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Table S1 | Characteristics and origins of first-in-class drugs approved by the US FDA: 1999-2013 Target-based drugs: Denileukin diftitox, Ontak Indication Cancer (cutaneous T-cell lymphoma) Molecule Biologic (fusion protein of IL-2 and diphtheria toxin fragment B) Structure Not applicable First Patent WO 8303971, Harvard College, Murphy, John R.

Hybrid proteins Application: 12.05.1983 Publication: 24.11.1983

Approved Feb. 5, 1999 Target/MoA IL-2 receptor expressing cells (receptor mediated endocytosis and

subsequent cleavage delivers the toxin and results in cell death due to inhibition of protein synthesis)

Approach Target-based, biologic First published Concept and first construct:

Williams, D.P. et al. Diphtheria toxin receptor binding domain substitution with interleukin-2: genetic construction and properties of a diphtheria toxin-related interleukin-2 fusion protein. Protein Eng 1, 493-8 (1987). Williams, D.P., Snider, C.E., Strom, T.B. & Murphy, J.R. Structure/function analysis of interleukin-2-toxin (DAB486-IL-2). Fragment B sequences required for the delivery of fragment A to the cytosol of target cells. J Biol Chem 265, 11885-9 (1990).

Discovered Following the initial idea, rational design and proof of concept, the fusion protein has been further optimized.



Orlistat, Xenical Indication Obesity Molecule Natural product (derived) Structure

First Patent EP 129748, Hoffmann-LaRoche, P. Hadvary, E. Hochuli, E. Kupfer, H.

Lengsfeld, E.K. Weibel Application: 05.06.1984 Publication: 02.01.1985 Hexadecanoic acid and hexadecadienoic acid derivatives

Approved April 23, 1999 Target/MoA Gastric and pancreatic lipases, enzyme inhibitor Approach Target-based Low molecular weight First published Target established:

Roy, C.C. et al. The role of gastric lipolysis on fat absorption and bile acid metabolism in the rat. Lipids 14, 811-5 (1979). Chemotype: Hadvary, P.E., Hochuli, E., Kupfer, H., Lengsfeld & E.K. Weibel, Leucine derivatives. Eur. Pat. Appl. 0,129,748 (1985). Weibel, E.K., Hadvary, P., Hochuli, E., Kupfer, E. & Lengsfeld, H. Lipstatin, an inhibitor of pancreatic lipase, produced by Streptomyces toxytricini. I. Producing organism, fermentation, isolation and biological activity. J Antibiot (Tokyo) 40, 1081-5 (1987). Final molecule: Barbier, P. & Schneider, F. Syntheses of Tetrahydrolipstatin and Absolute-Configuration of Tetrahydrolipstatin and Lipstatin. Helvetica Chimica Acta 70, 196-202 (1987).

Discovered Chemotype discovered by high throughput screening; final compound is a close derivative.



Zanamivir, Relenza Indication Influenza viral infection Molecule Low molecular weight, synthetic Structure

First Patent WO 9116320, Biota, L.M. von Itzstein, W.Y. Wu, T.V. Phan, B. Danylec,

B. Jin Application: 24.04.1991 Publication: 31.10.1991 Preparation of derivatives and analogs of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid as antiviral agents

Approved July 26, 1999 Target/MoA Neuraminidase, enzyme inhibitor Approach Target-based Low molecular weight First published Target established:

Palese, P., Tobita, K., Ueda, M. & Compans, R.W. Characterization of Temperature Sensitive Influenza-Virus Mutants Defective in Neuraminidase. Virology 61, 397-410 (1974). Chemotype: Meindl, P., Bodo, G., Palese, P., Schulman, J. & Tuppy, H. Inhibition of Neuraminidase Activity by Derivatives of 2-Deoxy-2,3-Dehydro-N-Acetylneuraminic Acid. Virology 58, 457-463 (1974). Final molecule: von Itzstein, M. et al. Rational Design of Potent Sialidase-Based Inhibitors of Influenza-Virus Replication. Nature 363, 418-423 (1993). (compound was synthesized in 1989 according to Wikipedia)

Discovered A sialic acid-based transition state analogue, the original chemotype, has been used as a starting point for rational drug design using the crystal structure of the enzyme.



Gemtuzumab, Mylotarg Indication Cancer (acute myeloid leukemia) Molecule Biologic (anti-CD33 antibody-calicheamicin conjugate) Structure Not applicable First Patent EP 689845, American Cyanamid, Hamann, Philip Ross; Hinman, Lois;

Hollander, Irwin; Holcomb, Ryan; Tsou, Hwei-Ru; Hallett, William; Weiss, Martin J. Preparation of conjugates of methyltrithio antitumor agents. Application: 01.06.1995 Publication: 03.01.1996

Approved May 17, 2000 (withdrawn 2010) Target/MoA Antibody against CD33, conjugated to the antitumour agent calicheamicin Approach Target-based, biologic First published Target discovered:

Griffin, J.D., Linch, D., Sabbath, K., Larcom, P. & Schlossman, S.F. A Monoclonal-Antibody Reactive with Normal and Leukemic Human Myeloid Progenitor Cells. Leukemia Research 8, 521-534 (1984). Antibody: Appelbaum, F.R. et al. The Use of Radiolabeled Anti-Cd33 Antibody to Augment Marrow Irradiation Prior to Marrow Transplantation for Acute Myelogenous Leukemia. Transplantation 54, 829-833 (1992). Concept of toxin antibody conjugation: Hinman, L.M. et al. Preparation and Characterization of Monoclonal-Antibody Conjugates of the Calicheamicins - a Novel and Potent Family of Antitumor Antibiotics. Cancer Res 53, 3336-3342 (1993). Final molecule: Sievers, E.L. et al. Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: A phase I study of an anti-CD33 calicheamicin immunoconjugate. Blood 93, 3678-3684 (1999).

Discovered Rational design of an antibody drug conjugate.



Mifepristone, Mifegyne Indication Termination of intra-uterine pregnancies Molecule Natural Substance (derived) Structure

First Patent FR 2497807, Roussel-Uclaf, J.G. Teutsch, G. Costerousse, D. Philibert, R.

Deraedt Application: 09.01.1981 Publication: 16.06.1982 Steroid derivatives substituted at the 11β position

Approved Sept. 28, 2000 (approved in France since 1988) Target/MoA Progesterone receptor, nuclear hormone receptor antagonist Approach Target-based, low molecular weight First published Target established:

Pincus, G. (ed.) The control of Fertility. 128-138 (Academic Press, New York, 1965). Final molecule: Belanger, A., Philibert, D. & Teutsch, G. Regio and Stereospecific Synthesis of 11-Beta-Substituted 19-Norsteroids - Influence of 11-Beta-Substitution on Progesterone-Receptor Affinity. Steroids 37, 361-382 (1981).

Discovered Final molecule is a derivative of norethisterone (Djerassi, C., Miramontes, L., Rosenkranz, G. & Sondheimer, F. Steroids .54. Synthesis of 19-nor-17-Alpha-Ethynyltestosterone and 19-nor-17-Alpha-Methyltestosterone. Journal of the American Chemical Society 76, 4092-4094 (1954)), found to be a progesterone receptor antagonist (Schreiber, J.R., Hsueh, A.J. & Baulieu, E.E. Binding of the anti-progestin RU-486 to rat ovary steroid receptors. Contraception 28, 77-85 (1983))



Imatinib, Glivec Indication Cancer (chronic myelogenous leukemia, gastrointestinal stromal tumors) Molecule Low molecular weight, synthetic Structure

First Patent EP 564409, Ciba-Geigy, J. Zimmermann

Application: 25.03.1993 Publication: 06.10.1993 Preparation of 2-anilinopyrimidines as antiatherosclerotics and neoplasm inhibitors

Approved May 10, 2001 Target/MoA Bcr-Abl; cAbl kinase inhibitor Approach Target-based, low molecular weight First published Target established:

Shtivelman, E., Lifshitz, B., Gale, R.P. & Canaani, E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature 315, 550-4 (1985). Chemotype: Buchdunger, E. et al. Selective inhibition of the platelet-derived growth factor signal transduction pathway by a protein-tyrosine kinase inhibitor of the 2-phenylaminopyrimidine class. Proc Natl Acad Sci U S A 92, 2558-62 (1995). Final molecule: Buchdunger, E. et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res 56, 100-4 (1996).

Discovered Chemotype discovered for other kinases using high throughput screening, subsequently optimized for specific cAbl inhibition (Druker, B.J. & Lydon, N.B. Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest 105, 3-7 (2000)).



Anakinra, Kineret Indication Rheumatoid arthritis Molecule Biologic (human interleukin 1 receptor antagonist) Structure Not applicable First Patent WO 1991008285, Synergen, Hageman, Robert; Eisenberg, Stephen P.;

Dripps, David; Evans, Ronald; Cudny, Henryk; Thompson, Robert C. Recombinant manufacture of human interleukin-1 inhibitor Application: 29.11.1990 Publication: 13.06.1991

Approved Nov. 14, 2001 Target/MoA IL-1 receptor / natural occurring receptor antagonist Approach Target-based, biologic First published Target and indication:

Nouri, A.M., Panayi, G.S. & Goodman, S.M. Cytokines and the chronic inflammation of rheumatic disease. I. The presence of interleukin-1 in synovial fluids. Clin Exp Immunol 55, 295-302 (1984). Therapeutic concept: Liao, Z., Grimshaw, R.S. & Rosenstreich, D.L. Identification of a specific interleukin 1 inhibitor in the urine of febrile patients. J Exp Med 159, 126-36 (1984). Cloning of the receptor antagonist (final molecule): Eisenberg, S.P. et al. Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature 343, 341-6 (1990).

Discovered Following the discovery of a natural IL1 receptor antagonist (1984), the protein was cloned in 1990 and produced recombinantly as a therapeutic.



Bosentan, Tracleer Indication Pulmonary arterial hypertension Molecule Low molecular weight, synthetic Structure

First Patent CA 2071193, Hoffmann-LaRoche, K. Burri, M. Clozel, W. Fischli, G.

Hirth, B. Loeffler, M. Bernd, H. Ramuz Application: 12.06.1992 Publication: 14.12.1992 Preparation of pyrimidinylarylsulfonamides and analogs for treatment of circulatory disorders.

Approved Nov. 20, 2001 Target/MoA Endothelin-A and endothelin-B receptor, GPCR antagonist Approach Target-based, low molecular weight First published Target established:

Receptor assay: Fischli, W., Clozel, M. & Guilly, C. Specific receptors for endothelin on membranes from human placenta. Characterization and use in a binding assay. Life Sci 44, 1429-36 (1989). ETA receptor cloned: Arai, H., Hori, S., Aramori, I., Ohkubo, H. & Nakanishi, S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature 348, 730-2 (1990). ETB receptor cloned: Sakurai, T. et al. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature 348, 732-5 (1990). Chemotype: Clozel, M. et al. Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist. Nature 365, 759-61 (1993). Final molecule: Clozel, M. et al. Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist. J Pharmacol Exp Ther 270, 228-35 (1994).

Discovered Chemotype (first orally active endothelin receptor antagonist) discovered by high throughput screening using membrane preparations, further optimized to final compound using cloned receptors.



Drotrecogin alfa, Xigris Indication Sepsis Molecule Biologic (recombinant activated protein C) Structure Not applicable First Patent EP 245949, Eli Lilly, Grinnel, Brian William

Gene expression enhancement in eukaryotic cells using BK virus enhancer in presence of large DNA virus immediate-early gene products Application: 09.04.1987 Publication: 19.11.1987

Approved Nov. 21, 2001 (withdrawn 2011) Target/MoA Reduced levels of protein C are found in most sepsis patients; activated

protein C is a serine protease with anti-thrombotic and anti-inflammatory activities, protease

Approach Target-based, biologic First published Concept established:

Taylor, F.B., Jr. et al. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 79, 918-25 (1987). Final molecule (recombinant enzyme): Ehrlich, H.J., Jaskunas, S.R., Grinnell, B.W., Yan, S.B. & Bang, N.U. Direct expression of recombinant activated human protein C, a serine protease. J Biol Chem 264, 14298-304 (1989).

Discovered Concept established with purified endogenous enzyme in baboons. Recombinant enzyme for therapeutic use has subsequently been produced. The drug has been withdrawn in 2011 due to lack of efficacy.



Rasburicase Indication Cancer (tumour lysis syndrome, hyperuricemia) Molecule Biologic (urate oxidase) Structure Not applicable First Patent EP 408461, Sanofi, Caput, Daniel; Ferrara, Pascual; Guillemot, Jean

Claude; Kaghad, Mourad; Legoux, Richard; Loison, Gerard; Larbre, Elizabeth; Lupker, Johannes; Leplatois, Pascal; et al. Cloning and expression of a cDNA for urate oxidase from Aspergillus flavus Application: 13.06.1990 Publication: 16.01.1991

Approved Dec. 7, 2002 (1975 in Europe) Target/MoA Urate oxidase catalyses the conversion of uric acid to allantoin (tumour

lysis leads to elevated levels of uric acid, the final step in the catabolism of purines; allantoin is significantly more soluble than uric acid and can be eliminated efficiently), enzyme

Approach Target-based, biologic First published Concept and therapy:

Oberling, F. & Lang, J.M. [Letter: Hyperuricemia in hematological pathology. Therapy and prevention using urate oxidase]. Nouv Presse Med 3, 2026 (1974). Final molecule (recombinant enzyme): Legoux, R. et al. Cloning and expression in Escherichia coli of the gene encoding Aspergillus flavus urate oxidase. J Biol Chem 267, 8565-70 (1992).

Discovered Since 1975, a nonrecombinant form of urate oxidase (Uricozyme) has been available in Europe; the recombinant form has subsequently been generated.



Alefacept Indication Psoriasis Molecule Biologic (LFA3-IgG Fc fusion protein) Structure Not applicable First Patent WO 8809820, Biogen; Dana-Farber Cancer Institute, Wallner, Barbara P.;

Springer, Timothy A.; Hession, Catherine; Tizard, Richard; Mattaliano, Robert; Dustin, Michael L. Cloning and sequencing of human lymphocyte function associated antigen-3 (LFA-3) cDNA Application: 03.06.1988 Publication: 15.12.1988

Approved Jan. 30, 2003 Target/MoA Binding to CD2, inhibiting its interaction with endogenous LFA3 Approach Target-based, biologic First published Concept established:

Shaw, S. et al. Two antigen-independent adhesion pathways used by human cytotoxic T-cell clones. Nature 323, 262-4 (1986). Final molecule: Miller, G.T. et al. Specific interaction of lymphocyte function-associated antigen 3 with CD2 can inhibit T cell responses. J Exp Med 178, 211-22 (1993). Indication: Ellis, C.N. & Krueger, G.G. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med 345, 248-55 (2001).

Discovered Rational design; used as a tool to study the biology of LFA3/CD2 interaction, subsequently been used as a therapeutic modality.



Enfuvirtide, Fuzeon Indication HIV infection Molecule Natural substance (derived) Structure

First Patent WO 9428920, Duke University, D.P Bolognesi, T.J. Matthews, C.T. Wild, S.O.

Barney, D.N. Lambert, S.R. Jr Petteway Synthetic peptide inhibitors of transmission of HIV and other viruses Application: 07.07.1994 Publication: 22.12.1994

Approved March 13, 2003 Target/MoA Peptide binds to gp41 and prevents conformational change which is essential for viral

entry Approach Target-based, low molecular weight First published Concept established:

Owens, R.J., Tanner, C.C., Mulligan, M.J., Srinivas, R.V. & Compans, R.W. Oligopeptide inhibitors of HIV-induced syncytium formation. AIDS Res Hum Retroviruses 6, 1289-96 (1990). Final molecule: Wild, C., Greenwell, T. & Matthews, T. A synthetic peptide from HIV-1 gp41 is a potent inhibitor of virus-mediated cell-cell fusion. AIDS Res Hum Retroviruses 9, 1051-3 (1993). Mechanism of action (cellular): Wild, C.T., Shugars, D.C., Greenwell, T.K., McDanal, C.B. & Matthews, T.J. Peptides corresponding to a predictive alpha-helical domain of human immunodeficiency virus type 1 gp41 are potent inhibitors of virus infection. Proc Natl Acad Sci U S A 91, 9770-4 (1994). Mechanism of action (molecular): Kliger, Y. et al. Mode of action of an antiviral peptide from HIV-1. Inhibition at a post-lipid mixing stage. J Biol Chem 276, 1391-7 (2001).

Discovered Peptides from gp41 have been found to inhibit viral infection in vitro. Subsequently, the most potent sequence has been identified and shown to be a viral entry inhibitor.



Pegvisomant, Somavert Indication Acromegaly Molecule Biologic (peggylated human growth hormone variant) Structure Not applicable First Patent 2004037245, Genentech, Cunningham, Brian C.; Lowman, Henry B.;

Wells, James A.; Clark, Ross G.; Olson, Kenneth; Fuh, Germaine G. Human growth hormone variants and conjugates with PEG, enhanced affinity for receptor, and acromegaly, tumor, or diabetic retinopathy treatment Application: 20.09.1996 Publication: 27.03.1997

Approved March 25, 2003 Target/MoA Human growth hormone receptor, receptor antagonist Approach Target-based, biologic First published Concept established:

Fuh, G. et al. Rational design of potent antagonists to the human growth hormone receptor. Science 256, 1677-80 (1992). Optimized protein: Lowman, H.B. & Wells, J.A. Affinity maturation of human growth hormone by monovalent phage display. J Mol Biol 234, 564-78 (1993). Peggylated protein: Olsen K, et al. Preparation and characterization of poly(ethylene glycol)ylated human growth hormone antagonist. In: Harris JM, Zalipsky S, eds. Poly(ethylene glycol). Chemistry and biological applications. Washington, DC: American Chemical Society; 170–181. (1997).

Discovered Rational design of antagonist based on natural agonist and mechanism of action. Subsequently the amino acid sequence has been optimized and the protein peggylated to improve the pharmacokinetic properties.



Aprepitant, Emend Indication Chemotherapy induced nausea and vomiting Molecule Low molecular weight, synthetic Structure

First Patent WO 9523798, Merck & Co, C.P. Dorn, J.J. Hale, M. MacCoss, S.G. Mills

Application: 28.02.1995 Publication: 08.09.1995 Preparation of morpholine tachykinin receptor antagonist prodrugs

Approved March 26, 2003 Target/MoA Neurokinin 1 receptor, GPCR antagonist Approach Target-based, low molecular weight First published Target established:

Cloning of the NK 1 receptor: Takeda, Y., Chou, K.B., Takeda, J., Sachais, B.S. & Krause, J.E. Molecular-Cloning, Structural Characterization and Functional Expression of the Human Substance-P Receptor. Biochemical and Biophysical Research Communications 179, 1232-1240 (1991). Indication: Bountra, C. et al. Antiemetic Profile of a Nonpeptide Neurokinin-Nk(1) Receptor Antagonist, Cp-99,994, in Ferrets. Eur J Pharmacol 249, R3-R4 (1993). First LMW inhibitor (different chemotype): Snider, R.M. et al. A Potent Nonpeptide Antagonist of the Substance-P (Nk1) Receptor. Science 251, 435-437 (1991). Chemotype: Hale, J.J. et al. 2(S)-((3,5-bis(trifluoromethyl)benzyl)oxy)-3(S)-phenyl-4-((3-oxo-1,2,4-triazol-5-yl)methyl)morpholine .1. A potent, orally active, morpholine-based human neurokinin-1 receptor antagonist. J Med Chem 39, 1760-1762 (1996). Final molecule: Hale, J.J. et al. Structural optimization affording 2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a potent, orally active, long-acting morpholine acetal human NK-1 receptor antagonist. J Med Chem 41, 4607-4614 (1998).

