT related pathways that at today is one of the more suggestive hypothesis to explain the anti-tumor effects of the different protease inhibitors [2]. Amprenavir efficiently activated PXR and induced PXR target gene expression in vitro and in vivo. Short-term exposure to amprenavirsignificantly increased plasma total cholesterol and atherogenic low-density lipoprotein cholesterol levels in wild-type mice, but not in PXR-deficient mice [3]. Amprenavir has been approved for adults and children; the recommended capsule doses are 1200 mg twice daily for adults and 20 mg/kg twice daily or 15 mg/kg 3 times daily for children < 13 years of age or adolescents < 50 kg [1].Clinical trial: A Study to Compare Three Doses of T-20 When Given in Combination With Abacavir, Amprenavir, Ritonavir, and Efavirenz to HIV-Infected Adults. Phase 2

Acetyl-11-Keto-β-Boswellic Acid (AKBA) is an active triterpenoid compound from the extract of Boswellia serrate; a novel Nrf2 activator.IC50 value:Target: Nrf2 activatorin vitro: AKBA significantly reduced infarct volumes and apoptotic cells, and also increased neurologic scores by elevating the Nrf2 and HO-1 expression in brain tissues in middle cerebral artery occlusion (MCAO) rats at 48 hours post reperfusion. In primary cultured neurons, AKBA increased the Nrf2 and HO-1 expression, which provided protection against OGD-induced oxidative insult. Additionally, AKBA treatment increased Nrf2 binding activity to antioxidant-response elements (ARE) [1]. AKBA significantly inhibited human colon adenocarcinoma growth, showing arrest of the cell cycle in G1-phase and induction of apoptosis[3]. AKBA triggered significant lipolysis in 3T3-L1 adipocytes as shown by reduced neutral lipids in cytosol and increased free fatty acids in culture medium. Increased lipolysis by AKBA was accompanied by up-regulation of lipolytic enzymes, adipocyte triglyceride lipase (ATGL) and hormone sensitive lipase (HSL), and a decreased expression of lipid droplet stability regulator perilipin. In addition, AKBA treatment reduced phenotypic markers of mature adipocyte aP2, adiponectin and glut-4 in mature adipocytes [5].in vivo: AKBA significantly prevented the formation of intestinal adenomatous polyps without toxicity to mice. AKBA's activity both in the prevention of small intestinal and colonic polyps was more potently than aspirin. Histopathologic examination revealed that AKBA's effect, that is the reduction of polyp size and degree of dysplasia, was more prominent in larger sized polyps, especially those originating in colon [2]. AKBA administration in mice effectively delayed the growth of HT-29 xenografts without signs of toxicity. The activity of AKBA was more potent than that of aspirin [3]. AKBA exhibited anti-cancer activity in vitro and in vivo. With oral application in mice, AKBA significantly inhibited SGC-7901 and MKN-45 xenografts without toxicity [4].

Temocapril Hydrochloride is a long-acting angiotensin-converting enzyme (ACE) inhibitor, used for the treatment of hypertension. Target: ACETemocapril hydrochloride is a novel prodrug-type angiotensin-I converting enzyme (ACE) inhibitor, lowering of the dose of temocapril might be recommended only in patients with severe renal insufficiency [1]. Temocapril is regarded as an ACE inhibitor the disposition and efficacy of which are little affected in patients with impaired liver function [2]. Oglemilast(GRC3886) is a potent PDE4 inhibitor, under clinical studies in the treatment of allergen-induced asthma.IC50 value:Target: PDE4

Udenafil(DA8159) is a PDE5 inhibitor used in urology to treat erectile dysfunction.Target: PDE5Udenafil is an oral PDE5 inhibitor. Udenafil significantly increased cAMP and cGMP levels and were more highly distributed in the prostate than plasma. The T/P ratio of udenafil was higher than tadalafil. These findings may help in the assessment of the feasibility of using PDE5 Is to concurrently treat both LUTS and erectile dysfunction [1]. After 12 weeks of treatment, the patients treated with udenafil showed significantly greater change from baseline in the IIEF-EF domain score compared with placebo (placebo, 0.20; 100-mg udenafil, 7.52; and 200-mg udenafil, 9.93, respectively) (P < 0.0001). udenafil significantly enhanced the rates of successful penetration (SEP Q2) and maintenance of erection (SEP Q3) (P < 0.0001) [2].MLN2238 rapidly hydrolyzes to MLN2238, which is a selective, orally bioavailable, second-generation proteasome inhibitor, inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with an IC50 value of 3.4 nM (Ki of 0.93 nM), and also inhibits the caspase-like (β1) and trypsin-like (β2) proteolytic sites with IC50 of 31 and 3500 nM, respectively.

GSK256066 is a selective PDE4B(equal affinity to isoforms A-D) inhibitor with IC50 of 3.2 pM, >380,000-fold selectivity versus PDE1/2/3/5/6 and >2500-fold selectivity against PDE4B versus PDE7.IC50 value: 3.2 pM [1]Target: PDE4Bin vitro: GSK256066 is a slow and tight binding inhibitor of PDE4B with apparent IC50 of 3.2 pM. GSK256066 is an extremely potent inhibitor of LPS-stimulated TNFα production in PBMCs with pIC50 of 11.0 and IC50 of 10 pM and human whole-blood cultures with pIC50 of 9.90 and IC50 of 126 pM. GSK256066 is highly selective for PDE4 (>3.8 × 105-fold versus PDE1, PDE2, PDE3, PDE5, and PDE6 and >2.5 × 103-fold against PDE7). GSK256066 inhibits PDE4 isoforms A-D with equal affinity [1].in vivo: GSK256066 inhibits the LPS-induced pulmonary neutrophilia with an ED50 of 1.1 μg/kg, achieving maximal inhibition of 72% at 30 μg/kg when given in the aqueous suspension. GSK256066 inhibits the LPS-induced pulmonary neutrophilia with ED50 of 2.9 μg/kg, achieving maximal inhibition of 62% when given in the dry powder formulation. GSK256066 shows a moderate plasma clearance of 39 ml/min/kg, a moderate volume of distribution of 0.8 L/kg, and a relatively short half-life of 1.1 hour in the male CD rat [1]. GSK256066 sustains at a high lung concentration of 2.6 μg/g after intra-tracheal administration as an aqueous suspension at a dose of 30 μg/kg in rats [2]. GSK256066 (10 μg/kg) is administered intratracheally at different times (2, 6, 12, 18, 24, and 36 hours) before LPS administration, inhibiting LPS-Induced Pulmonary Neutrophilia in rat lipopolysaccharide (LPS)-induced models of acute pulmonary inflammation. GSK256066 (0.3–100 μg/kg) inhibits LPS-induced increases in exhaled nitric oxide with ED50 of 35 μg/kg in rat. GSK256066 (10 μg/kg) is administered half a hour before OVA administration in rat, inhibiting OVA-induced pulmonary eosinophilia with ED50 of 0.4 μg/kg. GSK256066 administered intratracheally as a dry powder blended in respiratory-grade lactose at doses of 3 to 100 μg/kg 2 hours before inhaled LPS challenge in ferrets, inhibiting LPS-induced pulmonary neutrophilia with ED50 of 18 μg/kg without inducing emetic episodes [3].