Discovered First LMW inhibitors discovered through high throughput screening (using membrane preparations), chemotype and final molecule derived through morphing of the published initial antagonists and further optimization.



Agalsidase beta, Fabrazyme Indication Fabry disease Molecule Biologic (Alpha-galactosidase A) Structure Not applicable First Patent WO 9412628, Mount Sinai School of Medicine, Desnick, Robert J.;

Bishop, David F.; Ioannou, Yiannis A. Biologically active human α-galactosidase A and its manufacture by expression of the cloned gene Application: 30.11.1993 Publication: 09.06.1994

Approved April 24, 2003 Target/MoA Alpha-galactosidase A, enzyme replacement therapy Approach Target-based, biologic First published Disease mechanism established:

Brady, R.O. et al. Enzymatic Defect in Fabrys Disease - Ceramidetrihexosidase Deficiency. New England Journal of Medicine 276, 1163-& (1967). Concept established: Dawson, G., Matalon, R. & Li, Y.T. Correction of Enzymic Defect in Cultured Fibroblasts from Patients with Fabrys-Disease - Treatment with Purified Alpha-Galactosidase from Ficin. Pediatric Research 7, 684-690 (1973). Molecule (recombinant enzyme): Ioannou, Y.A., Bishop, D.F. & Desnick, R.J. Overexpression of Human Alpha-Galactosidase-a Results in Its Intracellular Aggregation, Crystallization in Lysosomes, and Selective Secretion. Journal of Cell Biology 119, 1137-1150 (1992).

Discovered The genetic defect was discovered in 1967, the principle of enzyme replacement therapy established in 1973, and the recombinant protein production established in 1992.



Laronidase, Aldurazyme Indication Mucopolysaccharidosis type I Molecule Biologic (Iduronidase) Structure Not applicable First Patent WO 2002004616, BioMarin, Hendstrand, John M.; Qin, Minmin; Chan, Wia-Pan;

Chen, Lin; Fitzpatrick, Paul A.; Wendt, Dan J.; Zecherle, Gary N.; Starr, Christopher M.; Kakkis, Emil D. Large scale recombinant α-L-iduronidase production and purification for mucopolysaccharidosis I enzyme-replacement therapy Application: 09.11.2000 Publication: 17.01.2002

Approved April 30, 2003 Target/MoA Iduronidase, enzyme replacement therapy Approach Target-based, biologic First published Disease mechanism:

Bach, G., Weissman.B, Friedman, R. & Neufeld, E.F. Defect in Hurler and Scheie Syndromes - Deficiency of Alpha-Iduronidase. Proc Natl Acad Sci U S A 69, 2048-& (1972). Enzyme cloned: Scott, H.S. et al. Human Alpha-L-Iduronidase - Cdna Isolation and Expression. Proc Natl Acad Sci U S A 88, 9695-9699 (1991). Final molecule and concept established: Unger, E.G., Durrant, J., Anson, D.S. & Hopwood, J.J. Recombinant Alpha-L-Iduronidase - Characterization of the Purified Enzyme and Correction of Mucopolysaccharidosis Type-I Fibroblasts. Biochemical Journal 304, 43-49 (1994).

Discovered The genetic defect was discovered in 1972, the gene cloned in 1991, and the principle of enzyme replacement therapy established in 1994.



Gefitinib, Iressa Indication Cancer (breast, lung, others) Molecule Low molecular weight, synthetic Structure

First Patent WO 9633980, Zeneca, K.H. Gibson

Preparation of haloanilinoquinazolines as Class I receptor tyrosine kinase inhibitors Application: 23.04.1996 Publication: 31.10.1996

Approved May 5, 2003 Target/MoA EGF receptor; kinase inhibitor Approach Target-based, low molecular weight First published Target established:

Goustin, A.S., Leof, E.B., Shipley, G.D. & Moses, H.L. Growth-Factors and Cancer. Cancer Res 46, 1015-1029 (1986). Chemotype: Ward, W.H.J. et al. Epidermal Growth-Factor Receptor Tyrosine Kinase - Investigation of Catalytic Mechanism, Structure-Based Searching and Discovery of a Potent Inhibitor. Biochemical Pharmacology 48, 659-666 (1994). Final molecule: Woodburn J.R., et al., ZD1839, an epidermal growth factor tyrosine kinase inhibitor selected for clinical development. Journal of Immunotherapy 20, 408, (1997).

Discovered The chemotype was discovered by structure-based in silico screening and further optimized to the final molecule using an enzymatic assay.



Bortezomib, Velcade Indication Cancer (multiple myeloma, mantle cell lymphoma) Molecule Low molecular weight, synthetic Structure

First Patent WO 9613266, Proscript, J. Adams, Y.-T. Ma, R. Stein, M. Baevsky, L.

Grenier, L. Plamondon Boronic ester and acid compounds, synthesis and uses Application: 27.10.1995 Publication: 09.05.1996

Approved May 13, 2003 Target/MoA 26S proteasome, protease inhibitor Approach Target-based, low molecular weight First published Chemotype:

Vinitsky, A., Michaud, C., Powers, J.C. & Orlowski, M. Inhibition of the chymotrypsin-like activity of the pituitary multicatalytic proteinase complex. Biochemistry 31, 9421-8 (1992). Target/indication: Wada, M. et al. Serum concentration and localization in tumor cells of proteasomes in patients with hematologic malignancy and their pathophysiologic significance. J Lab Clin Med 121, 215-23 (1993). Final molecule: Palombella, V.J. et al. Role of the proteasome and NF-kappaB in streptococcal cell wall-induced polyarthritis. Proc Natl Acad Sci U S A 95, 15671-6 (1998).

Discovered Rational design and optimization based on peptide inhibitors and protease specificity



Omalizumab, Xolair Indication Asthma Molecule Biologic (anti-IgE antibody) Structure Not applicable First Patent WO 9901556, Genentech, Lowman, Henry B.; Presta, Leonard G.;

Jardieu, Paula M.; Lowe, John Improved anti-IgE antibodies and method of improving polypeptides Application: 30.06.1998 Publication: 14.01.1999

Approved June 20, 2003 Target/MoA Antibody against IgE, neutralizing the action of free IgE Approach Target-based, biologic First published Concept (and first antibodies):

Chang, T.W. et al. Monoclonal antibodies specific for human IgE-producing B cells: a potential therapeutic for IgE-mediated allergic diseases. Biotechnology (N Y) 8, 122-6 (1990). Antibody (murine): Presta, L.G. et al. Humanization of an antibody directed against IgE. J Immunol 151, 2623-32 (1993). Final molecule: Shields, R.L. et al. Inhibition of allergic reactions with antibodies to IgE. Int Arch Allergy Immunol 107, 308-12 (1995).

Discovered Rational generation of antibodies with desired specificities. A mouse monoclonal antibody was later humanized.



Efalizumab, Raptiva Indication Psoriasis Molecule Biologic (anti-LFA-1 antibody) Structure Not applicable First Patent WO 9823761, Genentech, Jardieu, Paula M.; Presta, Leonard G.

Humanized anti-CD11a antibodies Application: 20.10.1997 Publication: 04.06.1998

Approved Oct. 27, 2003 (withdrawn 2009) Target/MoA Antibody against the alpha subunit (CD11a) of LFA-1; inhibits the

activation of T cells Approach Target-based, biologic First published Target (and first antibody):

Davignon, D., Martz, E., Reynolds, T., Kurzinger, K. & Springer, T.A. Lymphocyte function-associated antigen 1 (LFA-1): a surface antigen distinct from Lyt-2,3 that participates in T lymphocyte-mediated killing. Proc Natl Acad Sci U S A 78, 4535-9 (1981). Antibody (murine): Hildreth, J.E., Gotch, F.M., Hildreth, P.D. & McMichael, A.J. A human lymphocyte-associated antigen involved in cell-mediated lympholysis. Eur J Immunol 13, 202-8 (1983). Final molecule (humanized antibody): Werther, W.A. et al. Humanization of an anti-lymphocyte function-associated antigen (LFA)-1 monoclonal antibody and reengineering of the humanized antibody for binding to rhesus LFA-1. J Immunol 157, 4986-95 (1996).

Discovered First antibodies used to study target biology; therapeutic antibody generated subsequently.



Cetuximab, Erbitux Indication Cancer (colon, head and neck) Molecule Biologic (anti-EGFR antibody) Structure Not applicable First Patent WO 9640210, Imclone, Goldstein, Neil I.; Giorgio, Nicholas A.; Jones,

Steven Tarran; Saldanha, Jose William Antibody and antibody fragments for inhibiting the growth of tumors Application: 07.06.1996 Publication: 19.12.1996

Approved Feb. 12, 2004 Target/MoA Antibody against epidermal growth factor receptor, receptor blocker Approach Target-based, biologic First published First mouse antibody:

Sato, J.D. et al. Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol Biol Med 1, 511-29 (1983). Concept: Goustin, A.S., Leof, E.B., Shipley, G.D. & Moses, H.L. Growth factors and cancer. Cancer Res 46, 1015-29 (1986). Clinical studies with mouse antibody: Divgi, C.R. et al. Phase I and imaging trial of indium 111-labeled anti-epidermal growth factor receptor monoclonal antibody 225 in patients with squamous cell lung carcinoma. J Natl Cancer Inst 83, 97-104 (1991). Final antibody (chimeric) Goldstein, N.I., Prewett, M., Zuklys, K., Rockwell, P. & Mendelsohn, J. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1, 1311-8 (1995).

Discovered Mouse monoclonal antibody generated in 1983 and used for initial clinical studies. Chimeric antibody produced for further studies to avoid anti-mouse antibody responses.



Bevacizumab, Avastin Indication Cancer (colon, lung, renal, glioblastoma) Molecule Biologic (anti-VEGF antibody) Structure Not applicable First Patent WO 9845331, Anti-VEGF antibodies, Baca, Manuel; Wells, James A.;

Presta, Leonard G.; Lowman, Henry B.; Chen, Yvonne Man-yee Anti-VEGF antibodies Application: 03.04.1998 Publication: 15.10.1998

Approved Feb. 26, 2004 Target/MoA Antibody against vascular endothelial growth factor A Approach Target-based, biologic First published Target identified:

Senger, D.R. et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219, 983-5 (1983). Target cloned: Leung, D.W., Cachianes, G., Kuang, W.J., Goeddel, D.V. & Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246, 1306-9 (1989). Antibody and proof of concept: Kim, K.J. et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362, 841-4 (1993). Final molecule: Presta, L.G. et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 57, 4593-9 (1997).

Discovered VEGF-A identified in 1983 and cloned in 1989. Antibody used for in vivo proof-of-concept studies in 1993 and humanized for therapeutic purposes.



Cinacalcet, Sensipar Indication Secondary hyperparathyroidism and hypercalcemia in patients with

parathyroid carcinoma Molecule Low molecular weight, synthetic Structure

First Patent US 6211244 NPS Pharmaceuticals, B.C. Van Wagenem, S.T. Moe, M.F.

Balandrin, E.G. Delmar, E.F. Nemeth Application 23.10.1995 Publication 03.04.2001 1-arylethylamines as calcium receptor ligands

Approved March 8, 2004 MoA Allosteric activation of the calcium-sensing receptor (directly lowers

parathyroid hormone levels by increasing the sensitivity of the calcium sensing receptors to activation by extracellular calcium, resulting in the inhibition of PTH secretion), GPCR agonist

Approach Target-based, low molecular weight First published Chemotype and indication:

Nemeth, E.F., Van Wagenen B.C., Balandrin M.F., Calcium receptor active molecules. Chem. Abstr. 119 P63054s. (1993). Nemeth, E.F. et al. Calcimimetics with potent and selective activity on the parathyroid calcium receptor. Proc Natl Acad Sci U S A 95, 4040-5 (1998). Final molecule: Goodman, W.G. et al. The Calcimimetic agent AMG 073 lowers plasma parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism. J Am Soc Nephrol 13, 1017-24 (2002).

Discovered The chemotype was discovered using a low throughput (20-40 compounds/week) assay based on a well-characterized cellular system set up to monitor the receptor (Nemeth, E.F. Misconceptions about calcimimetics. Skeletal Development and Remodeling in Health, Disease, and Aging 1068, 471-476 (2006)). The idea to test the specific chemotype came from fendiline, a calcium channel blocker discovered in the 1970s (Sprugel, W., Mitznegg, P. & Heim, F. Influence of Calcium Antagonist Fendiline on Tone and Motility of Guinea-Pig Gut Smooth-Muscle and Camp and Cgmp Concentrations of Isolated Terminal Ileum. Arzneimittel-Forschung/Drug Research 27-1, 571-574 (1977)).



Acamprosate, Campral Indication Alcohol dependence Molecule Natural substance (derived) Structure

First Patent WO 9948500, LIPHA, J.-J. Berthelon, P. Durbin

Preparation of metal salts of sulfonate- or phosphonate- or phosphinate-containing amidoalkanes and their use in the treatment of alcoholism Application: 27.01.1998 Publication: 29.07.1999

Approved July 29, 2004 (1989 in Europe) Target/MoA Based on similarity to GABA, thought to act through GABA receptors,

GPCR agonist Approach Target-based, low molecular weight First published Mechanistic understanding:

Enna, S.J. & Snyder, S.H. Properties of Gamma-Aminobutyric Acid (Gaba) Receptor-Binding in Rat-Brain Synaptic Membrane-Fractions. Brain Res 100, 81-97 (1975). Indication: Boismare, F. et al. A Homotaurine Derivative Reduces the Voluntary Intake of Ethanol by Rats - Are Cerebral Gaba Receptors Involved. Pharmacology Biochemistry and Behavior 21, 787-789 (1984).

Discovered Due to similarity to GABA, homotaurin has been shown to be a stable GABA receptor agonist. Mechanistic link to alcohol dependence made later. Approved in Europe since 1989



Natalizumab, Tysabri Indication Multiple sclerosis, Crohn’s disease Molecule Biologic (anti-VLA-4 (alpha4beta1 integrin) antibody) Structure Not applicable First Patent WO 2003072040, Elan, Taylor, Julie; Yednock, Ted A.

Administration of agents for the treatment of inflammation Application: 25.02.2003 Publication: 04.09.2003

Approved Nov. 23, 2004 Target/MoA Antibody against VLA-4, blocks leukocyte homing Approach Target-based, biologic First published Target established:

Yednock, T.A. et al. Prevention of Experimental Autoimmune Encephalomyelitis by Antibodies against Alpha-4-Beta-1 Integrin. Nature 356, 63-66 (1992). Mouse monoclonal antibody: Kent, S.J. et al. A Monoclonal-Antibody to Alpha-4 Integrin Suppresses and Reverses Active Experimental Allergic Encephalomyelitis. Journal of Neuroimmunology 58, 1-10 (1995). Final molecule: Leger, O.J. et al. Humanization of a mouse antibody against human alpha-4 integrin: a potential therapeutic for the treatment of multiple sclerosis. Hum Antibodies 8, 3-16 (1997).

Discovered The concept was established with tool antibodies. Subsequently a monoclonal antibody was generated and later humanized.



Palifermin, Kepivance Indication Cancer (chemotherapy-induced oral mucositis) Molecule Biologic (23 amino acid N-terminal truncation of keratinocyte growth

factor (FGF-7)) Structure Not applicable First Patent WO 9611952, Amgen, Method for purifying keratinocyte growth factors

Hsu, Eric W.; Kenney, William C.; Tressel, Tim Application: 12.10.1995 Publication: 25.04.1996

Approved Dec. 15, 2004 Target/MoA Keratinocyte growth factor stimulated cell growth, receptor agonist Approach Target-based, biologic First published Molecule identified:

Rubin, J.S. et al. Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc Natl Acad Sci U S A 86, 802-6 (1989). Molecule cloned : Finch, P.W., Rubin, J.S., Miki, T., Ron, D. & Aaronson, S.A. Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth. Science 245, 752-5 (1989). Concept established: Farrell, C.L. et al. Keratinocyte growth factor protects mice from chemotherapy and radiation-induced gastrointestinal injury and mortality. Cancer Res 58, 933-9 (1998).

Discovered The growth factor was discovered in 1989 and the therapeutic concept established in 1998.



Pramlintide, Symlin Indication Diabetes type 1 and 2 Molecule Natural substance (derived) Structure Not applicable First Patent WO 9310146, Amylin, Gaeta, Laura S. L.; Jones, Howard; Albrecht,

Elisabeth Preparation of amylin agonists for treatment of diabetes and hypoglycemia Application: 19.11.1992 Publication: 27.05.1993

Approved March 16, 2005 Target/MoA Human amylin variant Approach Target-based, low molecular weight First published Concept established:

Koda, J.E. et al. Amylin concentrations and glucose control. Lancet 339, 1179-80 (1992). Final molecule: Kolterman, O.G., Gottlieb, A., Moyses, C. & Colburn, W. Reduction of postprandial hyperglycemia in subjects with IDDM by intravenous infusion of AC137, a human amylin analogue. Diabetes Care 18, 1179-82 (1995).

Discovered Following the discovery of the role of amylin in glucose control, a more soluble analogue has been designed on the basis of the rat sequence.



Exenatide, Byetta Indication Diabetes type 2 Molecule Natural substance (derived) Structure Not applicable First Patent WO 9805351, Amylin, Young, Andrew A.; Gedulin, Bronislava; Beeley,

Nigel Robert Arnold; Prickett, Kathryn S. Preparation of exendin peptide analogs as agonists for regulating gastrointestinal motility Application: 08.08.1997 Publication: 12.02.1998

Approved April 28, 2005 Target/MoA GLP-1 receptor, GPCR agonist Approach Target-based, low molecular weight First published Chemotype (first peptides):

Parker, D.S. et al. Amino acid sequences of helospectins, new members of the glucagon superfamily, found in Gila monster venom. J Biol Chem 259, 11751-5 (1984). Final molecule: Eng, J., Kleinman, W.A., Singh, L., Singh, G. & Raufman, J.P. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem 267, 7402-5 (1992). Mechanism of action: Goke, R. et al. Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells. J Biol Chem 268, 19650-5 (1993).

Discovered Peptides of the glucagon superfamily with secretagogue activity were found in the saliva of lizards; a search for additional peptides of the glucagon superfamily led to the discovery of exenatide (exendin-4).



Galsulfase, Naglazyme Indication Mucopolysaccharidosis type VI Molecule Biologic (arylsulfatase B) Structure Not applicable First Patent WO 2001083722, BioMarin, Starr, Christopher M.

Methods for treating MPS-VI using human N-acetylgalactosamine-4-sulfatase and cells lines for producing the enzyme recombinantly Application: 25.04.2001 Publication: 08.11.2001

Approved May 31, 2005 Target/MoA Acetylsulfatase B, enzyme replacement therapy Approach Target-based, biologic First published Disease mechanism established:

O'Brien, J.F., Cantz, M. & Spranger, J. Maroteaux-Lamy disease (mucopolysaccharidosis VI), subtype A: deficiency of a N-acetylgalactosamine-4-sulfatase. Biochem Biophys Res Commun 60, 1170-7 (1974). Enzyme cloned: Peters, C. et al. Phylogenetic conservation of arylsulfatases. cDNA cloning and expression of human arylsulfatase B. J Biol Chem 265, 3374-81 (1990). Final molecule (recombinant enzyme) and concept: Anson, D.S. et al. Correction of human mucopolysaccharidosis type-VI fibroblasts with recombinant N-acetylgalactosamine-4-sulphatase. Biochemical Journal 284 ( Pt 3), 789-94 (1992).




Ramelteon, Rozerem Indication Insomnia Molecule Natural Substance (derived) Structure

First Patent WO 9732871, Takeda, S. Ohkawa, O. Uchikawa, K. Fukatsu, M.

Miyamoto Preparation of tricyclic compounds with binding affinity for melatonin receptor Application: 05.03.1997 Publication: 12.09.1997

Approved July 22, 2005 Target/MoA Melatonin MT1 and MT2 receptor, GPCR agonist Approach Target-based, low molecular weight First published Target established:

Reppert, S.M., Weaver, D.R. & Ebisawa, T. Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron 13, 1177-85 (1994). Final molecule: Hirai, S. et al. Metabolites of febrifugine and its synthetic analogue by mouse liver S9 and their antimalarial activity against Plasmodium malaria parasite. J Med Chem 46, 4351-9 (2003).

Discovered The final molecule is a derivative of melatonin which is a known natural substance inducing sleep (Marczynski, T.J., Yamaguchi, N., Ling, G.M. & Grodzinska, L. Sleep induced by the administration of melatonin (5-methoxyn-acetyltryptamine) to the hypothalamus in unrestrained cats. Experientia 20, 435-7 (1964)).



Sorafenib, Nexavar Indication Cancer (renal, liver) Molecule Low molecular weight, synthetic Structure

First Patent WO 2000042012, Bayer, B. Riedl, J. Dumas, U. Khire, T.B. Lowinger,

W.J. Scott, R.A. Smith, J.E. Wood, M.-K. Monahan, R. Natero, J. Renick, R.N. Sibley Preparation of ω-carboxy(hetero)aryl substituted diphenyl ureas as raf kinase inhibitors Application: 12.01.2000 Publication: 20.07.2000

Approved Dec. 20, 2005 Target/MoA Raf, VEGF receptor; kinase inhibitor Approach Target-based, low molecular weight First published Target established:

Kasid, U. et al. Effect of antisense c-raf-1 on tumorigenicity and radiation sensitivity of a human squamous carcinoma. Science 243, 1354-6 (1989). First LMW inhibitor (different chemotype): Claremon, D.A., Heimbrook, D.C., Liverton, N., Selnick, H.G., Huber, H.E., Mantlo, N.B., & Patrick, D.R., Preparation of imidazole derivatives for treatment of Raf-mediated disease. UK Patent GB 2306108 (1997). Hall-Jackson, C.A. et al. Paradoxical activation of Raf by a novel Raf inhibitor. Chem Biol 6, 559-68 (1999). Chemotype: Smith, R.A. et al. Discovery of heterocyclic ureas as a new class of raf kinase inhibitors: identification of a second generation lead by a combinatorial chemistry approach. Bioorganic & Medicinal Chemistry Letters 11, 2775-8 (2001). Final molecule: Lowinger, T.B., Riedl, B., Dumas, J. & Smith, R.A. Design and discovery of small molecules targeting raf-1 kinase. Curr Pharm Des 8, 2269-78 (2002).

Discovered Chemotype discovered by high throughput screening for Raf inhibition and further optimized. Project started in 1994 (Wilhelm, S. et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5, 835-44 (2006)).



Abatacept, Orencia Indication Rheumatoid arthritis Molecule Biologic (CTLA4-IgG Fc fusion protein) Structure Not applicable First Patent WO 9300431, Bristol-Myers, Linsley, Peter S.; Ledbetter, Jeffrey A.;

Damle, Nitin K.; Brady, William. CTLA4 receptor, its cDNA cloning and fusion proteins and uses of the fusion proteins. Application: 16.06.1992 Publication: 07.01.1993

Approved Dec. 23, 2005 Target/MoA Binding to CD80 and CD86, inhibiting the interaction with CD28 Approach Target-based, biologic First published Concept and molecule:

Linsley, P.S. et al. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 174, 561-9 (1991). Indication: Knoerzer, D.B., Karr, R.W., Schwartz, B.D. & Mengle-Gaw, L.J. Collagen-induced arthritis in the BB rat. Prevention of disease by treatment with CTLA-4-Ig. J Clin Invest 96, 987-93 (1995).

Discovered The molecule (fusion protein) has originally been generated as a tool to study the function of CTLA-4 and subsequently been used as a therapeutic modality.



Conivaptan, Vaprisol Indication Hyponatremia Molecule Low molecular weight, synthetic Structure

First Patent WO 9503305, Yamanouchi, A. Tanaka, H. Koshio, N. Taniguchi,

A.Matsuhisa, K.-i. Sakamoto, A. Yamazaki, T. Yatsu Preparation of fused benzazepine derivs. as arginine vasopressin antagonists Application: 19.07.1994 Publication: 02.02.1995

Approved Dec. 29, 2005 Target/MoA Vasopressin V1A and V2 receptor, GPCR antagonist Approach Target-based, low molecular weight First published Target established:

Stassen, F.L. et al. Molecular mechanisms of novel antidiuretic antagonists: analysis of the effects on vasopressin binding and adenylate cyclase activation in animal and human kidney. J Pharmacol Exp Ther 223, 50-4 (1982). V2 receptor cloned: Lolait, S.J. et al. Cloning and characterization of a vasopressin V2 receptor and possible link to nephrogenic diabetes insipidus. Nature 357, 336-9 (1992). V1A receptor cloned: Thibonnier, M. et al. Molecular cloning, sequencing, and functional expression of a cDNA encoding the human V1a vasopressin receptor. J Biol Chem 269, 3304-10 (1994). First non-peptide inhibitor (different chemotype): Yamamura, Y. et al. OPC-21268, an orally effective, nonpeptide vasopressin V1 receptor antagonist. Science 252, 572-4 (1991). Chemotype: Yamamura, Y. et al. Characterization of a novel aquaretic agent, OPC-31260, as an orally effective, nonpeptide vasopressin V2 receptor antagonist. Br J Pharmacol 105, 787-91 (1992). Final molecule: Yatsu, T. et al. Pharmacological profile of YM087, a novel nonpeptide dual vasopressin V1A and V2 receptor antagonist, in dogs. Eur J Pharmacol 321, 225-30 (1997).

Discovered First non-peptidic antagonist discovered by high throughput screening using membrane preparations. The benzazepin chemotype was derived from this initial antagonist through modifications and further optimized to the final molecule.



Sunitinib, Sutent Indication Cancer (renal cell carcinoma and gastrointestinal stromal tumour) Molecule Low molecular weight, synthetic Structure

First Patent WO 2001060814, Sugen, P.C. Tang, T. Miller, X. Li, L. Sun, C.C. Wei, S.

Shirazian, C. Liang, T. Vojkovsky, A.S. Nematalla Preparation of pyrrole substituted 2-indolinone protein kinase inhibitors for treatment of cancer. Application: 15.02.2001 Publication: 23.08.2001

Approved Jan. 26, 2006 Target/MoA Platelet-derived growth factor and vascular endothelial growth factor

receptors, KIT, Flt3; kinase inhibitor Approach Target-based, low molecular weight First published Target established:

PDGF-R: Goustin, A.S., Leof, E.B., Shipley, G.D. & Moses, H.L. Growth factors and cancer. Cancer Res 46, 1015-29 (1986).Goustin AS, Leof EB, Shipley GD, Moses HL, Cancer Res. 1986 Mar;46(3):1015-29, Growth factors and cancer VEGF-R: Shweiki, D., Itin, A., Soffer, D. & Keshet, E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359, 843-5 (1992). Chemotype: Fong, T.A. et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res 59, 99-106 (1999). Final molecule: Sun, L. et al. Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J Med Chem 46, 1116-9 (2003).

Discovered Chemotype discovered by high throughput screening for VEGF receptor inhibition. First optimized for specific inhibition of VEGF receptor and PDGF receptor, later optimized for combined inhibition.



Alglucosidase alfa, Lumizyme, Myozyme Indication Pompe disease (Glycogen storage disease type II) Molecule Biologic (alpha-glucosidase) Structure Not applicable First Patent WO 9951724, Pharming, Van Corven, Emile; Weggeman, Miranda

Chromatographic purification of human acid α-glucosidase and its use for treatment of Pompe's disease Application: 06.04.1999 Publication: 14.10.1999

Approved April 28, 2006 Target/MoA Alpha-glucosidase, enzyme replacement therapy Approach Target-based, biologic First published Disease mechanism:

Hers, H.G. Alpha-Glucosidase Deficiency in Generalized Glycogen-Storage Disease (Pompes Disease). Biochemical Journal 86, 11-& (1963). Concept and enzyme: Vanderploeg, A.T. et al. Receptor-Mediated Uptake of Acid Alpha-Glucosidase Corrects Lysosomal Glycogen-Storage in Cultured Skeletal-Muscle. Pediatric Research 24, 90-94 (1988). Final molecule (recombinant enzyme): Fuller, M., VanDerPloeg, A., Reuser, A.J.J., Anson, D.S. & Hopwood, J.J. Isolation and characterisation of a recombinant, precursor form of lysosomal acid alpha-glucosidase. European Journal of Biochemistry 234, 903-909 (1995).

Discovered The genetic defect was discovered in 1963, the principle of enzyme replacement therapy established in 1988 (previous attempts have failed as the enzyme forms used were not taken up by cells), and the recombinant protein production established in 1995.



Idursulfase, Elaprase Indication Mucopolysaccharidosis type II Molecule Biologic (Iduronate-2-sulfatase) Structure Not applicable First Patent US 5728381, Wilson, Peter J.; Morris, Charles Phillip; Anson, Donald

Stewart; Occhiodoro, Teresa; Bielicki, Julie; Clements, Peter Roy; Hopwood, John Joseph Glycosylation variants of iduronate 2-sulfatase Application: 07.06.1995 Publication: 17.031998

Approved June 24, 2006 Target/MoA Iduronate-2-sulfatase, enzyme replacement therapy Approach Target-based, biologic First published Disease mechanism established:

Bach, G., Eisenberg, F., Jr., Cantz, M. & Neufeld, E.F. The defect in the Hunter syndrome: deficiency of sulfoiduronate sulfatase. Proc Natl Acad Sci U S A 70, 2134-8 (1973). Enzyme cloned: Wilson, P.J. et al. Hunter syndrome: isolation of an iduronate-2-sulfatase cDNA clone and analysis of patient DNA. Proc Natl Acad Sci U S A 87, 8531-5 (1990). Final molecule (recombinant enzyme) and concept: Bielicki, J., Hopwood, J.J., Wilson, P.J. & Anson, D.S. Recombinant human iduronate-2-sulphatase: correction of mucopolysaccharidosis-type II fibroblasts and characterization of the purified enzyme. Biochemical Journal 289 ( Pt 1), 241-6 (1993).




Sitagliptin, Januvia Indication Diabetes type-2 Molecule Low molecular weight, synthetic Structure

First Patent WO 2003004498, Merck, S.D. Edmondson, M.H. Fisher, D. Kim, M.

McCoss, E.R. Parmee, A.E. Weber, J. Xu Preparation of β-amino tetrahydroimidazo[1,2-a]pyrazines and tetrahydrotrioazolo[4,3-a]pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes. Application: 05.07.2002 Publication: 16.01.2003

Approved Oct. 16, 2006 Target/MoA Dipeptidylpeptidase 4, protease inhibitor Approach Target-based, low molecular weight First published Target established:

Mentlein, R., Gallwitz, B. & Schmidt, W.E. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum. European Journal of Biochemistry 214, 829-35 (1993). Chemotype: Xu, J. et al. Discovery of potent and selective beta-homophenylalanine based dipeptidyl peptidase IV inhibitors. Bioorganic & Medicinal Chemistry Letters 14, 4759-62 (2004). Final molecule: Kim, D. et al. (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]tria-zolo[4,3-a]pyrazin-7(8H)- yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 48, 141-51 (2005).

Discovered Chemotype discovered by high throughput screening for dipeptidylpeptidase 4 inhibition and further optimized to final molecule.



Aliskiren, Rasilez, Tekturna Indication Hypertension Molecule Low molecular weight, synthetic Structure

First Patent EP 678503, Ciba-Geigy, R. Goeschke, J.K. Maibaum, W. Schilling, S.

Stutz, P. Rigollier, Y. Yamaguchi, N.C. Cohen, P. Herold Preparation of δ-amino-γ-hydroxy-ω-arylalkanoic acid amides as renin inhibitors Application: 07.04.1995 Publication: 25.10.1995

Approved March 5, 2007 Target/MoA Renin, protease inhibitor Approach Target-based, low molecular weight First published Target established:

Page, I.H. On the Nature of the Pressor Action of Renin. J Exp Med 70, 521-42 (1939). Chemotype: Gross, F., Lazar, J. & Orth, H. Inhibition of the renin-angiotensinogen reaction by pepstatin. Science 175, 656 (1972). Final molecule: Rahuel, J. et al. Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin. Chem Biol 7, 493-504 (2000).

Discovered The chemotype is a known inhibitor for other aspartic proteases, and the final molecule results from a rational drug discovery approach.



Eculizumab, Soliris Indication Paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic

syndrome Molecule Biologic (anti-C5 antibody) Structure Not applicable First Patent WO 9529697, Alexion, Evans, Mark J.; Matis, Louis; Mueller, Eileen

Elliott; Nye, Steven H.; Rollins, Scott; Rother, Russell P.; Springhorn, Jeremy P.; Squinto, Stephen P.; Thomas, Thomas C.; et al. Anti-complement C5 antibodies for the treatment of glomerulonephritis and other inflammatory diseases Application: 01.05.1995 Publication: 09.11.1995

Approved March 16, 2007 Target/MoA Antibody against complement C5 (preventing cleavage/activation) Approach Target-based, biologic First published First antibodies:

Wurzner, R. et al. Inhibition of terminal complement complex formation and cell lysis by monoclonal antibodies. Complement Inflamm 8, 328-40 (1991). Final molecule: Thomas, T.C. et al. Inhibition of complement activity by humanized anti-C5 antibody and single-chain Fv. Mol Immunol 33, 1389-401 (1996). Indication: Hillmen, P. et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 350, 552-9 (2004).

Discovered Anti-C5 antibodies were originally generated to treat inflammatory diseases (Matis, L.A. & Rollins, S.A. Complement-specific antibodies: designing novel anti-inflammatories. Nat Med 1, 839-42 (1995)). Efficacy in the approved indications was established in subsequent studies.



Maraviroc, Selzentry Indication HIV infection Molecule Low molecular weight, synthetic Structure

First Patent WO 2001090106, Pfizer, M. Perros, D.A. Price, B.L.C. Stammen, A.

Wood Preparation of therapeutic tropane derivatives Application: 09.05.2001 Publication: 29.11.2001

Approved Aug. 6, 2007 Target/MoA CCR5, inhibits the interaction between the viral gp120 protein and CCR5

thus blocking entry of the virus, GPCR antagonist Approach Target-based, low molecular weight First published Target established:

Deng, H. et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature 381, 661-6 (1996). First LMW inhibitor (different chemotype): Baba, M. et al. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc Natl Acad Sci U S A 96, 5698-703 (1999). Final molecule: Dorr, P. et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother 49, 4721-32 (2005).

Discovered Chemotype discovered by high throughput screening for CCR5 binding and further optimized.



Raltegravir, Isentress Indication HIV infection Molecule Low molecular weight, synthetic Structure

First Patent WO 2003035077, IRBM, B. Crescenzi, C. Gardelli, E. Muraglia, E. Nizi,

F. Orvieto, P. Pace, G. Pescatore, A. Petrocchi, M. Poma, M. Rowley, R. Scarpelli, V. Summa Preparation of N-substituted hydroxypyrimidinone carboxamide inhibitors of HIV integrase Application: 21.10.2002 Publication: 01.05.2003

Approved Oct. 12, 2007 Target/MoA HIV integrase, enzyme inhibitor Approach Target-based, low molecular weight First published Target established:

Bushman, F.D., Fujiwara, T. & Craigie, R. Retroviral DNA integration directed by HIV integration protein in vitro. Science 249, 1555-8 (1990). First LMW inhibitor (different chemotype): Fesen, M.R., Kohn, K.W., Leteurtre, F. & Pommier, Y. Inhibitors of human immunodeficiency virus integrase. Proc Natl Acad Sci U S A 90, 2399-403 (1993). Chemotype: Hazuda, D.J. et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 287, 646-50 (2000). Final molecule: Monteagudo, E. et al. Studies of metabolism and disposition of potent human immunodeficiency virus (HIV) integrase inhibitors using 19F-NMR spectroscopy. Xenobiotica 37, 1000-12 (2007).

Discovered Chemotype discovered by high throughput screening for enzyme inhibition and further optimized. Same chemotype was also found for hepatitis C virus NS5B polymerase and both projects cross-fertilized each other (Summa, V. et al. Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J Med Chem 51, 5843-55 (2008)).



Tetrahydrobiopterin, Sapropterin, Kuvan Indication Phenylketonuria Molecule Natural substance (derived) Structure

First Patent Substance (chiral):

EP 153696, Kanegafuchi Chemical Industry, M. Azuma, T. Ohashi, K. Watanabe Application: 21.02.1985 Publication: 04.09.1985 Use: WO 2005049000, BioMarin Pharmaceutical, D. Oppenheimer, E.D. Kakkis, F.D. Price, A. Dorenbaum Application: 17.11.2004 Publication: 02.06.2005

Approved Dec. 13, 2007 Target/MoA Tetrahydrobiopterin is a cofactor for phenylalanine hydroxylase. Defective

synthesis of the cofactor leads to phenylalanine accumulation Approach Target-based, low molecular weight First published Disease mechanism:

Kaufman, S., Holtzman, N.A., Milstien, S., Butler, L.J. & Krumholz, A. Phenylketonuria due to a deficiency of dihydropteridine reductase. N Engl J Med 293, 785-90 (1975). Therapeutic concept: Danks, D.M., Cotton, R.G. & Schlesinger, P. Letter: Tetrahydrobiopterin treatment of variant form of phenylketonuria. Lancet 2, 1043 (1975).

Discovered Following the discovery of the disease mechanism, a cofactor supplementation therapy was elaborated.



Romiplostim, Nplate Indication Chronic idiopathic thrombocytopenic purpura Molecule Biologic (Mpl-binding peptides fused to IgG Fc domain ) Structure Not applicable First Patent WO 2000024770, Amgen, Liu, Chuan-fa; Feige, Ulrich; Cheetham, Janet

Thrombopoietic peptides for increasing platelet or platelet precursor counts in mammals Application: 22.10.1999 Publication: 04.05.2000

Approved Aug. 22, 2008 Target/MoA Mpl receptor (thrombopoietin receptor), receptor agonist Approach Target-based, biologic First published Target:

Methia, N., Louache, F., Vainchenker, W. & Wendling, F. Oligodeoxynucleotides antisense to the proto-oncogene c-mpl specifically inhibit in vitro megakaryocytopoiesis. Blood 82, 1395-401 (1993). Ligand: de Sauvage, F.J. et al. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature 369, 533-8 (1994). Final molecule: Broudy, V.C. & Lin, N.L. AMG531 stimulates megakaryopoiesis in vitro by binding to Mp1. Cytokine 25, 52-60 (2004).

Discovered Following the discovery of thrombopoietin, an artificial Fc fusion protein was designed to mimic thrombopoietin but avoid an immune response.



Canakinumab, Ilaris Indication Cryopyrin-associated periodic syndromes (CAPS) Molecule Biologic (anti-IL1 antibody) Structure Not applicable First Patent WO 2002016436, Novartis, Gram, Hermann; Di Padova, Franco E.