Boceprevir is a novel, potent, highly selective, orally bioavailable HCV NS3 protease inhibitor with Ki of 14 nM in both enzyme assay and EC90 of 350 nM in cell-based replicon assay.

JZL 184 is a potent and selective inhibitor of MAGL with IC50 of 8 nM and 4 μM for inhibition of MAGL and FAAH in mouse brain membranes respectively.IC50 value: 8 nM [1]Target: MAGL inhibitorin vitro: JZL184 prolongs DSE in Purkinje neurons in cerebellar slices and DSI in CA1 pyramidal neurons in hippocampal slices. JZL184 is more potent in inhibiting mouse MAGL than rat MAGL [2]. in vivo: When administered to mice at 16 mg/kg, intraperitoneally, JZL 184 reduces MAGL activity by 85%, elevates brain 2-AG levels by 8-fold, and elicits analgesic activity in a variety of pain assays that qualitatively mimics direct central cannabinoid (CB1) agonists [1]. Acute administration of JZL184 to FAAH(-/-) mice enhanced the magnitude of a subset of cannabimimetic responses, repeated JZL184 treatment led to tolerance to its antinociceptive effects, cross-tolerance to the pharmacological effects of Δ(9)-tetrahydrocannabinol, decreases in CB1 receptor agonist-stimulated guanosine 5'-O-(3-[(35)S]thio)triphosphate binding, and dependence as indicated by rimonabant-precipitated withdrawal behaviors, regardless of genotype [3].

Vardenafil Hcl is a PDE5 inhibitor used for treating erectile dysfunction.Target: PDE5Vardenafil specifically inhibited the hydrolysis of cGMP by PDE5 with an IC50 of 0.7 nM (6.6 nM). In contrast, the IC50 of vardenafil for PDE1 was 180 nM; for PDE6, 11 nM; for PDE2, PDE3 and PDE4, more than 1000 nM. Relative to PDE5, the ratios of the IC50 for PDE1 were 257 (60), for PDE6 16 (7.4). Vardenafil significantly enhanced the SNP-induced relaxation of human trabecular smooth muscle at 3 nM (10 nM). Vardenafil also significantly potentiated both ACh-induced and transmural electrical stimulation-induced relaxation of trabecular smooth muscle [1]. Both vardenafil doses(10 mg or 20 mg) significantly enhanced theOdanacatib is a potent, selective, and neutral inhibitor of cathepsin K (human/rabbit) with IC50 of 0.2 nM/1 nM, and demonstrates high selectivity versus off-target cathepsin B, L, S.Argatroban monohydrate is a direct, selective thrombin inhibitor.Target: ThrombinArgatroban may have a complementary effect for preventing thrombus formation without aggravating bleeding tendency because of its monotarget specificity to thrombin. Administration (0.5 to 2 micrograms/kg/min) of argatroban is a safe anticoagulant for left heart bypass in repairs of traumatic aortic rupture associated with multiple organ injuries [1]. Argatroban, as compared with heparin, appears to enhance reperfusion with TPA in patients with AMI, particularly in those patients with delayed presentation. The incidences of major bleeding and adverse clinical outcome were lower in the patients receiving argatroban [2].

Sivelestat(ONO5046; LY544349; EI546) is a competitive inhibitor of human neutrophil elastase(IC50 = 44 nM; Ki=200 nM); also inhibited leukocyte elastase obtained from rabbit, rat, hamster and mouse.IC50 value: 44 nM [1]Target: neutrophil elastaseONO-5046 did not inhibit trypsin, thrombin, plasmin, plasma kallikrein, pancreas kallikrein, chymotrypsin and cathepsin G even at 100 microM. In in vivo studies, ONO-5046 suppressed lung hemorrhage in hamster (ID50 = 82 micrograms/kg) by intratracheal administration and increase of skin capillary permeability in guinea pig (ID50 = 9.6 mg/kg) by intravenous administration, both of which were induced by human neutrophil elastase [1]. Sivelestat sodium hydrate is an anti-neutrophil elastase inhibitor and may be one of the treatment options for acute respiratory failure due to pneumocystis pneumonia in AIDS patients [2].

Dutasteride (GG745) is a potent inhibitor of both 5 alpha-reductase isozymes. Dutasteride may possess off-target effects on the androgen receptor (AR) due to its structural similarity to DHT.IC50 Value:Target: 5 alpha-reductasein vitro: Dutasteride inhibited (3)H-T conversion to (3)H-DHT and, as anticipated, inhibited T-induced secretion of PSA and proliferation. However the drug also inhibited DHT-induced PSA secretion and cell proliferation (IC(50) approximately 1 microM). Dutasteride competed for binding the LNCaP cell AR with an IC(50) approximately 1.5 microM. High concentrations of dutasteride (10-50 microM), but not finasteride, in steroid-free medium, resulted in enhanced cell death, possibly by apoptosis [1]. Dutasteride reduces cell viability and cell proliferation in both cell lines tested (androgen-responsive (LNCaP) and androgen-unresponsive (DU145) human prostate cancer (PCa)) [2].in vivo: GG745 has a terminal half-life of approximately 240 hr, and single doses of >10 mg decreased DHT levels significantly more than did single 5-mg doses of finasteride [3]. In placebo treated men without prostate cancer there was an 8.3% median increase in PSA at month 24 compared with -59.5% in those who received dutasteride, using doubled values to correct for dutasteride treatment [4].Toxicity: Dutasteride may affect male fertility and steroid hormone dynamics. Therefore, a 21-day reproduction study was conducted to determine the effects of dutasteride (10, 32 and 100 μg/L) on fish reproduction. Exposure to dutasteride significantly reduced fecundity of fish and affected several aspects of reproductive endocrine functions in both males and females [5].Clinical trial: Bioequivalence Study Of Dutasteride Five 0.1 mg And One 0.5 mg Soft Gelatin Capsules In Healthy Male Volunteers. Phase 1