Human antibodies to human IL-1β for treating IL-1β-mediated diseases Application: 20.08.2001 Publication: 28.02.2002

Approved June 17, 2009 Target/MoA Antibody against IL1, prevents binding of IL1 to its receptor, cytokine

antagonist Approach Target-based, biologic First published Target established:

Nouri, A.M.E., Panayi, G.S. & Goodman, S.M. Cytokines and the Chronic Inflammation of Rheumatic Disease .1. The Presence of Interleukin-1 in Synovial-Fluids. Clin Exp Immunol 55, 295-302 (1984). Indication: Hoffman, H.M., Mueller, J.L., Broide, D.H., Wanderer, A.A. & Kolodner, R.D. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nature Genetics 29, 301-305 (2001). Agostini, L. et al. NALP3 forms an IL-l beta-Processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 20, 319-325 (2004). Final molecule: Alten, R. et al. The human anti-IL-1 beta monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis. Arthritis Research & Therapy 10 (2008).

Discovered The pro-inflammatory role of IL1 has been discovered in 1984, the molecular mechanism underlying cryopyrin associated periodic syndromes was established between 2001 and 2004.



Ustekinumab, Stelara Indication Psoriasis Molecule Biologic (anti-IL12p40 antibody) Structure Not applicable First Patent WO 2002012500, Centocor, Giles-Komar, Jill; Knight, David M.; Peritt,

David; Scallon, Bernard; Shealy, David Anti-IL-12 antibodies for diagnosing and treating psoriasis and multiple sclerosisAnti-IL-12 antibodies for diagnosing and treating psoriasis and multiple sclerosis Application: 07.08.2001 Publication: 14.02.2002

Approved Sept. 25, 2009 Target/MoA Antibody against the common p40 subunit of IL12 and IL23, cytokine

antagonist Approach Target-based, biologic First published Cloning and first antibody:

Wolf, S.F. et al. Cloning of Cdna for Natural-Killer-Cell Stimulatory Factor, a Heterodimeric Cytokine with Multiple Biologic Effects on T-Cells and Natural-Killer-Cells. Journal of Immunology 146, 3074-3081 (1991). Target established (IL12): Hsieh, C.S. et al. Development of Th1 Cd4+ T-Cells through Il-12 Produced by Listeria-Induced Macrophages. Science 260, 547-549 (1993). Target established (IL23): Oppmann, B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13, 715-725 (2000). Indication: Yawalkar, N., Karlen, S., Hunger, R., Brand, C.U. & Braathen, L.R. Expression of interleukin-12 is increased in psoriatic skin. Journal of Investigative Dermatology 111, 1053-1057 (1998). Final molecule: Brok, H.P.M. et al. Prevention of experimental autoimmune encephalomyelitis in common marmosets using an anti-IL-12p4O monoclonal antibody. Journal of Immunology 169, 6554-6563 (2002).

Discovered The role of IL12 in Th1 cell development was discovered in 1993. The cytokine was studied in several T-cell driven diseases, and a potential role in psoriasis established in 1998. IL23 which shares the p40 subunit with IL12 was discovered in 2000. p40-directed neutralizing antibodies were used to study the role of IL12 since its cloning in 1991. Ustekinumab was first published in 2002.



Ecallantide, Kalbitor Indication Hereditary angioedema Molecule Biologic (modified naturally occurring protease inhibitor) Structure Not applicable First Patent US 20050164928, Dyax, Ladner, Robert C.; Ley, Arthur C.; Hirani,

Shirish; Williams, Anthony; De Simoni, Maria Grazia; Bergamaschini, Luigi Kunitz domain-containing kallikrein-inhibitors for treating or preventing ischemia and/or reperfusion injury Application: 27.09.2004 Publication: 28.07.2005

Approved Dec. 1, 2009 Target/MoA Plasma kallikrein, protease inhibitor Approach Target-based, biologic First published Target established:

Gigli, I., Mason, J.W., Colman, R.W. & Austen, K.F. Interaction of Plasma Kallikrein with Cibar Inhibitor. Journal of Immunology 104, 574-& (1970). Inhibitory concept: Markland, W., Ley, A.C. & Ladner, R.C. Iterative optimization of high-affinity protease inhibitors using phage display .2. Plasma kallikrein and thrombin. Biochemistry 35, 8058-8067 (1996). Final molecule: Williams, A. & Baird, L.G. DX-88 and HAE: a developmental perspective. Transfusion and Apheresis Science 29, 255-258 (2003).

Discovered The basis for the therapeutic concept was established in 1970 with the discovery that plasma kallikrein is inhibited by endogenous C1 inhibitor. The first protein-based inhibitor design was published in 1996.



Tocilizumab, Actemra Indication Rheumatoid arthritis Molecule Biologic (anti-IL-6 receptor antibody) Structure Not applicable First Patent EP 409607, Kishimoto, Tadamitsu

Antibody to human interleukin 6 receptor Application: 19.07.1990 Publication: 23.01.1991

Approved Jan. 8, 2010 Target/MoA Antibody to IL-6 receptor preventing its activation by IL-6, receptor

antagonist Approach Target-based, biologic First published Target identified:

Yamasaki, K. et al. Cloning and Expression of the Human Interleukin-6 (Bsf-2/Ifn-Beta-2) Receptor. Science 241, 825-828 (1988). Mouse monoclonal antibody: Hirata, Y. et al. Characterization of Il-6 Receptor Expression by Monoclonal and Polyclonal Antibodies. Journal of Immunology 143, 2900-2906 (1989). Indication: De Benedetti, F. et al. Correlation of Serum Interleukin-6 Levels with Joint Involvement and Thrombocytosis in Systemic Juvenile Rheumatoid-Arthritis. Arthritis and Rheumatism 34, 1158-1163 (1991). Final molecule (humanized antibody): Sato, K. et al. Reshaping a Human-Antibody to Inhibit the Interleukin 6-Dependent Tumor-Cell Growth. Cancer Res 53, 851-856 (1993).

Discovered Following the cloning of the receptor in 1988, a mouse monoclonal antibody was generated which was subsequently humanized.



Collagenase clostridium histolyticum, Xiaflex Indication Dupuytren’s contracture Molecule Biologic (mixture of type I and type II collagenases from Clostridium

histolyticum) Structure Not applicable First Patent WO 2007089851, Auxilium, Sabatino, Gregory L.; Del Tito, Benjamin J.,

Jr.; Bassett, Phillip J.; Tharia, Hazel A.; Hitchcock, Antony G. Process for preparation of Clostridium histolyticum collagenase I and collagenase II for drug use Application: 30.01.2007 Publication: 09.08.2007

Approved Feb. 2, 2010 Target/MoA Enzymatic collagen lysis, protease Approach Target-based, biologic First published Concept:

Hueston, J.T. Enzymic fasciotomy. Hand 3, 38-40 (1971). Final molecule: Starkweather, K.D. et al. Collagenase in the treatment of Dupuytren's disease: an in vitro study. J Hand Surg Am 21, 490-5 (1996).

Discovered Collagenases from Clostridium histolyticum have been known since 1953. The therapeutic principle was described in 1971 and collagenases used the first time for lysis of Dupuytren's cords in 1996.



Carglumic acid, Carbaglu Indication Hyperammonemia Molecule Low molecular weight, natural substance derived Structure

First Patent FR 5805, P. Wirth

N-Carbamylglutamic acid salts (use for hyperammonemia mentioned) Application: 25.07.1966 Publication: 25.03.1968

Approved March 18, 2010 (2003 in Europe) Target/MoA Carbamoyl phosphate synthetase 1 (the drug acts as a mimetic of acetyl

glutamate which is lacking due to the deficiency of the enzyme N-acetylglutamate synthetase), enzyme activator

Approach Target-based, low molecular weight First published Disease mechanism established:

Gatfield, P.D., Taller, E., Wolfe, D.M. & Haust, M.D. Hyperornithinemia, hyperammonemia, and homocitrullinuria associated with decreased carbamyl phosphate synthetase I activity. Pediatric Research 9, 488-97 (1975) Final molecule: Bachmann, C., Colombo, J.P. & Jaggi, K. N-acetylglutamate synthetase (NAGS) deficiency: diagnosis, clinical observations and treatment. Adv Exp Med Biol 153, 39-45 (1982).

Discovered The molecular disease pathology was discovered in 1981 and, based on the mechanistsic understanding, a therapeutic compound defined.



Denosumab, Prolia, Xgeva Indication Osteoporosis Molecule Biologic (anti-RANKL antibody) Structure Not applicable First Patent WO 2003002713, Abgenix, Boyle, William J.; Martin, Francis H.;

Corvalan, Jose R.; Davis, Geoffrey C. Human antibodies to human osteoprotegerin ligand for diagnosis and treatment of osteopenic disorders Application: 25.06.2002 Publication: 09.01.2003

Approved June 1, 2010 Target/MoA Antibody to RANKL preventing its binding to RANK, cytokine

antagonist Approach Target-based, biologic First published Target identified:

Anderson, D.M. et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390, 175-9 (1997). Indication: Lacey, D.L. et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165-76 (1998). First polyclonal antibodies with therapeutic efficacy: Tsukii, K. et al. Osteoclast differentiation factor mediates an essential signal for bone resorption induced by 1 alpha,25-dihydroxyvitamin D3, prostaglandin E2, or parathyroid hormone in the microenvironment of bone. Biochem Biophys Res Commun 246, 337-41 (1998). Final molecule: Bekker, P.J. et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res 19, 1059-66 (2004).

Discovered The target was identified in 1997 and its biological role for osteoclast biology established in 1998. Anti-RANKL polyclonal antibodies were shown to have a therapeutic effect and the fully human anti-RANKL monoclonal antibody was described in 2004



Tesamorelin, Egrifta Indication Lipodystrophy associated with HIV infection Molecule Natural substance (derived) Structure Not applicable First Patent WO 9637514, Theratechnologies, Ibea, Michel; Abritat, Thierry; Brazeau,

Paul Chimeric fatty body-pro-GRF analogs with increased biological potency Application: 22.05.1996 Publication: 28.11.1996

Approved Nov. 10, 2010 Target/MoA Growth hormone releasing factor analogue with high plasma stability

which stimulates the release of growth hormone, agonist Approach Target-based, low molecular weight First published Cloning of human growth hormone releasing factor :

Mayo, K.E., Vale, W., Rivier, J., Rosenfeld, M.G. & Evans, R.M. Expression-cloning and sequence of a cDNA encoding human growth hormone-releasing factor. Nature 306, 86-8 (1983). Indication: Wanke, C., Gerrior, J., Kantaros, J., Coakley, E. & Albrecht, M. Recombinant human growth hormone improves the fat redistribution syndrome (lipodystrophy) in patients with HIV. AIDS 13, 2099-103 (1999). Koutkia, P. et al. Growth hormone-releasing hormone in HIV-infected men with lipodystrophy: a randomized controlled trial. JAMA 292, 210-8 (2004). Final molecule: Abribat, T., Chapdelaine, A., Gravel, D., Dubreuil, P., Ibea, M., Brazeau, P., In: Proceedings of the Fifth European Congress of Endocrinology. Turin, Italy, 9–13 June, abstract O-093, Specificity and potency of TH9507, a new growth hormone-releasing factor analogue: preclinical and clinical data. (2001).

Discovered Human growth hormone releasing factor was cloned in 1983. A more plasma stable analogue was synthesized and originally developed for age-associated conditions. Based on findings with growth hormone, the growth hormone releasing factor analogue was also used for treatment of HIV lipodystrophy.



Roflumilast, Daxas, Daliresp Indication Chronic obstructive pulmonary disease Molecule Low molecular weight, synthetic Structure

First Patent WO 9501338, Byk Gulden, H. Amschler, D. Flockerzi, B. Gutterer, A.

Hatzelmann, C. Schudt, R. Beume, U. Kilian, H.P.O. Wolf Preparation of fluoroalkoxy-substituted benzamides as cyclic nucleotide phosphodiesterase inhibitors Application: 02.07.1994. Publication: 12.01.1995.

Approved Feb. 28, 2011 Target/MoA Phosphodiesterase 4, enzyme inhibitor Approach Target-based, low molecular weight First published Target established:

Torphy, T.J. & Undem, B.J. Phosphodiesterase Inhibitors - New Opportunities for the Treatment of Asthma. Thorax 46, 512-523 (1991). Chemotype: Schwabe, U., Miyake, M., Ohga, Y. & Daly, J.W. 4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (ZK 62711): a potent inhibitor of adenosine cyclic 3',5'-monophosphate phosphodiesterases in homogenates and tissue slices from rat brain. Mol Pharmacol 12, 900-10 (1976). Ashton, M.J. et al. Selective type IV phosphodiesterase inhibitors as antiasthmatic agents. The syntheses and biological activities of 3-(cyclopentyloxy)-4-methoxybenzamides and analogues. J Med Chem 37, 1696-703 (1994). Final molecule: Hatzelmann, A. & Schudt, C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther 297, 267-79 (2001).

Discovered Phosphodiesterase enzymes have been identified in the 1970’s and non-selective and selective inhibitors developed. These inhibitors have been used in the 1980’s to study the biology of these enzymes. A potential role of PDE 4 in lung diseases has become evident in the early 1990’s. The final molecule is partly based on Rolipram, a PDE inhibitor synthesized in 1976.



Belimumab, Benlysta Indication Systemic lupus erythematosus Molecule Biologic (anti-B-cell activating factor antibody) Structure Not applicable First Patent WO 2003055979, Human Genome Sciences, Ruben, Steven M.; Barash,

Steven C.; Choi, Gil H.; Vaughan, Tristan J.; Hilbert, David. Human anti-BLyS antibodies for diagnosis, prognosis and therapy of autoimmune, inflammatory, infectious and proliferative diseases Application: 14.11.2002 Publication: 10.07.2003

Approved March 9, 2011 Target/MoA Antibody to B-cell activating factor preventing its receptor binding,

cytokine antagonist Approach Target-based, biologic First published Target established:

Moore, P.A. et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science 285, 260-3 (1999). First antibodies: Edwards, B.M. et al. The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BLyS. J Mol Biol 334, 103-18 (2003). Final molecule and proof-of-concept: Baker, K.P. et al. Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator. Arthritis and Rheumatism 48, 3253-65 (2003).

Discovered The target was discovered in 1999 and therapeutic antibodies developed subsequently.



Ipilimumab, Yervoy Indication Cancer (melanoma) Molecule Biologic (anti-CTLA-4 antibody) Structure Not applicable First Patent WO 2001014424, Medarex, Korman, Alan J.; Halk, Edward L.; Lonberg,

Nils Human CTLA-4 antibodies and their uses Application: 24.08.2000 Publication: 01.05.2001

Approved March 25, 2011 Target/MoA Antibody against CTLA-4 blocking its function Approach Target-based, biologic First published First antibodies for functional studies:

Linsley, P.S. et al. Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J Exp Med 176, 1595-604 (1992). Therapeutic concept established: Leach, D.R., Krummel, M.F. & Allison, J.P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734-6 (1996). Final molecule: Hodi, F.S. et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A 100, 4712-7 (2003).

Discovered Antibodies against CTLA-4 have been generated in 1992 and used to study its function. The therapeutic concept was established in 1996 and the fully human therapeutic antibody published in 2003.



Abiraterone, Zytiga Indication Cancer (prostate) Molecule Natural substance (derived) Structure

First Patent GB 2265624, British Technology Group, S.E. Barrie, M. Jarman, G.A.

Potter 17-(3-Pyridyl)-substituted steroids useful in cancer treatment Application: 15.03.1993 Publication: 06.10.1993

Approved April 26, 2011 Target/MoA CYP17, an enzyme in the androgen biosynthesis pathway, enzyme

inhibitor Approach Target-based, low molecular weight First published Therapeutic concept:

Sikka, S.C., Swerdloff, R.S. & Rajfer, J. In vitro inhibition of testosterone biosynthesis by ketoconazole. Endocrinology 116, 1920-5 (1985). Final molecule: Barrie, S.E. et al. Pharmacology of novel steroidal inhibitors of cytochrome P450(17) alpha (17 alpha-hydroxylase/C17-20 lyase). J Steroid Biochem Mol Biol 50, 267-73 (1994).

Discovered The antifungal drug ketoconazole was found to also be an anti-androgenic drug through inhibition of CYP17. Subsequently more specific and more potent inhibitors of CYP17 were sought.



Boceprevir, Victrelis & Telaprevir, Incivek Indication Hepatitis C viral infection Molecule Low molecular weight, synthetic Structures Boceprevir Telaprevir

First Patents

Boceprevir: WO 2002008244, Schering, A.K. Saksena et al. Preparation of peptides as NS3-serine protease inhibitors of hepatitis C virus Application: 19.06.2001, Publication: 31.01.2002 Telaprevir: WO 2002018369, Eli Lilly, Babine, R. E., Chen, S.-H., Lamar, J. E., Snyder, N. J., Sun, X. D., Tebbe, M. J., Victor, F., Wang, Q. M., Yip, Y. Y., Collado, I., Garcia-Paredes, C., Parker, R. S. I., Jin, L., Guo, D., and Glass, J. I. Preparation of peptidomimetic protease inhibitors Application: 31.08.2001, Publication: 07.03.2002

Approved May 13 & 23, 2011 Target/MoA

NS3/4A protease inhibitor

Approach Target-based, low molecular weight First published

Target established: Bartenschlager, R., Ahlborn-Laake, L., Mous, J. & Jacobsen, H. Nonstructural protein 3 of the hepatitis C virus encodes a serine-type proteinase required for cleavage at the NS3/4 and NS4/5 junctions. J Virol 67, 3835-44 (1993). Chemotype: Bennett, J.M. et al. The identification of alpha-ketoamides as potent inhibitors of hepatitis C virus NS3-4A proteinase. Bioorganic & Medicinal Chemistry Letters 11, 355-7 (2001). Final molecules: Boceprevir: Malcolm, B.A. et al. SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells. Antimicrob Agents Chemother 50, 1013-20 (2006). Telaprevir: Lin, C. et al. In vitro resistance studies of hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061: structural analysis indicates different resistance mechanisms. J Biol Chem 279, 17508-14 (2004).

Discovered The viral NS3/4A protease was identified as a potential anti-viral target in



1993. Subsequent studies of its substrate specificity led to the rational design of inhibitors using peptide-based compounds.



Rivaroxaban, Xarelto

Indication Thrombosis Molecule Low molecular weight, synthetic Structure

First Patent WO 2003000256, Bayer, A. Straub, T. Lampe, J. Pernerstorfer, E.

Perzborn, J. Pohlmann, S. Roehrig, K.-H. Schlemmer Preparation of substituted oxazolidinones for combinational therapy in the treatment and/or prophylaxis of thromboembolic diseases Application: 07.06.2002 Publication: 03.01.2003

Approved July 1, 2011 Target/MoA Factor Xa protease inhibitor Approach Target-based, low molecular weight First published Target validated:

Schaffer, L.W., Davidson, J.T., Vlasuk, G.P. & Siegl, P.K. Antithrombotic efficacy of recombinant tick anticoagulant peptide. A potent inhibitor of coagulation factor Xa in a primate model of arterial thrombosis. Circulation 84, 1741-8 (1991). Final molecule: Roehrig, S. et al. Discovery of the novel antithrombotic agent 5-chloro-N-{((5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor. J Med Chem 48, 5900-8 (2005).

Discovered The role of factor X in haemostasis has been known since the 1950’s and the target was validated using naturally occurring polypeptide factor Xa inhibitors in 1991. The compound was discovered by high throughput screening using a biochemical assay and subsequently optimized.