Ketoconazole is an imidazole anti-fungal agent, a CYP3A4 and CYP24A1 inhibitor.Target: CYP3A4 CYP24A1Ketoconazole, an imidazole anti-fungal agent, has often produced features of androgen deficiency including decreased libido, gynecomastia, impotence, oligospermia, and decreased testosterone levels, in men being treated for chronic mycotic infections [1]. Ketoconazole also is a cytochrome P450 inhibitor [2].Ketoconazole (KTZ), on the antischistosomal potential of these quinolines against Schistosoma mansoni infection by evaluating parasitological, histopathological, and biochemical parameters. Mice were classified into 7 groups: uninfected untreated (I), infected untreated (II), infected treated orally with PZQ (1,000 mg/kg) (III), QN (400 mg/kg) (IV), KTZ (10 mg/kg)+QN as group IV (V), HF (400 mg/kg) (VI), and KTZ (as group V)+HF (as group VI) (VII). KTZ plus QN or HF produced more inhibition (P<0.05) in hepatic CYP450 (85.7% and 83.8%) and CYT b5 (75.5% and 73.5%) activities, respectively, than in groups treated with QN or HF alone. This was accompanied with more reduction in female (89.0% and 79.3%), total worms (81.4% and 70.3%), and eggs burden (hepatic; 83.8%, 66.0% and intestinal; 68%, 64.5%), respectively, and encountering the granulomatous reaction to parasite eggs trapped in the liver.[3] CYP24A1 inhibitor enhances antiproliferative effects, increases systemic calcitriol exposure, and promotes the activation of caspase-independent apoptosis pathway.[4]

Oprozomib (ONX 0912; PR047) is an orally bioavailable inhibitor for CT-L activity of 20S proteasome β5/LMP7 with IC50 of 36 nM/82 nM.IC50 value: 36 nM/82 nM(20S proteasome β5/LMP7) [1]Target: 20S proteasomeThe anti-MM activity of Oprozomib is associated with activation of caspase-8, caspase-9, caspase-3, and PARP, as well as inhibition of migration of MM cells and angiogenesis. Oprozomib is demonstrated an absolute bioavailability of up to 39% in rodents and dogs. It is well tolerated with repeated oral administration at doses resulting in >80% proteasome inhibition in most tissues and elicited an antitumor response in multiple human tumor xenograft and mouse syngeneic models.

Moexipril HCl is a potent orally active non-sulfhydryl angiotensin converting enzyme(ACE) inhibitor, which is used for the treatment of hypertension and congestive heart failure. Target: ACEMoexipril is a long-acting ACE inhibitor suitable for once-daily administration, and like some ACE inhibitors, moexipril is a prodrug and needs to be hydrolyzed in the liver into its active carboxylic metabolite, moexiprilat, to become effective [1]. Upon oral administration of moexipril (10 mg/kg/day) to spontaneously hypertensive rats, plasma angiotensin II concentration decreased to undetectable levels, plasma ACE activity was inhibited by 98% and plasma angiotensin I concentration increased 8.6-fold 1 h after dosing. At 24 h, plasma angiotensin I and angiotensin II concentrations had returned to pretreatment levels, whereas plasma ACE activity was still inhibited by 56%. Four-week oral administration of moexipril (0.1-30 mg/kg/day) to spontaneously hypertensive rats lowered blood pressure and differentially inhibited ACE activity in plasma, lung, aorta, heart and kidney in a dose-dependent fashion [2, 3].Nafamostat mesylate, a synthetic serine protease inhibitor, is an anticoagulant.Target: Serine ProteaseTranilast (FUT-175) is an antiallergic drug for bronchial asthma. It has been used for the treatment of allergic disorders such as asthma, allergic rhinitis and atopic dermatitis. It has also been investigated for use as an antiproliferative drug on drug-eluting stents.A 20-40 mg/h dose of FUT-175 prolonged coagulation time sufficiently in the instrumental blood of the extracorporeal circuit but not in the systemic blood. Its anticoagulant activity decreased immediately after hemodialysis. Therefore, we could manage all patients without any bleeding trouble during hemodialysis with FUT-175 as an anticoagulant. Although there were side effects of FUT-175, such as nausea, vomiting, itching and eruption, they were not serious, and FUT-175 could be administered without interruption. FUT-175 seems to be useful as an anticoagulant during hemodialysis for patients susceptible to bleeding.

TM5275 sodium is a plasminogen activator inhibitor (PAI-1) with an IC50 of 6.95 μM.

DMP 777 is a potent, selective, and orally active human leukocyte elastase (HLE) inhibitor.

Atorvastatin (hemicalcium salt) is a potent HMG-CoA reductase inhibitor with the IC50 value of 8 nM.Naringin is a major flavanone glycoside obtained from tomatoes, grapefruits, and many other citrus fruits. Naringin exhibits biological properties such as antioxidant, anti-inflammatory, and antiapoptotic activities.

17-AAG is a potent HSP90 inhibitor with IC50 of 5 nM, having a 100-fold higher binding affinity for HSP90 derived from tumour cells than HSP90 from normal cells.Darunavir ethanolate (TMC114 ethanolate) is a potent HIV protease inhibitor used to treat and prevent HIV/AIDS. Darunavir has a Ki of 1 nM for wild type HIV-1 protease. RA190, a bis-benzylidine piperidon, inhibits proteasome function by covalently binding to cysteine 88 of ubiquitin receptor RPN13.

GW3965 (hydrochloride) is a potent, selective LXR agonist for hLXRα and hLXRβ with EC50 of 190 and 30 nM, respectively.

SR9243 is a liver-X-receptor (LXR) inverse agonist that induces LXR-corepressor interaction.

Pepstatin is a potent inhibitor of aspartyl proteases, and inhibits the aspartic proteases cathepsin D, pepsin, and renin.

Carfilzomib is an irreversible proteasome inhibitor with IC50 of < 5 nM in ANBL-6 and RPMI 8226 cells.Ritonavir is an inhibitor of HIV protease used to treat HIV infection and AIDS.

Alvelestat (AZD9668) is a novel, oral inhibitor of neutrophil elastase (NE) with the pIC50 of 7.9 for Human NE.IC50 Value: 7.9 ± 0.12 (pIC50, Human NE); 4.9 nM (Ki value, Human NE) [1]Target: Neutrophil elastasein vitro: AZD9668 had a high binding affinity for human NE (KD = 9.5 nM) and potently inhibited NE activity. The calculated pIC50 (IC50) and Ki values for AZD9668 for human NE were 7.9 (12 nM) and 4.9 nM, respectively. In contrast to earlier NE inhibitors, the interaction between AZD9668 and NE was rapidly reversible. AZD9668 was also highly selective for NE over other neutrophil-derived serine proteases. In cell-based assays, AZD9668 inhibited plasma NE activity in zymosan-stimulated whole blood. In isolated human polymorphonuclear cells, AZD9668 inhibited NE activity on the surface of stimulated cells and in the supernatant of primed, stimulated cells.AZD9668 showed good crossover potency to NE from other species [1]. in vivo: Six hundred and fifteen patients were randomised: placebo (302), AZD9668 60 mg bid (313). AZD9668 showed no effect on lung function: change in mean pre-bronchodilator FEV1 versus placebo was 0.01L (95% confidence interval: -0.03, 0.05; p=0.533). AZD9668 did not significantly improve respiratory signs and symptoms, SGRQ-C score or time to first exacerbation. Adverse events were similar for AZD9668 and placebo [2]. AZD9668 was well tolerated at single doses up to 150 mg and multiple doses up to 70 mg twice daily. PK were dose linear; median time to peak plasma concentration was reached at 0.5 - 1.5 hours and the short elimination half-life was consistent with twice daily dosing. Steady state was reached by Day 2 of twice daily dosing with negligible accumulation. Approximately 40% of AZD9668 was eliminated renally as unchanged compound. Ex vivo zymosan-stimulated inhibition of NE activity was dose-dependent, with maximal inhibition achieved at 60 mg [4].Toxicity: A total of 838 patients were randomised to AZD9668 5 mg bid (212 patients), 20 mg bid (206 patients), 60 mg bid (202 patients) or placebo (218 patients). AZD9668 showed no effect on lung function, respiratory signs and symptoms, QoL or biomarkers [3].Clinical trial: Phase II study of a neutrophil elastase inhibitor (AZD9668) in patients with bronchiectasis.

Darunavir(TMC114) is an HIV protease inhibitor.IC50 Value: Target: HIV ProteaseDarunavir HIV-1 antiviral structurally is similar to amprenavir and it is second generation HIV-1-protease inhibitor. Darunavir is a drug used to treat HIV infection. It is in the protease inhibitor class. Prezista is an OARAC recommended treatment option for treatment-naive and treatment-experienced adults and adolescents.

KML29 is a potent and selective MAGL inhibitor with IC50 = 5.9, 15, and 43 nM in human, mouse, and rat brain proteomes, respectively.IC50 value: 15, 43, and 5.9 nM (mouse, rat, and human brain proteomes)Target: MAGLin vitro: KML29 potently and selectively inhibits MAGL with minimal cross-reactivity toward other central and peripheral serine hydrolases, including no detectable activity against FAAH.[1]in vivo: KML29 a potentially very useful tool to explore the consequences of inhibiting MAGL in the whole animal and in multiple species, and provides greater selectivity than JZL184 in inhibiting MAGL. [2]

Aliskiren(CGP 60536) is a direct renin inhibitor with IC50 of 1.5 nM.IC50 value: 1.5 nM [1]Target: reninin vitro: Aliskiren hemifumarate appears to bind to both the hydrophobic S1/S3-binding pocket and to a large, distinct subpocket that extends from the S3-binding site towards the hydrophobic core of renin. Oral bioavailability of Aliskiren hemifumarate is 2.4% in rats, 16% in marmosets and about 2.5% in humans [2].in vivo: Aliskiren hemifumarate (< 10 mg/kg, oral) inhibits plasma renin activity and lowers blood pressure in sodium-depleted marmosets[3].Once-daily oral treatment with Aliskiren hemifumarate lowers blood pressure effectively, with a safety and tolerability profile, in patients with mild-to-moderate hypertension[4].

VER-155008 is a novel, small molecule inhibitor of Hsc70/Hsp70 with GI50 of 5.3-14.4 uM in human breast and colon cancer cell lines.IC50 value: 5.3-14.4 uM(GI50); 80 nM(Kd) [1] [2]Target: Hsp70 inhibitorin vitro: VER-155008 inhibited the proliferation of human breast and colon cancer cell lines with GI(50)s in the range 5.3-14.4 microM, and induced Hsp90 client protein degradation in both HCT116 and BT474 cells. As a single agent, VER-155008 induced caspase-3/7 dependent apoptosis in BT474 cells and non-caspase dependent cell death in HCT116 cells. VER-155008 potentiated the apoptotic potential of a small molecule Hsp90 inhibitor in HCT116 but not HT29 or MDA-MB-468 cells [1]. VER-155008 (HCT116 GI50 = 5 μM), has similar potencies in both Grp78 and Hsp70 [2]. Inhibition of Hsp70/Hsc70 activity with VER 155008 attenuated the protection afforded by N-acetyl cysteine in a dose-responsive manner [3]. in vivo: VER-155008 demonstrated rapid metabolism and clearance, along with tumor levels below the predicted pharmacologically active level [1].