Vemurafenib, Zelboraf Indication Cancer (melanoma) Molecule Low molecular weight, synthetic Structure

First Patent WO 2007002325, Plexxikon, P.N. Ibrahim et al. Pyrrolo[2,3-b]pyridine

derivatives as protein kinase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of diseases Application: 21.06.2006 Publication: 04.01.2007

Approved Aug. 17, 2011 Target/MoA BRAF V600E mutant kinase inhibitor Approach Target-based Low molecular weight First published Target established:

Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949-54 (2002). Chemotype: Tsai, J. et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci U S A 105, 3041-6 (2008). Final molecule: Sala, E. et al. BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells. Mol Cancer Res 6, 751-9 (2008).

Discovered The chemotype was discovered by fragment-based screening using a panel of recombinant kinases. The chemotype was subsequently further optimized to the final inhibitor.



Brentuximab vedotin, Adcetris Indication Cancer (anaplastic large cell lymphoma, Hodgkin lymphoma) Molecule Biologic (anti-CD30 antibody-monomethyl auristatin E conjugate) Structure Not applicable First Patent WO 2003043583, Seattle Genetics, Law, Che-Leung; Klussman, Kerry;

Wahl, Alan F.; Senter, Peter; Doronina, Svetlana; Toki, Brian Anti-CD30 antibody-cytotoxic agent conjugates for treating non-cancer immunological disorders Application: 20.11.2002 Publication: 30.05.2003

Approved Aug. 19, 2011 Target/MoA Anti-CD30 antibody conjugated to the antimitotic agent monomethyl

auristatin E Approach Target-based, biologic First published Target discovered:

Kaudewitz, P., Stein, H., Burg, G., Mason, D.Y. & Braun-Falco, O. Atypical cells in lymphomatoid papulosis express the Hodgkin cell-associated antigen Ki-1. Journal of Investigative Dermatology 86, 350-4 (1986). First antibody-drug conjugate: Falini, B. et al. Response of refractory Hodgkin's disease to monoclonal anti-CD30 immunotoxin. Lancet 339, 1195-6 (1992). Final molecule: Francisco, J.A. et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood 102, 1458-65 (2003).

Discovered The specific CD30 expression pattern was established in 1986. To increase the therapeutic efficacy of anti-CD30 antibodies they were subsequently conjugated to toxins.



Icatibant, Firazyr Indication Hereditary angioedema Molecule Natural Substance (derived) Structure

First Patent DE 3938751, Henke, Stephan; Anagnostopulos, Hinisto; Breipohl, Gerhard; Knolle,

Jochen; Fehlhaber, Hans Wolfram; Stechl, Jens; Schoelkens, Berward Preparation of H-D-Argpeptidylarginines and analogs as bradykinin antagonists Application: 21.11. 1989 Publication: 31.05.1990

Approved Aug. 25, 2011 Target/MoA Bradykinin B2 receptor, GPCR antagonist Approach Target-based, low molecular weight First published Target established:

Fields, T., Ghebrehiwet, B. & Kaplan, A.P. Kinin formation in hereditary angioedema plasma: evidence against kinin derivation from C2 and in support of "spontaneous" formation of bradykinin. J Allergy Clin Immunol 72, 54-60 (1983). Chemotype: Vavrek, R.J. & Stewart, J.M. Competitive antagonists of bradykinin. Peptides 6, 161-4 (1985). Final molecule: Hock, F.J. et al. Hoe 140 a new potent and long acting bradykinin-antagonist: in vitro studies. Br J Pharmacol 102, 769-73 (1991)..

Discovered The link between hereditary angioedema and bradykinin production was made in 1983. Originally, bradykinin receptor antagonists have been synthesized for inflammatory and other diseases. The antagonists were rationally designed based on the peptide sequence of bradykinin.



Crizotinib, Xalkori Indication Cancer (ALK-positive non-small cell lung cancers) Molecule Low molecular weight, synthetic Structure

First Patent WO 2006021881, Pfizer, J.J. Cui, L.A. Funk, L. Jia, P.-P. Kung, J.J. Meng,

M.D. Nambu, M.A. Pairish, H. Shen, M.B. Tran-Duble Preparation of pyrazole-substituted aminoheteroaryl compounds as c-Met protein kinase inhibitors for use against cancer and other abnormal cell growth disorders Application: 15.08.2005 Publication: 02.03.2006

Approved Aug. 26, 2011 Target/MoA Anaplastic lymphoma kinase (ALK) inhibitor Approach Target-based, low molecular weight First published Target identified:

Morris, S.W. et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 263, 1281-4 (1994). Final molecule: Zou, H.Y. et al. An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res 67, 4408-17 (2007). Indication: Soda, M. et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448, 561-6 (2007).

Discovered ALK was identified as a potential target for non-Hodgkin’s lymphoma in 1994. The compound was originally developed as a c-Met inhibitor by screening using the recombinant enzyme, and was found to also have equal potency for ALK inhibition. The role of the ALK fusion protein in non-small-cell lung cancer was discovered independently at about the same time.



Ruxolitinib, Jakavi Indication Cancer (intermediate or high-risk myelofibrosis) Molecule Low molecular weight, synthetic Structure

First Patent US 20070135461, Incyte, J.D. Rodgers, S. Shepard, T.P. Maduskuie, H.

Wang, N. Falahatpisheh, M. Rafalski, A.G. Arvanitis, L. Storace, R.K. Jalluri, J.S. Fridman, K. Vaddi Preparation of heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors Application: 12.12.2006 Publication: 14.07.2007

Approved Nov. 16, 2011 Target/MoA JAK1/JAK2 kinase inhibitor Approach Target-based Low molecular weight First published Chemotype:

Changelian, P.S. et al. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science 302, 875-8 (2003). Target established: James, C. et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434, 1144-8 (2005). Final molecule: Lin, Q. et al. Enantioselective synthesis of Janus kinase inhibitor INCB018424 via an organocatalytic aza-Michael reaction. Org Lett 11, 1999-2002 (2009).

Discovered The genetic mutation in JAK2 leading to constitutive activation has been discovered in 2005. The compound is based on a previously described JAK3 inhibitor and was further optimized for JAK1/JAK2 selective inhibition using the recombinant enzymes and biochemical assay systems.



Glucarpidase, Voraxaze Indication Methotrexate overdose Molecule Biologic (bacterial carboxypeptidase G2) Structure Not applicable First Patent EP 121352, Atkinson, Anthony; Minton, Nigel Peter; Sherwood, Roger

Franklin A leader sequence to promote the secretion of gene products Application: 06.03.1984 Publication: 10.10.1984

Approved Jan. 17, 2012 Target/MoA The enzyme removes the carboxyl glutamate from methotrexate leading to

an inactive product, enzyme Approach Target-based, biologic First published Enzyme discovered:

Levy, C.C. & Goldman, P. The enzymatic hydrolysis of methotrexate and folic acid. J Biol Chem 242, 2933-8 (1967). Therapeutic concept: Chabner, B.A., Johns, D.G. & Bertino, J.R. Enzymatic cleavage of methotrexate provides a method for prevention of drug toxicity. Nature 239, 395-7 (1972). Final molecule: Minton, N.P., Atkinson, T. & Sherwood, R.F. Molecular cloning of the Pseudomonas carboxypeptidase G2 gene and its expression in Escherichia coli and Pseudomonas putida. J Bacteriol 156, 1222-7 (1983).

Discovered Following the discovery of the enzymatic reaction in 1967 and the establishment of the therapeutic concept in 1972, an enzyme with optimal activity has been cloned and recombinantly produced in 1983.



Vismodegib, Erivedge Indication Cancer (basal cell carcinoma) Molecule Low molecular weight, synthetic Structure

First Patent WO 2006028958, Genentech, Curis, J. Gunzner, D. Sutherlin, M. Stanley,

L. Bao, G. Castanedo, R. Lalonde, S. Wang, M. Reynolds, S. Savage, K. Malesky, M. Dina Preparation of arylpyridines as inhibitors of hedgehog signaling Application: 02.09.2005 Publication: 16.03.2006

Approved Jan. 30, 2012 Target/MoA Smoothened receptor; GPCR antagonist Approach Target-based, low molecular weight First published Target established:

Johnson, R.L. et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272, 1668-71 (1996). First smoothened antagonist: Taipale, J. et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406, 1005-9 (2000). Final molecule: Robarge, K.D. et al. GDC-0449-a potent inhibitor of the hedgehog pathway. Bioorganic & Medicinal Chemistry Letters 19, 5576-81 (2009).

Discovered The genetic link between the hedgehog pathway and basal cell carcinoma has been made in 1996. The chemotype has been discovered through high throughput screening and further optimized to the final molecule.



Ivacaftor, Kalydeco Indication Cystic Fibrosis Molecule Low molecular weight, synthetic Structure

First Patent WO 2006002421, Vertex, S.S. Hadida-Ruah, A.R. Hazlewood, P.D.J.

Grootenhuis, F.F. Van Goor, A.K Singh, J. Zhou, J. McCartney Quinolinonecarboxamides as modulators of ATP-binding cassette transporters, their preparation, pharmaceutical compositions, and use in therapy Application: 24.06.2005 Publication: 05.01.2006

Approved Jan. 31, 2012 Target/MoA Potentiator of the cystic fibrosis transmembrane conductance regulator,

ion channel modulator Approach Target-based, low molecular weight First published Target gene identified:

Kerem, B. et al. Identification of the cystic fibrosis gene: genetic analysis. Science 245, 1073-80 (1989). Specific gene defect (G551D): Curtis, A., Nelson, R., Porteous, M., Burn, J. & Bhattacharya, S.S. Association of less common cystic fibrosis mutations with a mild phenotype. J Med Genet 28, 34-7 (1991). Target function established: Anderson, M.P., Rich, D.P., Gregory, R.J., Smith, A.E. & Welsh, M.J. Generation of cAMP-activated chloride currents by expression of CFTR. Science 251, 679-82 (1991). Chemotype: Pedemonte, N. et al. Phenylglycine and sulfonamide correctors of defective delta F508 and G551D cystic fibrosis transmembrane conductance regulator chloride-channel gating. Mol Pharmacol 67, 1797-807 (2005). Final molecule: Van Goor, F. et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A 106, 18825-30 (2009).

Discovered The gene harboring cystic fibrosis mutants has been cloned in 1989 and its function subsequently elucidated. The chemotype has been discovered by high throughput screening with a functional assay using cells that express CFTR mutants. The same assay has been employed for further compound optimization.



Mirabegron, Myrbetriq Indication Overactive bladder Molecule Low molecular weight, synthetic Structure

First Patent Compound:

WO 9920607, Yamanouchi, T. Maruyama, T. Suzuki, K. Onda, M. Hayakawa, H. Moritomo, T. Kimizuka, T. Matsui Preparation of amides as antidiabetics Application: 15.10.1998 Publication: 29.04.1999 Use: WO 2004041276, Yamanouchi, T. Takasu, S. Sato, M. Ukai, T. Maruyama Remedy for overactive bladder comprising acetic acid anilide derivative as the active ingredient Application: 04.11.2003 Publication: 21.05.2004

Approved June 28, 2012 Target/MoA Beta3-adrenergic receptor, GPCR agonist Approach Target-based, low molecular weight First published Target cloned:

Emorine, L.J. et al. Molecular characterization of the human beta 3-adrenergic receptor. Science 245, 1118-21 (1989). Indication: Igawa, Y. et al. Possible beta 3-adrenoceptor-mediated relaxation of the human detrusor. Acta Physiol Scand 164, 117-8 (1998). Final molecule: Takasu, T. et al. Effect of (R)-2-(2-aminothiazol-4-yl)-4'-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl}acetanilide (YM178), a novel selective beta3-adrenoceptor agonist, on bladder function. J Pharmacol Exp Ther 321, 642-7 (2007).

Discovered The receptor was cloned in 1989 and first inhibitors synthesized for other indications. The target rationale for the current indication has been established in 1998. The chemotype of the final molecule was derived from previously known and marketed beta1/2 receptor agonists and optimized for beta3 receptor selectivity.



Linaclotide, Linzess Indication Chronic idiopathic constipation, irritable bowel syndrome with constipation Molecule Natural Substance (derived) Structure

First Patent WO 2004069165, Microbia, Currie, Mark G.; Mahajan-Miklos, Shalina

Methods and compositions using guanylate cyclase C receptor activators for the treatment of gastrointestinal disorders Application: 28.01.2004 Publication: 19.08.2004

Approved Aug. 30, 2012 Target/MoA

Guanylyl cyclase C receptor, receptor agonist

Approach Target-based, low molecular weight First published

Biological concept: Hughes, J.M., Murad, F., Chang, B. & Guerrant, R.L. Role of cyclic GMP in the action of heat-stable enterotoxin of Escherichia coli. Nature 271, 755-6 (1978). Target cloned: Schulz, S., Green, C.K., Yuen, P.S. & Garbers, D.L. Guanylyl cyclase is a heat-stable enterotoxin receptor. Cell 63, 941-8 (1990). Final molecule: Bueno, L., Beaufrand, C., Mahajan-Miklos, S., Bryant, A.P. & Currie, M.G. Antinociceptive actions of MD-1100, a novel therapeutic agent for c-IBS, in animal models of visceral pain. American Journal of Gastroenterology 99, S283-S283 (2004).

Discovered Heat stable enterotoxin and homologous endogenous peptides stimulate fluid secretion through a guanylyl cyclase receptor. The biological concept was discovered in 1978 and the receptor cloned in 1990. Linaclotide is based on the sequence of the natural peptides (rational design).



Ocriplasmin, Jetrea Indication Symptomatic vitreomacular adhesion Molecule Biologic (recombinant microplasmin, a truncated form of human plasmin) Structure Not applicable First Patent WO 2004052228, Thromb-X, Pakola, Steve; De Smet, Marc

Pharmacological vitreolysis Application: 05.012.2003 Publication: 24.06.2004

Approved Oct. 17, 2012 Target/MoA Proteolysis-induced posterior vitreous detachment, protease Approach Target-based, biologic First published Identification of enzyme variant:

Wu, H.L., Shi, G.Y. & Bender, M.L. Preparation and Purification of Microplasmin. Proc Natl Acad Sci U S A 84, 8292-8295 (1987). Therapeutic concept: Hikichi, T., Yanagiya, N., Kado, M., Akiba, J. & Yoshida, A. Posterior vitreous detachment induced by injection of plasmin and sulfur hexafluoride in the rabbit vitreous. Retina-the Journal of Retinal and Vitreous Diseases 19, 55-58 (1999). Molecule (recombinant enzyme): Nagai, N. et al. Recombinant human microplasmin: production and potential therapeutic properties. Journal of Thrombosis and Haemostasis 1, 307-313 (2003). Therapy: Gandorfer, A. et al. Posterior vitreous detachment induced by microplasmin. Investigative Ophthalmology & Visual Science 45, 641-647 (2004).

Discovered The therapeutic concept has initially been established with plasmin based on knowledge about its substrate specificity. Microplasmin, first produced in 1987, has originally been developed for thromboembolic disease and later been used for the ophthalmic indication.



Perampanel, Fycompa Indication Epilepsy Molecule Low molecular weight, synthetic Structure

First Patent WO 2001096308, Eisai, S. Nagato, K. Ueno, K. Kawano, Y. Norimine, K.

Ito, T. Hanada, M. Ueno, H. Amino, M. Ogo, S. Hatakeyama, Y. Urawa, H. Naka, A.J. Groom, L. Rivers, T. Smith Preparation of 1,2-dihydropyridinone compounds and use thereof as AMPA receptor and kainite receptor inhibitors Application: 08.06.2001 Publication: 20.12.2001

Approved Oct. 22, 2012 Target/MoA AMPA receptor, ion channel antagonist Approach Target-based, low molecular weight First published Receptor discovered:

Honore, T., Lauridsen, J. & Krogsgaardlarsen, P. The Binding of [Ampa-H-3, a Structural Analog of Glutamic-Acid, to Rat-Brain Membranes. Journal of Neurochemistry 38, 173-178 (1982). First antagonists: Honore, T. et al. Quinoxalinediones - Potent Competitive Non-Nmda Glutamate Receptor Antagonists. Science 241, 701-703 (1988). Receptor cloned (first subunit): Hollmann, M., Osheagreenfield, A., Rogers, S.W. & Heinemann, S. Cloning by Functional Expression of a Member of the Glutamate Receptor Family. Nature 342, 643-648 (1989). Final molecule: Bialer, M. et al. Progress report on new antiepileptic drugs: A summary of the Tenth Eilat Conference (EILAT X). Epilepsy Res 92, 89-124 (2010).

Discovered The role of glutamate in epilepsy was first hypothesized in 1954 (Hayashi, T., Effects of sodium glutamate on the nervous system. Keio J. Med. 3:192–193 (1954)), and the AMPA receptor discovered in 1982 and cloned in 1989. The inhibitor was identified through high-throughput screening using a series of cellular assays to select for non-competitive antagonists and subsequently optimized (Hibi, S. et al. Discovery of 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile (perampanel): a novel, noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor antagonist. J Med Chem 55, 10584-600 (2012).



Tofacitinib, Xeljanz Indication Rheumatoid arthritis Molecule Low molecular weight, synthetic Structure

First Patent WO 2002096909, Pfizer, G.E. Wilcox, C. Koecher, T. Vries, M.E.

Flanagan, M.J. Munchhof Optical resolution of (1-benzyl-4-methylpiperidin-3-yl)-methylamine and the use thereof for the preparation of pyrrolo[2,3-d]pyrimidines as protein kinase inhibitors Application: 29.05.2002 Publication: 05.12.2002

Approved Nov. 6, 2012 Target/MoA Jak-3 kinase inhibitor Approach Target-based, low molecular weight First published Target established:

Macchi, P. et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 377, 65-8 (1995). Final molecule: Changelian, P.S. et al. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science 302, 875-8 (2003). Final indication: Milici, A.J., Kudlacz, E.M., Audoly, L., Zwillich, S. & Changelian, P. Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis. Arthritis Research & Therapy 10, R14 (2008).

Discovered The target rationale was established in 1995 based on Jak-3 mutations in humans leading to immunodeficiency. The chemotype was identified by high throughput screening using a biochemical Jak-3 assay and further optimized to the final molecule. The inhibitor was originally developed for transplantation and later for rheumatoid arthritis.



Raxibacumab, ABthrax Indication Inhalational anthrax Molecule Biologic (anti-Bacillus anthracis protective antigen antibody) Structure Not applicable First Patent Information not found Approved Dec. 14, 2012 Target/MoA Antibody to Bacillus anthracis protective antigen inhibits the binding to its

cellular receptor Approach Target-based, biologic First published Target identified:

Beall, F.A., Taylor, M.J. & Thorne, C.B. Rapid lethal effect in rats of a third component found upon fractionating the toxin of Bacillus anthracis. J Bacteriol 83, 1274-80 (1962). Therapeutic principle: Little, S.F., Leppla, S.H. & Cora, E. Production and characterization of monoclonal antibodies to the protective antigen component of Bacillus anthracis toxin. Infect Immun 56, 1807-13 (1988). Final molecule: Subramanian, G.M. et al. A phase 1 study of PAmAb, a fully human monoclonal antibody against Bacillus anthracis protective antigen, in healthy volunteers. Clin Infect Dis 41, 12-20 (2005).

Discovered The target was identified in 1962 and the first neutralizing antibodies pulished in 1988. The final antibody was first described in 2005.