KC7F2 is a potent HIF-1 pathway inhibitor and that its potential as a cancer therapy agent warrants further study.Target：HIFin vitro: KC7F2 is the second HIF-1α inhibitor. KC7F2 is shown to inhibit the proliferation of cancer cells, an effect that is increased in hypoxia, while non-tumor cells are less sensitive. KC7F2 decreases HIF-1α levels by downregulating HIF-1α protein synthesis. [2] KC7F2 markedly inhibits HIF-mediated transcription in cells derived from different tumor types, including glioma, breast and prostate cancers and exhibited enhanced cytotoxicity under hypoxia. KC7F2 prevents the activation of HIF-target genes such as Carbonic Anhydrase IX, Matrix Metalloproteinase 2 (MMP2), Endothelin 1 and Enolase 1. KC7F2 works through the down-regulation of HIF-1α protein synthesis, an effect accompanied by the suppression of the phosphorylation of eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) and p70 S6 kinase (S6K), key regulators of HIF-1α protein synthesis.[1]

ONX-0914 (PR-957) is a potent and selective immunoproteasome inhibitor with minimal cross-reactivity for the constitutive proteasome.IC50 Value: ~10 nM [1]in vitro: PR-957 blocked presentation of LMP7-specific, MHC-I-restricted antigens in vitro and in vivo. Selective inhibition of LMP7 by PR-957 blocked production of interleukin-23 (IL-23) by activated monocytes and interferon-gamma and IL-2 by T cells [1].in vivo: In mouse models of rheumatoid arthritis and lupus, ONX-0914 treatment reverses signs of disease and results in reductions in cellular infiltration, cytokine production and autoantibody levels at well-tolerated doses. The maximum tolerated dose (MTD) of ONX-0914 in mice to be 30 mg/kg body weight. IFN-g release is inhibited by ~60% at LMP7-selective concentrations of ONX-0914 and by ~90% at higher concentrations. Production of IL-2 is also inhibited by ~50% [1].Ivosidenib is a inhibitor of IDH1. The detailed information please refer to WO2015127172A1 and WO2015138839A1.Target: IDH1(R,S)-Ivosidenib is a inhibitor of Isocitrate Dehydrogenase (IDH1).Target: IDH1

Fosinopril Sodium is the ester prodrug of an angiotensin-converting enzyme (ACE) inhibitor, used for the treatment of hypertension and some types of chronic heart failure.Target: ACEFosinopril is a phosphinic acid-containing ester prodrug that belongs to the angiotensin-converting enzyme (ACE) inhibitor class of medications. It is rapidly hydrolyzed to fosinoprilat, its principle active metabolite. Fosinoprilat inhibits ACE, the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATII). ATII regulates blood pressure and is a key component of the renin-angiotensin-aldosterone system (RAAS). Fosinopril may be used to treat mild to moderate hypertension, as an adjunct in the treatment of congestive heart failure, and to slow the rate of progression of renal disease in hypertensive individuals with diabetes mellitus and microalbuminuria or overt nephropathy [1-3].

Torcetrapib(CP-529414) is a CETP inhibitor with IC50 of 37 nM, elevates HDL-C and reduces nonHDL-C in plasma.IC50 value: 37 nM [1]Target: CETP inhibitorin vitro: Torcetrapib dose-dependently increases aldosterone release from H295R cells after either 24 or 48 h of treatment with an EC50 of approximately 80 nM, this effect is mediated by calcium channel as calcium channel blockers completely blocks torcetrapib-induced corticoid release and calcium increase. Torcetrapib (1 μM) significantly increases the expression of steroidogenic gene, CYP11B2 and CYP11B1, in H295R cell lines [2].in vivo: Torcetrapib (< 100 mg, daily) changes the plasma distribution of CETP, as the apparent molecular weight of the CETP has shifted to a larger form, by 2 hours after the dose in healthy young subjects. Torcetrapib treatment with 10 mg, 30 mg, 60 mg, and 120 mg daily and 120 mg twice daily results in 16%, 28%, 62%, 73%, and 91% increases in plasma HDL-C, respectively, with no significant changes in TPC in healthy young subjects. [1] Torcetrapib results in an increase of 72.1% in high-density lipoprotein cholesterol and a decrease of 24.9% in low-density lipoprotein cholesterol, in addition to an increase of 5.4 mm Hg in systolic blood pressure, a decrease in serum potassium, and increases in serum sodium, bicarbonate, and aldosterone, in patients at high cardiovascular risk after 12 months' treatment [3]. Torcetrapib (90 mg/kg/day) results in a 70% inhibition of CE transfer in rabbits fed an atherogenic diet. Torcetrapib (90 mg/kg/day) increases mean HDL-C levels by above 3-fold and apoA-I levels by 2.5-fold in plasma in rabbits fed an atherogenic diet. Torcetrapib-treated animal has a multiple-fold increase in HDL-C AUC and a corresponding reduction in aortic lesion area with 60% reduction of aortic free cholesterol (FC) and cholesteryl ester (EC) in rabbits fed an atherogenic diet. Torcetrapib-treated rabbits stimulate free cholesterol efflux to a significantly greater extent than does sera from control rabbits [4].

Apoptozole is an inhibitor of heat shock protein 70 (Hsp70; 65% inhibition at 200 μM) that acts by blocking its ATPase activity.target: Hsp70 [1]In vitro: Apoptozole binds HSP70 but not other types of heat shock proteins and induces caspase-dependent apoptosis. Apoptozole does not affect interactions of HSP70 with ASK1, JNK, BAX, and AIF. [1] Apoptozole aggregates under aqueous conditions. [2]In vivo: Animal studies indicate that Az treatment retards tumor growth in a xenograft mouse model without affecting mouse viability. [1]

Dabigatran etexilate(BIBR-1048) is the orally active prodrug of dabigatran; Dabigatran is a reversible and selective, direct thrombin inhibitor (DTI) with Ki value of 4.5 nM.IC50 Value: 4.5 nM (Ki); 10 nM(Thrombin-induced platelet aggregation) [1]in vitro: Dabigatran selectively and reversibly inhibited human thrombin(Ki: 4.5 nM) as well as thrombin-induced platelet aggregation (IC(50): 10 nM), while showing no inhibitory effect on other platelet-stimulating agents.Thrombin generation in platelet-poor plasma (PPP), measured as the endogenous thrombin potential (ETP) was inhibited concentration-dependently (IC(50): 0.56 microM). Dabigatran demonstrated concentration-dependent anticoagulant effects in various species in vitro, doubling the activated partial thromboplastin time (aPTT), prothrombin time (PT) and ecarin clotting time (ECT) in human PPP at concentrations of 0.23, 0.83 and 0.18 microM, respectively [1]. in vivo: Dabigatran prolonged the aPTT dose-dependently after intravenous administration in rats (0.3, 1 and 3 mg/kg) and rhesus monkeys (0.15, 0.3 and 0.6 mg/kg). Dose- and time-dependent anticoagulant effects were observed with dabigatran etexilate administered orally to conscious rats (10, 20 and 50 mg/kg) or rhesus monkeys (1, 2.5 or 5 mg/kg), with maximum effects observed between 30 and 120 min after administration, respectively [1]. Patients treated with dabigatran etexilate experienced fewer ischaemic strokes (3.74 dabigatran etexilate vs 3.97 warfarin) and fewer combined intracranial haemorrhages and haemorrhagic strokes (0.43 dabigatran etexilate vs 0.99 warfarin) per 100 patient-years [2].Clinical trial: An Evaluation of the Pharmacokinetics and Pharmacodynamics of Oral Dabigatran Etexilate in Hemodialysis Patients . Phase1

Lopinavir is a potent HIV protease inhibitor with Ki of 1.3 pM.Target: HIV proteaseLopinavir is a potent inhibitor of Rh123 efflux in Caco-2 monolayers with IC50 of 1.7 mM. Lopinavir exposure (72 hours) in LS 180V cells reduces the content of intracellular Rh123. Lopinavir induces P-glycoprotein immunoreactive protein and messenger RNA levels in LS 180V cells. Lopinavir inhibits subtype C clone C6 with IC50 of 9.4 nM. Lopinavir inhibits CYP3A with IC50 of 7.3 mM in human liver microsomes, while produces negligible or weak inhibition of human CYP1A2, 2B6, 2C9, 2C19 and 2D6. Lopinavir (10 mg/kg, orally) results in Cmax of 0.8 μg/mL and oral bioavailability of 25% in rats.Teneligliptin hydrobromide is a potent chemotype prolylthiazolidine-based DPP-4 inhibitor, which competitively inhibits human plasma, rat plasma, and human recombinant DPP-4 in vitro, with IC50s of approximately 1 nM.

GSK256066 is a selective PDE4B(equal affinity to isoforms A-D) inhibitor with IC50 of 3.2 pM, >380,000-fold selectivity versus PDE1/2/3/5/6 and >2500-fold selectivity against PDE4B versus PDE7.IC50 value: 3.2 pM [1]Target: PDE4Bin vitro: GSK256066 is a slow and tight binding inhibitor of PDE4B with apparent IC50 of 3.2 pM. GSK256066 is an extremely potent inhibitor of LPS-stimulated TNFα production in PBMCs with pIC50 of 11.0 and IC50 of 10 pM and human whole-blood cultures with pIC50 of 9.90 and IC50 of 126 pM. GSK256066 is highly selective for PDE4 (>3.8 × 105-fold versus PDE1, PDE2, PDE3, PDE5, and PDE6 and >2.5 × 103-fold against PDE7). GSK256066 inhibits PDE4 isoforms A-D with equal affinity [1].in vivo: GSK256066 inhibits the LPS-induced pulmonary neutrophilia with an ED50 of 1.1 μg/kg, achieving maximal inhibition of 72% at 30 μg/kg when given in the aqueous suspension. GSK256066 inhibits the LPS-induced pulmonary neutrophilia with ED50 of 2.9 μg/kg, achieving maximal inhibition of 62% when given in the dry powder formulation. GSK256066 shows a moderate plasma clearance of 39 ml/min/kg, a moderate volume of distribution of 0.8 L/kg, and a relatively short half-life of 1.1 hour in the male CD rat [1]. GSK256066 sustains at a high lung concentration of 2.6 μg/g after intra-tracheal administration as an aqueous suspension at a dose of 30 μg/kg in rats [2]. GSK256066 (10 μg/kg) is administered intratracheally at different times (2, 6, 12, 18, 24, and 36 hours) before LPS administration, inhibiting LPS-Induced Pulmonary Neutrophilia in rat lipopolysaccharide (LPS)-induced models of acute pulmonary inflammation. GSK256066 (0.3–100 μg/kg) inhibits LPS-induced increases in exhaled nitric oxide with ED50 of 35 μg/kg in rat. GSK256066 (10 μg/kg) is administered half a hour before OVA administration in rat, inhibiting OVA-induced pulmonary eosinophilia with ED50 of 0.4 μg/kg. GSK256066 administered intratracheally as a dry powder blended in respiratory-grade lactose at doses of 3 to 100 μg/kg 2 hours before inhaled LPS challenge in ferrets, inhibiting LPS-induced pulmonary neutrophilia with ED50 of 18 μg/kg without inducing emetic episodes [3].

Anacetrapib is a potent CETP inhibitor, with IC50s of 7.9±2.5 nM and 11.8±1.9 nM for rhCETP and C13S CETP mutant, respectively.Evacetrapib is a potent and selective of CETP inhibitor, which inhibits human recombinant CETP protein (5.5 nM IC50) and CETP activity in human plasma (36 nM IC50) in vitro.Lonafarnib is an orally bioavailable farnesyl protein transferase (FPTase) inhibitor for H-ras, K-ras and N-ras with IC50 of 1.9 nM, 5.2 nM and 2.8 nM, respectively.

Alvespimycin hydrochloride is a potent inhibitor of Hsp90, binding to Hsp90 with EC50 of 62±29 nM.