Teduglutide, Gattex, Revestive Indication Short bowel syndrome Molecule Natural Substance (derived) Structure

First Patent WO 9739031, Ontario Inc, Allelix, Drucker, Daniel J.; Crivici, Anna E.; Sumner-Smith, Martin Glucagon-like peptide-2 analogs Application: 11.04.1997 Publication: 23.10.1997

Approved Dec. 21, 2012 Target/MoA GLP-2 receptor, GPCR agonist Approach Target-based, low molecular weight First published Biological mechanism identified:

Drucker, D.J., Erlich, P., Asa, S.L. & Brubaker, P.L. Induction of intestinal epithelial proliferation by glucagon-like peptide 2. Proc Natl Acad Sci U S A 93, 7911-6 (1996). Therapeutic concept established: Tsai, C.H., Hill, M., Asa, S.L., Brubaker, P.L. & Drucker, D.J. Intestinal growth-promoting properties of glucagon-like peptide-2 in mice. Am J Physiol 273, E77-84 (1997). Final molecule: Sigalet, D.L. & Martin, G.R. Hormonal therapy for short bowel syndrome. J Pediatr Surg 35, 360-3; discussion 364 (2000).

Discovered The biological role of GLP-2 was discovered in 1996. Subsequently a proteolytically more stable analogue (alanine to glycine replacement at position 2) has been designed for therapeutic purposes.



Lomitapide, Juxtapid, Lojuxta Indication Familial hypercholesterolaemia Molecule Low molecular weight, synthetic Structure

First Patent WO 9626205, Bristol-Myers Squibb, J.R. Wetterau II, D.Y. Sharp, R.E.

Gregg, S.A. Biller, J.A. Dickson, R.M. Lawrence, D.R. Magnin, M.A. Poss, J.A. Robl et al. Preparation of 9-(piperidinoalkyl)fluorene-9-carboxamides and analogs as microsomal triglyceride transfer protein inhibitors Application: 01.02.1996 Publication: 29.08.1996

Approved Dec. 21, 2012 Target/MoA Microsomal triglyceride transfer protein inhibitor, enzyme inhibitor Approach Target-based, low molecular weight First published Target established:

Wetterau, J.R. et al. Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science 258, 999-1001 (1992). Target cloned: Sharp, D. et al. Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia. Nature 365, 65-9 (1993). Chemotype: Jamil, H. et al. An inhibitor of the microsomal triglyceride transfer protein inhibits apoB secretion from HepG2 cells. Proc Natl Acad Sci U S A 93, 11991-5 (1996). Final molecule: Wetterau, J.R. et al. An MTP inhibitor that normalizes atherogenic lipoprotein levels in WHHL rabbits. Science 282, 751-4 (1998).

Discovered The target rationale was established in 1992 and the target cloned in 1993. The chemotype was discovered by high throughput screening using the purified enzyme and subsequently optimized to the final molecule.



Mipomersen sodium, Kynamro Indication Homozygous familial hypercholesterolemia Molecule Natural substance (derived), antisense oligonucleotide Structure G*-C*-C*-U*-C*-dA-dG-dT-dC-dT-dG-dmC-dT-dT-dmC-G*-C*-A*-

C*-C* [d = 2'-deoxy, * = 2'-O-(2-methoxyethyl)] First Patent WO 2003097662, Isis Pharmaceuticals, Crooke, Rosanne M.; Graham,

Mark J. Antisense modulation of apolipoprotein B expression and treatment of diseases associated with abnormal lipid or cholesterol metabolism Application: 15.05.2003 Publication: 27.11.2003

Approved Jan. 29, 2013 Target/MoA Apolipoprotein B inhibitor Approach Target-based, low molecular weight First published Target:

Innerarity, T.L. et al. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci U S A 84, 6919-23 (1987). Chemotype: Soutschek, J. et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432, 173-8 (2004). Final molecule: Kastelein, J.J. et al. Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B. Circulation 114, 1729-35 (2006)._ENREF_1

Discovered Rational approach using antisense oligonucleotides



Canagliflozin, Invokana Indication Type 2 diabetes Molecule Natural product (derived) Structure

First Patent US 20050233988, Tanabe Seiyaku Co., Nomura, Sumihiro; Kawanishi,

Eiji; Ueta, Kiichiro Preparation of glycosides as antidiabetic agents and having inhibitory activity against sodium-dependent transporter Application: 31.01.2005 Publication: 20.10.2005

Approved March 29, 2013 Target/MoA Sodium-glucose transport protein subtype 2 (SGLT2), enzyme inhibitor Approach Target-based, low molecular weight First published Target:

Kanai, Y., Lee, W.S., You, G., Brown, D. & Hediger, M.A. The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Invest 93, 397-404 (1994). Chemotype: Oku, A. et al. T-1095, an inhibitor of renal Na+-glucose cotransporters, may provide a novel approach to treating diabetes. Diabetes 48, 1794-800 (1999). Final molecule: Nomura, S. et al. Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J Med Chem 53, 6355-60 (2010).

Discovered The transporter was cloned in 1992 (Wells, R.G. et al. Cloning of a human kidney cDNA with similarity to the sodium-glucose cotransporter. Am J Physiol 263, F459-65 (1992) and characterized in 1994. The chemotype, inspired by the natural product phlorizin, was optimized to selectively inhibit SGLT2 using a cellular assay with an exogenously overexpressed transporter.



Riociguat, Adempas Indication Pulmonary arterial hypertension and chronic thromboembolic pulmonary

hypertension Molecule Low molecular weight, synthetic Structure

First Patent WO 2003095451, Bayer, Alonso-alija, Cristina; Bischoff, Erwin; Muenter,

Klaus; Stasch, Johannes-Peter; Stahl, Elke; Weigand, Stefan; Feurer, Achim Preparation of [(pyrazolopyridinyl)pyrimidinyl]carbamates stimulating soluble guanylate cyclase for treating cardiovascular diseases and/or sexual dysfunction Application: 25.04.2003 Publication: 20.11.2003

Approved Oct. 8, 2013 Target/MoA Stimulator of soluble guanylate cyclase, enzyme Approach Target-based, low molecular weight First published Target:

Mittal, C.K. & Murad, F. Activation of guanylate cyclase by superoxide dismutase and hydroxyl radical: a physiological regulator of guanosine 3',5'-monophosphate formation. Proc Natl Acad Sci U S A 74, 4360-4 (1977). Schultz, K. & Schultz, G. Sodium nitroprusside and other smooth muscle-relaxants increase cyclic GMP levels in rat ductus deferens. Nature 265, 750-1 (1977). Chemotype: Ko, F.N., Wu, C.C., Kuo, S.C., Lee, F.Y. & Teng, C.M. YC-1, a novel activator of platelet guanylate cyclase. Blood 84, 4226-33 (1994). Final molecule: Schermuly, R.T. et al. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J 32, 881-91 (2008).

Discovered The target rationale was established in the late 1970s. The chemotype was discovered by a systems-based approach in 1994 and later used as a chemical starting point in a target-based drug discovery effort using the recombinant enzyme.



Ibrutinib, Imbruvica Indication Mantle cell lymphoma Molecule Low molecular weight, synthetic Structure

First Patent WO 2008121742, Pharmacyclics, Honigberg, Lee; Verner, Erik; Buggy,

Joseph J.; Loury, David; Chen, Wei Preparation of substituted pyrazolopyrimidinamines as therapeutic inhibitors of Bruton's tyrosine kinase and other kinases Application: 27.03.2008 Publication: 09.10.2008

Approved Nov. 13, 2013 Target/MoA Bruton’s tyrosine kinase inhibitor Approach Target-based, low molecular weight First published Target established:

Thomas, J.D. et al. Colocalization of X-linked agammaglobulinemia and X-linked immunodeficiency genes. Science 261, 355-8 (1993). Rawlings, D.J. et al. Mutation of unique region of Bruton's tyrosine kinase in immunodeficient XID mice. Science 261, 358-61 (1993). Chemotype: Missbach, M. et al. A novel inhibitor of the tyrosine kinase Src suppresses phosphorylation of its major cellular substrates and reduces bone resorption in vitro and in rodent models in vivo. Bone 24, 437-49 (1999). Final molecule: Pan, Z. et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. ChemMedChem 2, 58-61 (2007).

Discovered The fundamental target biology was discovered in 1993. Pyrrolo[2,3-d]pyrimidines have been identified as tyrosine kinase inhibitors by screening various compound collections using biochemical kinase assays. The final molecule was rationally designed by introducing an electrophilic group capable of irreversibly inactivating the target.



Sofosbuvir, Sovaldi, Virunon Indication Hepatitis C viral infection Molecule Natural substance (derived) Structure

First Patent Absolute configuration of the phosphoamidate asymmetric center

undefined: WO 2008121634, Pharmasset, Sofia, Michael J.; Du, Jinfa; Wang, Peiyuan; Nagarathnam, Dhanapalan Preparation of nucleoside phosphoramidate prodrugs as antiviral agents Application: 26.03.2008 Publication: 09.10.2008 Absolute configuration of the phosphoamidate asymmetric center defined: WO 2010135520, Chimerix, Almond, Merrick; Lanier, Ernest Randall; Musso, David Lee; Ware, Roy Preparation of nucleosides and nucleotides for treating viral infection Application: 20.05.2010 Publication: 25.10.2010

Approved Dec. 6, 2013 Target/MoA HCV NS5B polymerase, enzyme inhibitor Approach Target-based, low molecular weight First published Target:

Behrens, S.E., Tomei, L. & De Francesco, R. Identification and properties of the RNA-dependent RNA polymerase of hepatitis C virus. EMBO J 15, 12-22 (1996). Chemotype: Clark, J.L. et al. Design, synthesis, and antiviral activity of 2'-deoxy-2'-fluoro-2'-C-methylcytidine, a potent inhibitor of hepatitis C virus replication. J Med Chem 48, 5504-8 (2005). Final molecule: Sofia, M.J. et al. Discovery of a beta-d-2'-deoxy-2'-alpha-fluoro-2'-beta-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J Med Chem 53, 7202-18 (2010).

Discovered Rational design, the molecule is a cytidine analogue (prodrug) optimized for selectivity and pharmacokinetic properties.



Systems-based drugs Cilostazol, Pletal Indication Intermittent claudication in peripheral vascular disease (inhibits platelet

aggregation) Molecule Low molecular weight, synthetic Structure

First Patent BE 878548, Otsuka

Application 01.09.1978 Publication 31.08.1979 Therapeutic tetrazolylalkoxycarbostyril derivatives

Approved Jan. 15, 1999 MoA PDE3, enzyme inhibitor Approach Systems-based, chemocentric First published Chemotype and MoA:

Hidaka, H. et al. Selective inhibitor of platelet cyclic adenosine monophosphate phosphodiesterase, cilostamide, inhibits platelet aggregation. J Pharmacol Exp Ther 211, 26-30 (1979) Final molecule: Shintani, S. et al. General pharmacological properties of cilostazol, a new antithrombotic drug. Part II: Effect on the peripheral organs. Arzneimittelforschung 35, 1163-72 (1985).

Discovered Testing of discrete compounds in rabbit plasma for inhibition of platelet aggregation. It was known since the mid 1960’s that inhibitors of cyclic nucleotide phosphodiesterase block platelet aggregation, and the initial compound was subsequently shown to be an inhibitor of cyclic adenosine monophosphate phosphodiesterase.



Sirolimus, Rapamune Indication Transplantation, coronary stent coating Molecule Natural product (derived) Structure

First Patent DE 2347682, Ayerst, McKenna & Harrison, Sehgal, Surendra N.;

Blazekovic, Teodora M.; Vezina, Claude Application 21.09.1973 Publication 11.04.1974 Antifungal antibiotic

Approved Sept. 15, 1999 MoA mTOR (in complex with FKBP12), kinase inhibitor Approach Systems-based, phenotypic screening First published Molecule:

Vezina, C., Kudelski, A. & Sehgal, S.N. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo) 28, 721-6 (1975). Concept: Martel, R.R., Klicius, J. & Galet, S. Inhibition of the immune response by rapamycin, a new antifungal antibiotic. Can J Physiol Pharmacol 55, 48-51 (1977). Indication: Calne, R.Y. et al. Rapamycin for immunosuppression in organ allografting. Lancet 2, 227 (1989). Mechanism of action: Heitman, J., Movva, N.R. & Hall, M.N. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253, 905-9 (1991).

Discovered Sirolimus was isolated from a streptomycete and found to have antifungal activity. It was later found to be immunosuppressive, and its mechanism of action was elucidated.



Pemirolast, Alamast Indication Itch associated with allergic conjunctivitis Molecule Low molecular weight, synthetic Structure

First patent US 4122274, Bristol Myers, Juby, Peter Frederick

Application 25.05.1977 Publication 24.10.1978 3-Tetrazolyl-5,6,7,8-substituted pyrido[1,2-a]pyrimidin-4-ones

Approved Sept. 24, 1999 MoA Mast cell stabilizer, target unknown Approach Systems-based, chemocentric First published Patent (Final compound with mechanism of action):

Juby, P.F. 3-tetrazolo-5,6,7,8-substituted-pyrido[1,2-a]pyrimidin-4-ones. U.S. Patent 4,122,274 (1978). Final molecule (in vivo studies): Yanagihara, Y., Kasai, H., Kawashima, T. & Shida, T. Immunopharmacological studies on TBX, a new antiallergic drug (1). Inhibitory effects on passive cutaneous anaphylaxis in rats and guinea pigs. Jpn J Pharmacol 48, 91-101 (1988).

Discovered Compound tested in in vivo model (passive cutaneous anaphylaxis).



Levetiracetam, Keppra Indication Epilepsy Molecule Low molecular weight, synthetic Structure

First Patent EP 162036 UCB, Gobert, Jean; Geerts, Jean Pierre; Bodson, Guy

Application 14.05.1985 Publication 21.11.1985 Antihypoxic, antiischemic, single compound in patent

Approved Nov. 30, 1999 MoA Not fully understood; may bind to synaptic vesicle glycoprotein 2A and

inhibit presynaptic calcium channels (Vogl, C., Mochida, S., Wolff, C., Whalley, B.J. & Stephens, G.J. The Synaptic Vesicle Glycoprotein 2A Ligand Levetiracetam Inhibits Presynaptic Ca2+ Channels through an Intracellular Pathway. Mol Pharmacol 82, 199-208 (2012).

Approach Systems-based, chemocentric First published Chemotype:

Piracetam was first synthesized in 1964 by Corneliu E. Giurgea; shown to be nootropic (memory enhancing); launched by UCB in the early 1970s. Giurgea, C., Lefevre, D., Lescrenier, C. & David-Remacle, M. Pharmacological protection against hypoxia induced amnesia in rats. Psychopharmacologia 20, 160-8 (1971) Giurgea, C.E., Greindl, M.G. & Preat, S. Nootropic drugs and aging. Acta Psychiatr Belg 83, 349-58 (1983). Indication: Kunneke, P.S. & Malan, G.M. A controlled clinical trial on the effect of piracetam in epileptic children. Br J Clin Pract 33, 266-71 (1979). Final molecule: Verloes, R., Scotto, A.M., Gobert, J. & Wulfert, E. Effects of nootropic drugs in a scopolamine-induced amnesia model in mice. Psychopharmacology (Berl) 95, 226-30 (1988).

Discovered In vivo testing of specific compounds and close derivatives. Piracetam as the initial chemotype was first synthesized in 1964 and launched by UCB in the early 1970s as memory enhancer. Its anti-epileptic activity was established in 1979.



Zonisamide, Zonegran Indication Epilepsy Molecule Low molecular weight, synthetic Structure

First Patent JP 53077057, Dainippon, Uno, Hitoshi; Kurokawa, Mikio; Masuda,

Yoshinobu Application 16.12.1976 Publication 08.07.1978 Anticonvulsant and antiepileptic activities

Approved March 27, 2000 [marketed in Japan since 1989] MoA Unknown Approach Systems-based, chemocentric First published Final molecule with indication:

Uno, H., Kurokawa, M., Masuda, Y. & Nishimura, H. Studies on 3-substituted 1,2-benzisoxazole derivatives. 6. Syntheses of 3-(sulfamoylmethyl)-1,2-benzisoxazole derivatives and their anticonvulsant activities. J Med Chem 22, 180-3 (1979).

Discovered Testing of specific compounds in in vivo model. Discovered in 1972 (Wikipedia) by Uno, H et al. The first paper (1979) cites prior unpublished results. 1,2-benzisoxazole derivatives were tested in a maximal electroshock seizure model.



Docosanol, Abreva Indication Herpes simplex virus (topical treatment) Molecule Low molecular weight, synthetic Structure

First Patent US 5166219, Lidak (first patent for pharmaceutical use, compound appears

in other patents much earlier) Application 29.07.1991 Publication 24.11.1992 Treatment of inflammatory diseases, viral infections

Approved July 25, 2000 MoA Target unclear, inhibits the fusion of virus with cells Approach Systems-based, chemocentric First published Chemotype and indication:

For bacteriophage: Snipes, W., Person, S., Keller, G., Taylor, W. & Keith, A. Inactivation of lipid-containing viruses by long-chain alcohols. Antimicrob Agents Chemother 11, 98-104 (1977). For HSV: Sands, J., Auperin, D. & Snipes, W. Extreme sensitivity of enveloped viruses, including herpes simplex, to long-chain unsaturated monoglycerides and alcohols. Antimicrob Agents Chemother 15, 67-73 (1979). Final molecule: Katz, D.H., Marcelletti, J.F., Khalil, M.H., Pope, L.E. & Katz, L.R. Antiviral activity of 1-docosanol, an inhibitor of lipid-enveloped viruses including herpes simplex. Proc Natl Acad Sci U S A 88, 10825-9 (1991).

Discovered Specific compounds tested in an in vitro system (based on finding that butylated hydroxyl toluene, a food additive which is integrated into membranes and can disturb membranes, has antiviral activity: Snipes, W., Person, S., Keith, A. & Cupp, J. Butylated hydroxytoluene inactivated lipid-containing viruses. Science 188, 64-6 (1975).



Caspofungin, Cancidas Indication Fungal infections Molecule Natural Product (derived) Structure

First Patent WO 9421677, Merck, Balkovec, James M.; Bouffard, Frances Aileen;

Black, Regina M. Application 10.03.1994 Publication 29.10.1994 Cyclohexapeptide antimycotics

Approved Jan. 26, 2001 MoA 1,3-beta-glucan synthase, enzyme inhibitor Approach Systems-based, chemocentric First published Chemotype (echinocandin) with antifungal activity:

Benz, F., Knusel, F., Nuesch, J., Treichler, H.J. & Voser, W. Metabolic Products of Microorganism .143. Echinocandin B, a New Polypeptide Antibiotic from Aspergillus Nidulans Var Echinulatus - Isolation and Building Units. Helvetica Chimica Acta 57, 2459-2477 (1974). MoA: Sawistowska-Schroder, E.T., Kerridge, D. & Perry, H. Echinocandin inhibition of 1,3-beta-D-glucan synthase from Candida albicans. FEBS Lett 173, 134-8 (1984). Final molecule: Bouffard, F.A. et al. Synthesis and antifungal activity of novel cationic pneumocandin B(o) derivatives. J Med Chem 37, 222-5 (1994).

Discovered The chemotype was isolated in 1974 from a microorganism and found to have antifungal activity. Further compounds were synthezised to increase potency and antifungal spectrum.