Nelfinavir(AG-1341) is a potent and orally bioavailable human immunodeficiency virus HIV-1 protease inhibitor (Ki=2 nM) and is widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection. IC50 Valur: 2 nM (Ki for HIV-1 protease) [2]Target: HIV Proteasein vitro: In vitro exposure (72 hours) of HAECs to NEL (0.25-2 μg/mL) decreased both basal (2.5-fold) and insulin-induced NO production (4- to 5-fold). NEL suppressed insulin-induced phosphorylation of both Akt and eNOS at serine residues 473 and 1177, respectively. NEL decreased tyrosine phosphorylation of IR-β, IRS-1, and PI3K. Coexposure to troglitazone (TRO; 250 nM) ameliorated the suppressive effects of NEL on insulin signaling and NO production. Coexposure to TRO also increased eNOS expression in NEL-treated HAECs [1]. AG1343 is a potent enzyme inhibitor (Ki = 2 nM) and antiviral agent (HIV-1 ED50 = 14 nM). An X-ray cocrystal structure of the enzyme-AG1343 complex reveals how the novel thiophenyl ether and phenol-amide substituents of the inhibitor interact with the S1 and S2 subsites of HIV-1 protease, respectively [2].in vivo: In vivo studies indicate that AG1343 is well absorbed orally in a variety of species and possesses favorable pharmacokinetic properties in humans [2].

Sildenafil citrate is a potent phosphodiesterase type 5 (PDE5) inhibitor with IC50 of 5.22 nM.Darapladib is a potent inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2) with IC50 of 0.25 nM.Saquinavir(Ro 31-8959) is an HIV Protease inhibitor used in antiretroviral therapy. IC50 Value: Target: HIV ProteaseSaquinavir is a protease inhibitor. Proteases are enzymes that cleave protein molecules into smaller fragments. HIV protease is vital for both viral replication within the cell and release of mature viral particles from an infected cell. Saquinavir binds to the active site of the viral protease and prevents cleavage of viral polyproteins, preventing maturation of the virus. Saquinavir inhibits both HIV-1 and HIV-2 proteases.Studies have also looked at Saquinavir as a possible anti-cancer agent.Telaprevir is a highly selective, reversible, and potent peptidomimetic inhibitor of the HCV NS3-4A protease, the steady-state inhibitory constant (Ki) of Telaprevir is 7 nM against a genotype 1 (H strain) NS3 protease domain plus a NS4A cofactor peptide.Indinavir sulfate(MK-639 sulfate; L735524 sulfate ) is a potent and specific HIV protease inhibitor that appears to have good oral bioavailability.Target: HIV ProteaseIndinavir(MK-639) is a protease inhibitor used as a component of highly active antiretroviral therapy (HAART) to treat HIV infection and AIDS.MK-639 appears to have significant dose-related antiviral activity and is well tolerated [1]. Inhibition constants (K(i)) of the antiviral drug indinavir for the reaction catalyzed by the mutant enzymes were about threefold and 50-fold higher for PR(L24I) and PR(I50V), respectively, relative to PR and PR(G73S). The dimer dissociation constant (K(d)) was estimated to be approximately 20 nM for both PR(L24I) and PR(I50V), and below 5 nM for PR(G73S) and PR. Crystal structures of the mutants PR(L24I), PR(I50V) and PR(G73S) were determined in complexes with indinavir, or the p2/NC substrate analog at resolutions of 1.10-1.50 Angstrom [2].

Dabigatran etexilate mesylate (BIBR 1048MS) is the orally active prodrug of dabigatran. Dabigatran is a reversible and selective, direct thrombin inhibitor (DTI) with Ki value of 4.5 nM.IC50 Value: 4.5 nM (Ki); 10 nM(Thrombin-induced platelet aggregation) [1]in vitro: Dabigatran selectively and reversibly inhibited human thrombin(Ki: 4.5 nM) as well as thrombin-induced platelet aggregation (IC(50): 10 nM), while showing no inhibitory effect on other platelet-stimulating agents.Thrombin generation in platelet-poor plasma (PPP), measured as the endogenous thrombin potential (ETP) was inhibited concentration-dependently (IC(50): 0.56 microM). Dabigatran demonstrated concentration-dependent anticoagulant effects in various species in vitro, doubling the activated partial thromboplastin time (aPTT), prothrombin time (PT) and ecarin clotting time (ECT) in human PPP at concentrations of 0.23, 0.83 and 0.18 microM, respectively [1]. in vivo: Dabigatran prolonged the aPTT dose-dependently after intravenous administration in rats (0.3, 1 and 3 mg/kg) and rhesus monkeys (0.15, 0.3 and 0.6 mg/kg). Dose- and time-dependent anticoagulant effects were observed with dabigatran etexilate administered orally to conscious rats (10, 20 and 50 mg/kg) or rhesus monkeys (1, 2.5 or 5 mg/kg), with maximum effects observed between 30 and 120 min after administration, respectively [1]. Patients treated with dabigatran etexilate experienced fewer ischaemic strokes (3.74 dabigatran etexilate vs 3.97 warfarin) and fewer combined intracranial haemorrhages and haemorrhagic strokes (0.43 dabigatran etexilate vs 0.99 warfarin) per 100 patient-years [2].Clinical trial: An Evaluation of the Pharmacokinetics and Pharmacodynamics of Oral Dabigatran Etexilate in Hemodialysis Patients . Phase1

Danoprevir is a peptidomimetic inhibitor of the NS3/4A protease of hepatitis C virus (HCV) with IC50 of 0.2-3.5 nM. The inhibition effect on HCV genotypes 1A/1B/4/5/6 is appr 10-fold higher than 2B/3A.

Edoxaban(DU-176) is an oral factor Xa (FXa) inhibitor in clinical development for stroke preventionIC50 Value:Target: factor XaEdoxaban is an oral factor Xa (FXa) inhibitor in clinical development for stroke prevention in patients with atrial fibrillation, an elderly population that frequently receives aspirin (ASA) and/or nonsteroidal anti-inflammatory drugs for concurrent illnesses[1].in vitro: Edoxaban PK was not affected by concomitant low-dose ASA or naproxen, but high-dose ASA increased systemic exposure of edoxaban by approximately 30%. The effects of edoxaban on prothrombin time, activated partial thromboplastin time, international normalized ratio, anti-FXa, and intrinsic FXa activity were not influenced by administration with ASA or naproxen. Inhibition of platelet aggregation by high-dose ASA, low-dose ASA, or naproxen was not affected by edoxaban[1].in vivo: Forty-eight subjects, aged 18 to 45 years, received either edoxaban 60 mg once daily × 7 days (n = 24) or digoxin 0.25 mg twice daily × 2 days and once daily × 5 days (n = 24) and then concomitantly for 7 days. Serial blood and urine samples were collected for digoxin and edoxaban concentrations on days 7 and 14. Serial coagulation assays were measured for edoxaban on days 7 and 14. Edoxaban PK parameters demonstrated mild increases in area under the curve and peak concentrations of 9.5% and 15.6%, respectively[2],Clinical trial: Pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in humans was reported[3].