Alemtuzumab, Campath Indication Cancer (chronic lymphocytic leukemia, cutaneous T-cell lymphoma, B-

cell chronic lymphocytic leukemia) Molecule Biologic (anti-CD52 antibody) Structure Not applicable First Patent WO 9207084, Wellcome Foundation, Ramage, Paul Ian Nicholas; Allen,

Geoffrey Purification of CDw52-specific antibodies with column chromatography Application: 17.10.1991 Publication: 30.04.1992

Approved May 7, 2001 Target/MoA Antibody against CD52 Approach Systems-based, phenotypic screening, biologic First published Initial antibody and concept:

Hale, G. et al. Removal of T cells from bone marrow for transplantation: a monoclonal antilymphocyte antibody that fixes human complement. Blood 62, 873-82 (1983). Final molecule (humanized antibody): Riechmann, L., Clark, M., Waldmann, H. & Winter, G. Reshaping human antibodies for therapy. Nature 332, 323-7 (1988). Antigen identified: Xia, M.Q., Tone, M., Packman, L., Hale, G. & Waldmann, H. Characterization of the CAMPATH-1 (CDw52) antigen: biochemical analysis and cDNA cloning reveal an unusually small peptide backbone. Eur J Immunol 21, 1677-84 (1991).

Discovered Antibodies raised against human peripheral blood mononuclear cells. The selected rat antibody was later humanized and the antigen (CD52) identified.



Nitisinone, Orfadin Indication Hereditary tyrosinemia type 1 Molecule Natural product (derived) Structure

First Patent EP 186118, Stauffer Chemical Co., C.G. Carter

Application 18.12.1985 Publication 02.07.1986 Cyclohexanediones as herbicides

Approved Jan. 18, 2002 MoA 4-hydroxyphenyl-pyruvate dioxygenase

(by inhibiting the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with HT-1, these catabolic intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate, which are responsible for the observed liver and kidney toxicity), enzyme inhibitor

Approach Systems-based, chemocentric First published Chemotype (as herbicide):

Gray, R.A., Russay, R.J., & Tseng, C.K. 1-Hydroxy-2-(alkylketo)-4,4,6,6-tetramethyl cyclohexen-3,5-diones. U.S. Patent 4,202,840 (1980). MoA (as herbicide): Schulz, A., Ort, O., Beyer, P. & Kleinig, H. SC-0051, a 2-benzoyl-cyclohexane-1,3-dione bleaching herbicide, is a potent inhibitor of the enzyme p-hydroxyphenylpyruvate dioxygenase. FEBS Lett 318, 162-6 (1993). Selection of molecule for human use (same enzyme target; human studies): Lindstedt, S., Holme, E., Lock, E.A., Hjalmarson, O. & Strandvik, B. Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. Lancet 340, 813-7 (1992).

Discovered Compound class known as herbicides since late 70’s (based on observations with natural products – beta-triketones – over many decades, MoA elucidated in late 1980’s, connection between MoA and human disease made in 1989 (reviewed in: Lock, E.A. et al. From toxicological problem to therapeutic use: the discovery of the mode of action of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), its toxicology and development as a drug. J Inherit Metab Dis 21, 498-506 (1998)).



Ezetimibe, Zetia Indication Cardiovascular, LDL cholesterol lowering Molecule Low molecular weight, synthetic Structure

First Patent WO 9508532, Schering Corp, S.B. Rosenblum, S. Dugar, D.A. Burnett,

J.W. Clader, B.A. McKittrick Application 14.09.1994 Publication 30.03.1995 Hypercholesterolemic agents

Approved Oct 25, 2002 MoA Inhibits sterol transporter, Niemann-Pick C1-like 1, to prevent intestinal

uptake of cholesterol Approach Systems-based chemocentric First published Chemotype and MoA:

Burnett, D.A., Caplen, M.A., Davis, H.R., Jr., Burrier, R.E. & Clader, J.W. 2-Azetidinones as inhibitors of cholesterol absorption. J Med Chem 37, 1733-6 (1994). Final molecule: Salisbury, B.G. et al. Hypocholesterolemic activity of a novel inhibitor of cholesterol absorption, SCH 48461. Atherosclerosis 115, 45-63 (1995).

Discovered Chemotype was known as an inhibitor for acetyl coenzyme A cholesterol acyltransferase (ACAT, an established target for inhibition of cholesterol absorption); in the optimization of ACAT inhibitors it became clear from the in vivo profile that some derivatives work through a different mechanism.



Nitazoxanide, Alinia Indication Anti-parasitic (Cryptosporidium and Giardia infections) Molecule Low molecular weight, synthetic Structure

First Patent DE 2438037, S.P.R.L. Phavic, Belg.

07.08.1974 20.02.1975 amebicides, anthelmintics, molluscicides, skin protecting fungicides, and Trichomonas inhibitors

Approved Nov. 22, 2002 MoA Interference with the pyruvate:ferredoxin oxidoreductase enzyme

dependent electron transfer reaction which is essential to anaerobic energy metabolism, enzyme inhibitor

Approach Systems-based, chemocentric First published Chemotype and indication (anti-parasitic, animal use):

Werbel, L.M. & Battaglia, J.R. Derivatives of 2-amino-5-nitrothiazole as potential schistosomicides. J Med Chem 14, 10-6 (1971). Final molecule: Rossignol, J.F. & Maisonneuve, H. Nitazoxanide in the treatment of Taenia saginata and Hymenolepis nana infections. Am J Trop Med Hyg 33, 511-2 (1984).

Discovered Chemotype known since 1950’s for anti-parasitic use in animals. Further derivatives and in vivo studies led to human use and final indication.



Miglustat, Zavesca Indication Gaucher disease Molecule Natural product (derived) (based on deoxynojirimycin) Structure

First Patent DE 2758025, Bayer, B. Junge, H.P. Krause, L. Mueller, W. Puls

Application 24.12.1977 Publication 12.07.1979 used in animal nutrition to reduce fat formation and cut down on feed protein requirements.

Approved July 31, 2003 MoA Glucosylceramide synthase, enzyme inhibitor Approach Systems-based, chemocentric First published Chemotype:

Hanozet, G., Pircher, H.P., Vanni, P., Oesch, B. & Semenza, G. An example of enzyme hysteresis. The slow and tight interaction of some fully competitive inhibitors with small intestinal sucrase. J Biol Chem 256, 3703-11 (1981). Final molecule and indication: Platt, F.M., Neises, G.R., Dwek, R.A. & Butters, T.D. N-butyldeoxynojirimycin is a novel inhibitor of glycolipid biosynthesis. J Biol Chem 269, 8362-5 (1994).

Discovered Deoxynojirimycin, a glucose analogue, has been shown to inhibit glucosidases. Based on this, deoxynojirimycin and a handful of derivatives have been tested in HL-60 cells for inhibition of glycolipid biosynthesis and then shown to inhibit glucosylceramide synthase.



Daptomycin, Cubicin Indication Antibacterial Molecule Natural product (derived) Structure

First Patent EP 178152, Eli Lilly, F.M. Huber, R.L. Pieper et al.

Application 08.10.1985 Publication 16.04.1986 antibiotics

Approved Sept. 12, 2003 MoA Molecule is a lipopeptide which binds to the bacterial cell membrane and

causes rapid polarization, other mechanism Approach Systems-based, phenotypic screening First published

Chemotype with indication: Debono,M., Barnhart, M., Carrell, C.B., Hoffman, J.A. & Hamill, R.L. Program Abstr. Intersci. Conf. Antimicrob. Agents Chemother. 20th, New Orleans, La., abstr. no. 68, (1980). [cited in: Eliopoulos, G.M., Thauvin, C., Gerson, B. & Moellering, R.C., Jr. In vitro activity and mechanism of action of A21978C1, a novel cyclic lipopeptide antibiotic. Antimicrob Agents Chemother 27, 357-62 (1985).] Final molecule: Eliopoulos, G.M. et al. In vitro and in vivo activity of LY 146032, a new cyclic lipopeptide antibiotic. Antimicrob Agents Chemother 30, 532-5 (1986).

Discovered Cellular in vitro phenotypic screen.



Memantine, Namenda Indication Alzheimer’s disease Molecule Low molecular weight, synthetic Structure

First Patent US 3391142, Eli Lilly, J. Mills, E. Krumkalns

Application 09.02.1966 Publication 02.07.1966 Antiviral agents DE 2219256, Merz, A. Scherm, P. Dezso, B. Jamiak Application 20.04.1972 Publication 08.11.1973 Use against parkinsonism

Approved Oct. 16, 2003 MoA NMDA receptor antagonist, 5-HT3 receptor antagonist, potentially α7

nAChR antagonist and D2 receptor agonist, ion channel/GPCR antagonist/ agonist

Approach Systems-based, chemocentric First published Molecule:

Gerzon, K., Krumkalns, E.V., Brindle, R.L., Marshall, F.J. & Root, M.A. The Adamantyl Group in Medicinal Agents. I. Hypoglycemic N-Arylsulfonyl-N' -Adamantylureas. J Med Chem 6, 760-3 (1963). Molecule for nervous system effects (causing hyperactivity): Costall, B. & Naylor, R.J. Neuropharmacological studies on D145 (1,3-dimethyl-5-aminoadamantan). Psychopharmacologia 43, 53-61 (1975). Final indication: Fleischhacker, W.W., Buchgeher, A. & Schubert, H. Memantine in the treatment of senile dementia of the Alzheimer type. Prog Neuropsychopharmacol Biol Psychiatry 10, 87-93 (1986).

Discovered Molecule synthesized as potential anti-diabetic agent in 1963 (Lilly); nervous system effects of Memantine discovered in a rat model for dopaminergic mechanisms in 1975. Clinical studies published in 1986.



Azacitidine, Vidaza Indication Myelodysplastic syndromes (cancer) Molecule Low molecular weight, natural substance (derived) Structure

First Patent DE 1140941, no assignee, J. Smrt, F. Sorm, V. Cerneckij

Application 30.10.1961 Publication 13.12.1962 Antimetabolite of the pyridine components of nucleic acids, single compound in patent

Approved May 19, 2004 MoA Irreversible inhibition of DNA methyltransferases (incorporated after

modification into DNA as cytosine analogue), enzyme inhibitor Approach Systems-based, chemocentric First published Final molecule with indication:

Sorm F, Pískala A, Cihák A, Veselý J, Experientia. 1964 Apr 15;20(4):202-3. 5-Azacytidine, a new, highly effective cancerostatic.

Discovered Compound tested in cellular assay and in vivo (leukemic cells in mice).



Ziconotide, Prialt Indication Severe chronic pain (intrathecal injection) Molecule Natural substance (derived) Structure L-Cysteinamide, L-cysteinyl-L-lysylglycyl-L-lysylglycyl-L-alanyl-L-

lysyl-L-cysteinyl-L-seryl-L-arginyl-L-leucyl-L-methionyl-L-tyrosyl-L-α-aspartyl-L-cysteinyl-L-cysteinyl-L-threonylglycyl-L-seryl-L-cysteinyl-L-arginyl-L-serylglycyl-L-lysyl-, cyclic (1�16),(8�20),(15�25)-tris(disulfide), 25-mer

First Patent WO 9107980, Neurex, G.P. Miljanich, R.S. Bitner, S.S. Bowersox, J.A. Fox, K.L. Valentino, D.H. Yamashiro Application 21.11.1990 Publication 13.06.1991 Neuronal calcium channel antagonist for treating ischemia-related neuronal damage

Approved Dec. 28, 2004 MoA N-type voltage-gated calcium channel, ion channel blocker Approach Systems-based, chemocentric First published Final molecule:

McIntosh, M., Cruz, L.J., Hunkapiller, M.W., Gray, W.R. & Olivera, B.M. Isolation and structure of a peptide toxin from the marine snail Conus magus. Arch Biochem Biophys 218, 329-34 (1982). MoA: Cruz, L.J. & Olivera, B.M. Calcium channel antagonists. Omega-conotoxin defines a new high affinity site. J Biol Chem 261, 6230-3 (1986). Indication: Chaplan, S.R., Pogrel, J.W. & Yaksh, T.L. Role of voltage-dependent calcium channel subtypes in experimental tactile allodynia. J Pharmacol Exp Ther 269, 1117-23 (1994).

Discovered Based on previous knowledge on toxins from marine snails, the molecule was isolated in a dedicated effort to find the toxin from Conus magus. The molecule was tested for its activity using membrane preparations.



Nelarabine, Arranon Indication Cancer (T-cell acute lymphoblastic leukemia and T-cell lymphoblastic

lymphoma) Molecule Natural substance (derived) Structure

First Patent EP 294114, Wellcome Foundation, T.A. Krenitsky, G.W. Koszalka, L.A.

Jones, D.R. Averett, A.R. Moorman Application 27.05.1988 Publication 07.12.1988 Purine arabinosides as antiviral agents

Approved Oct. 28, 2005 MoA Incorporation into DNA leads to inhibition of DNA synthesis and cell

death Approach Systems-based, chemocentric First published Chemotype with indication:

Kessel, D., Hall, T.C. & Wodinsky, I. Transport and phosphorylation as factors in the antitumor action of cytosine arabinoside. Science 156, 1240-1 (1967). Gudas, L.J., Ullman, B., Cohen, A. & Martin, D.W., Jr. Deoxyguanosine toxicity in a mouse T lymphoma: relationship to purine nucleoside phosphorylase-associated immune dysfunction. Cell 14, 531-8 (1978). Final molecule (active principle): Cohen, A., Lee, J.W. & Gelfand, E.W. Selective toxicity of deoxyguanosine and arabinosyl guanine for T-leukemic cells. Blood 61, 660-6 (1983). Final molecule (prodrug): Lambe, C.U. et al. 2-Amino-6-methoxypurine arabinoside: an agent for T-cell malignancies. Cancer Res 55, 3352-6 (1995).

Discovered Nucleoside analogues (e.g. cytosine arabinoside) are known cytotoxic drugs for haematologic cancers (1960’s). Deoxyguanosine analogues have been found to be selectively toxic for T-cells (1978). Arabinosyl guanine was found to be selectively toxic to T cells (1983); nelarabine is the water-soluble prodrug of arabinosyl guanine (1995)



Ranolazine, Ranexa Indication Chronic angina pectoris Molecule Low molecular weight, synthetic Structure

First Patent EP 126449, Syntex, A.F. Kluge, R.D. Clark, A.M. Strosberg, J.C. Pascal,

R.L. Whiting Application 17.05.1984 Publication 28.11.1984 Cardioselective aryloxy- and arylthiohydroxypropylpiperazinyl acetanilides which affect calcium entry

Approved Jan. 27, 2006 MoA Unclear; affects sodium and calcium channels, ion channel modulator Approach Systems-based, chemocentric First published Final molecule with indication:

Allely, M.C. & Alps, B.J. The effects of the novel anti-anginal compound RS 43285 on myocardial conduction in the anaesthetized dog. Br J Pharmacol 93, 375-82 (1988).

Discovered Testing of potential channel blockers in in vivo canine model of myocardial ischemia.



Lubiprostone, Amitiza Indication Irritable bowel syndrome and chronic constipation Molecule Natural substance (derived) Structure

First patent Compound:

EP 430552, Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyusho, R. Ueno, H. Osama Treatment of pulmonary dysfunction with 15-keto-prostaglandin compounds and their preparation and pharmaceutical compositions containing them Application: 21.11.1990 Publication: 05.06.1991 Use for abdominal discomfort: US 20040138308, Sucampo, R. Ueno, S. Kuno Method for treating abdominal discomfort with a chloride channel opener, especially a prostaglandin Application: 29.12.2003 Publication: 15.07.2004

Approved Jan. 31, 2006 MoA Unclear, may activate ClC-2 chloride channels Approach Systems-based chemocentric First published Chemotype with indication:

Christmas, A.J. The mouse anti-morphine constipation test--a simple laboratory test of the gastrointestinal side-effect potential of orally administered prostaglandin analogues. Prostaglandins 18, 279-84 (1979). Final molecule: Johanson, J.F., Gargano, M.A., Patchen, M.L., & Ueno R. Efficacy and safety of a novel compound, RU-0211, for the treatment of constipation (abstract). Gastroenterology. 122 suppl. A315 (2002).

Discovered In vivo testing of specific compounds probably based on the finding that a known side effect of prostaglandins is diarrhea.



Varenicline, Champix; Chantix Indication Smoking cessation Molecule Natural product (derived) Structure

N

NNH

First Patent WO 2001062736, Pfizer, P.R.P. Brooks, J.W. Coe

Application: 08.02.2001 Publication: 30.08.2001 Preparation of aryl-fused azapolycyclic compounds as nicotine binding inhibitors

Approved May 10, 2006 MoA Partial agonist of nicotinic acetylcholine receptors, ion channel agonist Approach Systems-based, chemocentric First published Chemotype:

Dale, H.H. & Laidlaw, P.P. The significance of the suprarenal capsules in the action of certain alkaloids. J Physiol 45, 1-26 (1912). Indication: Stoyanov, S., Yanachkova, M., Treatment of nicotinism with the Bulgarian drug, Tabex. Chimpharm Sofia 2,13 (1965). MoA: Papke, R.L. & Heinemann, S.F. Partial agonist properties of cytisine on neuronal nicotinic receptors containing the beta 2 subunit. Mol Pharmacol 45, 142-9 (1994). Final molecule: Coe, J.W. et al. Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation. J Med Chem 48, 3474-7 (2005).

Discovered Cytisine is known since 1912 as a natural product with nicotine like activity. Cytisine is marketed since the 1960’s in East European countries for smoking cessation. MoA discovered in 1994. Cytisine was the starting point for Varenicline. Assays for compound optimization were cellular, with specific readouts for several nAChR subtypes.



Vorinostat, SAHA, Zolinza Indication Cutaneous T-cell lymphoma (hematologic and solid tumours) Molecule Low molecular weight, synthetic Structure H

N

ONH

OOH

First Patent WO 9307148, Sloan Kettering Institute, R. Breslow, P.A. Marks, R.A.

Rifkind, B. Jursic Application 05.10.1992 Publication 15.04.1993 Alkanedioic acid derivatives, novel potent inducers of terminal differentiation and methods of use thereof

Approved Oct. 6, 2006 MoA Histone deacetylase (unspecific for class I and II), enzyme inhibitor Approach Systems-based, chemocentric First published Chemotype:

Reuben, R.C., Wife, R.L., Breslow, R., Rifkind, R.A. & Marks, P.A. A new group of potent inducers of differentiation in murine erythroleukemia cells. Proc Natl Acad Sci U S A 73, 862-6 (1976). Final molecule: Stowell, J.C., Huot, R.I. & Van Voast, L. The synthesis of N-hydroxy-N'-phenyloctanediamide and its inhibitory effect on proliferation of AXC rat prostate cancer cells. J Med Chem 38, 1411-3 (1995). Target/MoA: Richon, V.M. et al. A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc Natl Acad Sci U S A 95, 3003-7 (1998).

Discovered Serendipitous discovery (observational, non-intentional) that DMSO leads to cytodifferentiation and growth arrest in cell culture. Derivatization and optimization of the compound based on cell culture assays. MoA discovered with final compound.



Sinecatechins, Veregen Polyphenon E Indication Genital and perianal warts (anti-viral; topical) Molecule Natural product (derived) Structure Mixture First Patent JP 09110615, Mitsui Norin Co, T. Nomura, M. Hara

Application 17.10.1995 Publication 28.04.1997 Disinfectants containing catechins

Approved Oct. 31, 2006 MoA Unknown Approach Systems-based chemocentric First published Traditional Chinese medicine (Chinese book on pharmaceutical plants; ca.

200 BC) Indication: Wang, Z.Y. et al. Inhibitory effect of green tea on the growth of established skin papillomas in mice. Cancer Res 52, 6657-65 (1992).

Discovered Traditional Chinese medicine; several studies on anti-tumour activity between 1987 -1991 (cited in Wang, Z.Y. et al. Inhibitory effect of green tea on the growth of established skin papillomas in mice. Cancer Res 52, 6657-65 (1992))



Rufinamide, Inovelon, Banzel Indication Seizures, Epilepsy, Lennox-Gastaut syndrome Molecule Low molecular weight, synthetic Structure

NN N

F

FO

H2N

First Patent EP 199262, Ciba-Geigy, R. Meier

Application 15.04.1986 Publication 29.10.1986 Preparation of fluorinated phenylalkyltriazoles as anticonvulsants and pharmaceutical compositions containing them

Approved Nov. 14, 2008 MoA Unknown, probably stabilizing the inactive state of a sodium channnel Approach Systems-based, chemocentric First published Chemotype with indication:

Kadaba, P.K. Triazolines XIII: delta 2-1,2,3-triazolines, a new class of anticonvulsants. J Pharm Sci 73, 850-2 (1984). Final molecule: Brunner, L.A. & Powell, M.L. An automated method for the determination of a new potential antiepileptic agent (CGP 33101) in human plasma using high performance liquid chromatography. Biomed Chromatogr 6, 278-82 (1992).

Discovered Based on the finding that “several five-membered heterocyclic ring systems containing up to four nitrogen atoms have been synthesized and screened for anticonvulsant activity”, the chemotype was synthesized and tested in an in vivo mouse model for epilepsy.



Artemether-lumefantrine, Coartem, Riamet Indication Malaria Molecule Combination of a natural product derivative (artemether) and a low

molecular weight synthetic compound (lumefantrine) Structure Lumefantrine: Artemether:

First Patent Artemisinin: US 87365, AJ Lin, D.L. Klayman, W.K. Milhous

Application 20.08.1987 Publication 15.05.1988 Preparation of dihydroartemisinin derivatives as antimalarial agents Lumefantrine: CN 1042535, Chinese Academy of Military Medical Sciences, R Deng, J Zhong et al Application 10.11.1988 Publication 30.05.1990 Improved synthesis of antimalarial fluorenemethanol derivative Combination: WO 9202217, Ciba-Geigy, Chinese Academy of Military Medical Sciences, Y Zhou, D Ning, S Wang, D Ding, G Li, C Shan, G Liu Application 05.06.1991 Publication 20.02.1992 Antimalarial compositions containing benflumetol and artemisinin derivatives

Approved April 7, 2009 Target/MoA Unknown Approach Systems-based, phenotypic screening First published Molecule (Artemether):

Gu, H.M., Lu, B.F. & Qu, Z.X. [Antimalarial activities of 25 derivatives of artemisinine against chloroquine-resistant plasmodium berghei (author's transl)]. Zhongguo Yao Li Xue Bao 1, 48-50 (1980). Molecule (Lumefantrine): Wang, Y., Ding, D. & Ding, J., Enhancement of bioavailability of a hydrophobic fluorenemethanol antimalarial by oleic acid in soft gelatin capsules. Yaoxue Tongbao. 17, 4-7 (1982). Discovery (review): Miller, L.H. & Su, X. Artemisinin: discovery from the Chinese herbal garden. Cell 146, 855-8 (2011).

Discovered Discovered in 1972 by testing various traditional Chinese medicines in a rodent model of malaria (artemisinin). Little has been published about the discovery since this project was regarded secret by the Chinese military. Lumefantrine was also discovered in the same project.

Fingolimod, Gilenya Indication Multiple sclerosis Molecule Low molecular weight, synthetic



Structure

First Patent WO 9408943, Yoshitomi, T. Fujita, S. Sasaki, M. Yoneta, T. Mishina, K.

Adachi, K. Chiba Application: 18.10.1993 Publication: 28.04.1994 Preparation of 2-amino-1,3-propanediol compounds as immunosuppressants

Approved Sept. 21, 2010 Target/MoA Sphingosine 1-phosphate receptor, GPCR modulator Approach Systems-based, phenotypic screening First published Chemotype:

Fujita, T. et al. Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite. J Antibiot (Tokyo) 47, 208-15 (1994). Final molecule: Adachi, K. et al. Design, Synthesis, and Structure-Activity-Relationships of 2-Substituted-2-Amino-1,3-Propanediols - Discovery of a Novel Immunosuppressant, Fty720. Bioorganic & Medicinal Chemistry Letters 5, 853-856 (1995). Mechanism of Action: Mandala, S. et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296, 346-9 (2002).

Discovered The chemotype was discovered through a phenotypic screen for novel immunosuppressive natural products using a cellular assay (mixed lymphocyte reaction). Subsequent chemical optimization using in vitro and in vivo models serendipitously changed the mechanism of action which later was established to be sphingosine 1-phosphate receptor modulation.



Eribulin, Halaven Indication Cancer (breast cancer) Molecule Natural product (derived) (derivative of halochondrin B from the marine

sponge Halichondria okadai) Structure

First Patent WO 9965894, Eisai, B.A. Littlefield, M. Palme, B.M. Seletsky, M.J.

Towle, M.J. Yu, W. Zheng Application: 16.06.1999 Publication: 23.12.1999 Preparation of halichondrin analogs as anticancer or antimitotic agents

Approved Nov. 25, 2010 Target/MoA Microtubule inhibitor Approach Systems-based, phenotypic screening First published Chemotype and biological activity:

Uemura, D. et al. Norhalichondrin-a - an Antitumor Polyether Macrolide from a Marine Sponge. Journal of the American Chemical Society 107, 4796-4798 (1985). Final molecule: Towle, M.J. et al. In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res 61, 1013-1021 (2001). Mechanism of action: Jordan, M.A. et al. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Molecular Cancer Therapeutics 4, 1086-1095 (2005).

Discovered Studying active substances of marine organisms, halichondrin B was isolated and shown to have anti-tumour activity in a cellular assay. The final molecule was synthesized as a structurally simplified, fully synthetic analogue. The mechanism of action was established subsequently.



Ezogabine, Trobalt, Potiga Indication Epilepsy Molecule Low molecular weight, synthetic Structure

First Patent DE 4200259, Asta Medica, H.R. Dieter, J. Engel, B. Kutscher, E.

Polymeropoulos, S. Szelenyi, B. Nickel Application: 08.01.1992 Publication: 15.07.1993 1,2,4-triaminobenzene derivatives and a process for their preparation

Approved June 10, 2011 Target/MoA Potassium channel (KCNQ2/Q3) opener, ion channel agonist Approach Systems-based, chemocentric First published Chemotype:

Hiedl, P. Changes of the Pain Threshold Induced by Analgetic Drugs. Medizinische Klinik 74, 1497-1499 (1979). Indication: Seaman, C.A., Sheridan, P.H., Engel J., Molliere, M., Narang, P.K. & Nice, F.J., Flupirtine. In: B.S. Meldrum and R.J. Porter (Eds), New Anticonvulsant Drugs, Libbey, London, pp. 135-146. (1986). Final molecule: Yonekawa, W.D., Kapetanovic, I.M. & Kupferberg, H.J. The effects of anticonvulsant agents on 4-aminopyridine induced epileptiform activity in rat hippocampus in vitro. Epilepsy Res 20, 137-50 (1995). Mechanism of action established: The new anticonvulsant retigabine (D-23129) acts as an opener of K+ channels in neuronal cells, Rundfeldt C, Eur J Pharmacol. 1997 Oct 8;336(2-3):243-9.

Discovered Flupirtine, a close analogue of Ezogabine, was discovered in an effort to find novel analgesics with different mode of action to opiates between 1960-1970 (Szelenyi, I. Flupirtine, a re-discovered drug, revisited. Inflamm Res 62, 251-8 (2013)). Flupirtine is a 2,3,6 triaminopyridine derived from the known analgesic pyridium (discovered in the 1930’s). Synthesized compounds were directly tested in an animal model of pain. Ezogabine was synthesized as a back-up compound to flupirtine and both compounds were found to have anti-epileptic activity in various animal models. The mechanism of action was elucidated in 1997. Flupirtine is approved as an analgesic drug in Europe since 1984.



Ingenol mebutate, Picato Indication Cancer (actnic keratosis) Molecule Natural product (derived) Structure

First Patent WO 2001093885, Peplin Research, J.H. Aylward, P.G. Parsons, A.

Suhrbier, A. Kathleen Application: 07.06.2001 Publication: 13.12.2001 Euphorbiaceae macrocyclic diterpenes for the treatment of inflammation

Approved Jan. 23, 2012 Target/MoA unknown Approach Systems-based, chemocentric First published Therapeutic principle:

Plants of the Euphorbiaceae family have been used for treatment of cancers and warts since at least 400 BC. Weedon, D. & Chick, J. Home Treatment of Basal-Cell Carcinoma. Medical Journal of Australia 1, 928-928 (1976). Chemotype with activity: Kupchan, S.M., Uchida, I., Branfman, A.R., Dailey, R.G. & Fel, B.Y. Antileukemic Principles Isolated from Euphorbiaceae Plants. Science 191, 571-572 (1976). Compound isolated: Sayed, M.D. et al. Constituents of Egyptian Euphorbiaceae .9. Irritant and Cyto-Toxic Ingenane Esters from Euphorbia-Paralias L. Experientia 36, 1206-1207 (1980). Final molecule and indication (skin cancer): Ogbourne, S.M. et al. Antitumor activity of 3-ingenyl angelate: Plasma membrane and mitochondrial disruption and necrotic cell death. Cancer Res 64, 2833-2839 (2004).

Discovered Plants of the Euphorbiaceae family have been used for treatment of cancers and warts since at least 400 BC. The isolation of ingenol angelate as one of the active principles in 1983 led to the development of the drug.



Omacetaxine, Cephalotaxin, Ceflatonin, Myelostat Indication Cancer (chronic myeloid leukaemia) Molecule Natural product (derived) (homoharringtonine from the plant

Cephalotaxus harringtonia). Structure

First Patent Compound: US 840423, US Dept of Agriculture, N.E. Delfel, J.A. Rothfus

Application: 07.10.1977 Publication: 07.10.1977 Homodeoxyharringtonine and other cephalotaxine esters by tissue culture Use: EP 203386, Y. Liu Application: 25.0401986 Publication: 03.12.1986 Pharmaceutical composition for treating nonlymphatic leukemia and its components

Approved Oct. 26, 2012 Target/MoA Inhibition of translation by blocking the ribosomal A-site, enzyme

inhibitor Approach Systems-based, chemocentric First published Therapeutic principle:

Plant extracts are used in traditional Chinese medicine for treatment of diverse malignancies Molecule identified: Powell, R.G., Weisleder, D., Smith, C.R., Jr. & Rohwedder, W.K. Structures of harringtonine, isoharringtonine, and homoharringtonine. Tetrahedron Lett, 815-8 (1970). Molecule activity: Powell, R.G., Weislede.D & Smith, C.R. Antitumor Alkaloids from Cepha-lotaxus-Harringtonia - Structure and Activity. J Pharm Sci 61, 1227-& (1972). Mechanism of action: Tscherne, J.S. & Pestka, S. Inhibition of protein synthesis in intact HeLa cells. Antimicrob Agents Chemother 8, 479-87 (1975). Final indication: Chinese People’s Liberation Army 187th Hospital, Harringtonine in the treatment of acute leukemia: Clinical analyses of 72 cases. Chin Med J 3,163 (1978)

Discovered Used in traditional Chinese medicine, first isolated in 1970 and subsequently profiled in various tumor models. First tested for chronic myeloid leukaemia in 1978.



Bedaquiline, Sirturo Indication Tuberculosis Molecule Low molecular weight, synthetic Structure

First Patent WO 2005117875, Janssen, K.J.L.M: Andries, J.F.E. Van Gestel

Application: 24.05.2005 Publication: 15.12.2005 Preparation of aminohydroxyaralkylquinolines for the treatment of drug resistant mycobacterial diseases

Approved Dec. 28, 2012 Target/MoA Mycobacterium tuberculosis ATP synthase, enzyme inhibitor Approach Systems-based, phenotypic screening First published Chemotype:

Guillemont, J., Van Gestel, J, Venet, M., Poignet, H., Decrane, L. & Vernier, D. Quinoline derivatives and their use as mycobacterial inhibitors. WO Patent 2004/011436 (2004). Final molecule and MoA: Andries, K. et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 307, 223-7 (2005).

Discovered The final molecule was discovered at least 7 years prior to the first publication (Protopopova, M. et al. In search of new cures for tuberculosis. Medicinal Chemistry 3, 301-316 (2007)). The chemotype was found by high throughput screening using Mycobacterium smegmatis cultures. The target was subsequently identified through the characterization of resistant mutants.



Crofelemer, Provir, Virend Indication Diarrhea Molecule Natural product (derived) (Proanthocyanidine oligomer from the plant

Croton lechleri) Structure

First Patent US 20070254050, Trine Pharm., B.D. Quart, D.P. Rosenbaum, T.X.

Neenan, R.C. Blanks Application: 24.08.2006 Publication: 01.11.2007 Method for treatment of diarrhea-predominant irritable bowel syndrome comprising an inhibitor of chloride-ion transport such as crofelemer

Approved Dec. 31, 2012 Target/MoA CFTR and calcium-activated chloride channel, ion channel blocker. Approach Systems-based, chemocentric First published Molecule identified:

Ubillas, R. et al. SP-303, an antiviral oligomeric proanthocyanidin from the latex of Croton lechleri (Sangre de Drago). Phytomedicine 1, 77-106 (1994). Indication: Gabriel, S.E. et al. A novel plant-derived inhibitor of cAMP-mediated fluid and chloride secretion. Am J Physiol 276, G58-63 (1999). Mechanism of action: Tradtrantip, L., Namkung, W. & Verkman, A.S. Crofelemer, an antisecretory antidiarrheal proanthocyanidin oligomer extracted from Croton lechleri, targets two distinct intestinal chloride channels. Mol Pharmacol 77, 69-78 (2010).

Discovered The naturally occurring latex has been used by the indigenous people of South America to treat various diseases including diarrheas. The compound was isolated in 1994 as an anti-viral agent. The final indication was established in 1999 and the mechanism of action in 2010.



Dimethyl fumarate, Tecfidera Indication Multiple sclerosis Molecule Natural substance (derived) Structure

First Patent DE 19721099, Fumapharm A.-G., Joshi, Rajendra K.; Strebel, Hans-Peter

Use of fumaric acid derivatives in producing pharmaceutical compositions for treating polyarthritis or multiple sclerosis (Note: Fumaric acid monoalkyl esters, alone or combined with dialkyl fumarates for treatment of polyarthritis, multiple sclerosis and GvH.) Application: 20.05.1997 Publication: 26.11.1998 DE 19853487, Fumapharm A.-G., Joshi, Rajendra Kumar; Strebel, Hans-Peter Pharmaceutical uses of dialkyl fumarates Application: 19.11.1998 Publication: 25.05.2000

Approved March 27, 2013 (approved in Germany for psoriasis since 1994) Target/MoA Unclear, probably inducing an antioxidant response after depletion of

glutathione Approach Systems-based, chemocentric First published Chemotype:

Schweckendiek, W. [Treatment of psoriasis vulgaris]. Med Monatsschr 13, 103-4 (1959). Final molecule: Schweckendiek, W. Behandlung von Psoriasis vulgaris mit lipoidlöslichen Fumarsäureverbindungen. Medizin heute 15, 19-20 (1966). Indication: Joshi, R.K. & Strebel H.-P. Pharmaceutical uses of dialkyl fumarates Patent DE 19853487 (2000).

Discovered Serendipitous finding assuming that psoriasis might be caused by a metabolic disturbance involving the citrate cycle. W. Schweckendiek, who suffered from psoriasis, was working on C4 compounds of the citrate cycle and was taking fumaric acid in a self experiment. The final molecule was approved for treatment of psoriasis in Germany in 1994 and it was found later that 2 psoriasis patients who also suffered from MS improved in both diseases. This triggered further clinical trials in MS.



Trametinib, Mekinist Indication Melanoma Molecule Low molecular weight, synthetic Structure

First Patent WO 2005121142, Japan Tobacco Inc, Sakai, Toshiyuki; Kawasaki,

Hisashi; Abe, Hiroyuki; Hayakawa, Kazuhide; Iida, Tetsuya; Kikuchi, Shinichi; Yamaguchi, Takayuki; Nanayama, Toyomichi; Kurachi, Hironori; Tamaru, Masahiro; Hori, Yoshikazu; Takahashi, Mitsuru; Yoshida, Takayuki Preparation of 5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidines and related compounds as MEK inhibitors and p15 and p27 protein inducers for the treatment of cancer and rheumatic diseases Application: 10.06.2005 Publication: 22.12.2005

Approved May 29, 2013 Target/MoA MEK1 and MEK2, allosteric kinase inhibitor Approach Systems-based, phenotypic screening First published Concept:

Stone, S. et al. Genomic structure, expression and mutational analysis of the P15 (MTS2) gene. Oncogene 11, 987-91 (1995). Chemotype and mechanism of action: Yamaguchi, T. et al. Identification of JTP-70902, a p15(INK4b)-inductive compound, as a novel MEK1/2 inhibitor. Cancer Sci 98, 1809-16 (2007). Final molecule: Gilmartin, A.G. et al. GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin Cancer Res 17, 989-1000 (2011).

Discovered The chemotype was discovered using a cellular screen for inducers of p15INK4B and p27Kip1/CDKN1B and subsequently shown to be a specific, allosteric MEK1/MEK2 inhibitor.



Other drugs:

Aminolevulinic acid Indication Actinic keratosis Molecule Natural Substance (derived) Structure

First Patent Use of ALA as precursor for photodynamic tetrapyrroles:

WO 8600785, University of Illinois, C.A. Rebeiz, H.J. Hopen Photodynamic herbicides Application: 17.07.1985 Publication: 13.02.1986 Photodynamic Therapy: US 5234940, Queen’s University, J.C. Kennedy, R.H. Pottier, R.L. Reid Photochemotherapeutic method using 5-aminolevulinic acid Application: 08.04.1992 Publication: 10.08.1993 Use for actinic keratosis: DE 19852245, ASAT, H.W. Schmid, G. Burmeister Application: 12.11.1998 Publication: 18.05.2000

Approved Dec. 3, 1999 Target/MoA Photodynamic therapy (aminolevulinic acid is a precursor of

protoporphyrin IX, a precursor of heme and natural photosensitizer) First published Mechanistic understanding:

Berlin, N.I., Neuberger, A. & Scott, J.J. The metabolism of delta -aminolaevulic acid. 1. Normal pathways, studied with the aid of 15N. Biochemical Journal 64, 80-90 (1956). Therapeutic principle: Kennedy, J.C., Pottier, R.H. & Pross, D.C. Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience. J Photochem Photobiol B 6, 143-8 (1990).

Discovered Aminolevulinic acid has been established as a precursor for protoporphyrin IX in 1956. Increasing photosensitizing concentrations of protoporphyrin IX in actinic keratosis by application of aminolevulinic acid has been studied more than 30 years later.



Lucinactant, Surfaxin Indication Respiratory distress syndrome Molecule Natural substance (derived) Structure Not applicable First Patent WO 9735882, Ortho Pharmaceutical, Bornstein, Michael; Williams, N.

Adeyinka Lyophilized pulmonary surfactant peptide compositions Application: 06.03.1997 Publication: 02.10.1997

Approved March 6, 2012 Target/MoA The peptide mimics surfactant-associated protein B and lowers alveolar

surface tension Approach Target-based, low molecular weight First published Concept established:

Robertson, B. et al. Experimental neonatal respiratory failure induced by a monoclonal antibody to the hydrophobic surfactant-associated protein SP-B. Pediatric Research 30, 239-43 (1991). Final molecule: Cochrane, C.G. & Revak, S.D. Pulmonary surfactant protein B (SP-B): structure-function relationships. Science 254, 566-8 (1991).

Discovered Following the discovery of the protein several peptide mimetics were synthesized and studied for their efficacy.

characteristics and origins of first-in-class drugs ... information in format provided by eder et...

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