Daclatasvir is a potent HCV NS5A protein inhibitor, with mean EC50 values of 50 and 9 pM against genotype 1a and 1b replicons, respectively.

Clarithromycin is a macrolide antibiotic and a CYP3A4 inhibitor.Target: Antibacterial; CYP3A4Clarithromycin is a macrolide antibiotic used to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia (especially atypical pneumonias associated with Chlamydophila pneumoniae), skin and skin structure infections. Clarithromycin prevents bacteria from growing by interfering with their protein synthesis. It binds to the subunit 50S of the bacterial ribosome and thus inhibits the translation of peptides. Clarithromycin has similar antimicrobial spectrum as erythromycin, but is more effective against certain Gram-negative bacteria, particularly Legionella pneumophila. Besides this bacteriostatic effect, clarithromycin also has bactericidal effect on certain strains, such as Haemophilus influenzae, Streptococcus pneumoniae and Neisseria gonorrhoeae. Clarithromycin is a CYP3A4 inhibitor. Even low doses of the cytochrome P4503A4 (CYP3A4) inhibitor clarithromycin increase the plasma concentrations and effects of repaglinide. Concomitant use of clarithromycin or other potent inhibitors of CYP3A4 with repaglinide may enhance its blood glucose-lowering effect and increase the risk of hypoglycemia [1, 2].

Simeprevir is a potent HCV NS3/4A protease inhibitor, and inhibits HCV replication with EC50 of 8 nM.LX1606 Hippurate is a novel, orally-delivered inhibitor of tryptophan hydroxylase that reduces serotonin production.

Cobicistat is a potent, and selective inhibitor of cytochrome P450 3A (CYP3A) enzymes with IC50 of 30-285 nM.

Ledipasvir is an inhibitor of the hepatitis C virus NS5A, with EC50 values of 34 pM against GT1a and 4 pM against GT1b replicon.Angiotensin (1-7) inhibits purified canine angiotensin converting enzyme (ACE) activity with an IC50 of 0.65 μM.

LCZ696 is a dual angiotensin II receptor and neprilysin inhibitor.

Saquinavir mesylate is an HIV Protease Inhibitor used in antiretroviral therapy. IC50 Value:Target: HIV ProteaseSaquinavir is a protease inhibitor. Proteases are enzymes that cleave protein molecules into smaller fragments. HIV protease is vital for both viral replication within the cell and release of mature viral particles from an infected cell. Saquinavir binds to the active site of the viral protease and prevents cleavage of viral polyproteins, preventing maturation of the virus. Saquinavir inhibits both HIV-1 and HIV-2 proteases.Studies have also looked at Saquinavir as a possible anti-cancer agent.Astragaloside IV, an active component isolated from Astragalus membranaceus, suppresses the activation of ERK1/2 and JNK, and downregulates matrix metalloproteases (MMP)-2, (MMP)-9 in MDA-MB-231 breast cancer cells.

Atazanavir sulfate is a sulfate salt form of atazanavir that is an highly potent HIV-1 protease inhibitor.Target: HIV-1 protease inhibitorAtazanavir sulfate is a sulfate salt form of atazanavir that is an highly potent HIV-1 protease inhibitor. It has a pharmacokinetic profile that supports once-daily dosing and has demonstrated a unique resistance profile and superior virologic potency compared with other antiretrovirals in vitro. In subjects with HIV, atazanavir (400 mg once daily) produced rapid and sustained improvements in viral load and CD4 counts in both antiretroviral-naive as well as previously treated patients when used in combination with dual nucleoside reverse transcriptase inhibitor (NRTI) treatment [1].After intravenous (iv), oral (po) and intraportal (ip) administration of ATV at a dosage of 7 mg/kg, AUCs in HL rats were 12.41, 5.24 and 8.89 microg/mLh, respectively, and were significantly higher than those in control rats (4.09, 1.70 and 3.38 microg/mLh). Despite the decrease of distribution volume (Vd(ss)), the terminal half-life (t(1/2)) in HL tended to be shorter than in control, and hepatic distribution of ATV in HL rats was 4.8-fold increases. These results suggested that the uptake of ATV into liver might counteract the decrease of Vd(ss). On the other hand, there was no significant difference in bioavailability, and the lymphatic transport to AUC showed no statistical change. In conclusion, although the protein binding rate and AUC were significantly increased, the pharmacokinetics of ATV might be tolerated in HL [2].Clinical indications: HIV-1 infection Toxicity: torsades de pointes

Velpatasvir (VEL, GS-5816) is a novel pan-genotypic hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor with activity against genotype 1 (GT1) to GT6 HCV replicons.target: NS5AStibogluconate sodium is is a potent inhibitor of PTPases Src homology PTPase1 (SHP-1), SHP-2, and PTP1B, inhibits 99% of SHP-1, SHP-2 and PTP1B activity at 10 μg/ml, 100 μg/ml respectively.target: SHP-1, SHP-2, PTP1B.[1]In vitro: Stibogluconate sodium inhibits protein tyrosine phosphatases. Stibogluconate sodium targets the SHP-1 PTPase catalytic domain and forms stable complexes with the phosphatase. Stibogluconate sodium induces tyrosine phosphorylation of cellular proteins and augments IL-3-induces Jak2/Stat5 phosphorylation in Baf3 cells. Stibogluconate sodium augments IL-3-induced cell proliferation of Baf3 cells. [1]In vivo: SSG induces 61% growth inhibition of Renca tumors in BALB/c mice coincident with an increase (2-fold) in tumorinfiltrating macrophages (M). [2]Ledipasvir acetone is the active pharmaceutical ingredient of Ledipasvir. Ledipasvir is an inhibitor of the hepatitis C virus NS5A, with EC50 values of 34 pM against GT1a and 4 pM against GT1b replicon.

[xls] · web view... lower clearance and higher oral bioavailability compared to 9a. following...

Documents