direct renin inhibitors as antihypertensive drugs
DESCRIPTION
www.pharmaxchange.info. DIRECT RENIN INHIBITORS AS ANTIHYPERTENSIVE DRUGS. DATE – OCTOBER 23 rd , 2009 PRESENTED BY – AKUL MEHTA VIRGINIA COMMONWEALTH UNIVERSITY SCHOOL OF PHARMACY DEPARTMENT OF MEDICINAL CHEMISTRY. www.pharmaxchange.info. WHAT IS HYPERTENSION?. - PowerPoint PPT PresentationTRANSCRIPT
DIRECT RENIN INHIBITORS AS ANTIHYPERTENSIVE DRUGS
DATE – OCTOBER 23rd, 2009
PRESENTED BY – AKUL MEHTA
VIRGINIA COMMONWEALTH UNIVERSITYSCHOOL OF PHARMACYDEPARTMENT OF MEDICINAL CHEMISTRY
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WHAT IS HYPERTENSION?
Normal Blood Pressure = 120/80 Systolic = 90 – 119 mm Hg Diastolic = 60 – 79 mm Hg
Hypertension = High Blood Pressure
Known risk factor of several Cardiovascular Disorders
2Chobanian, A. V. et al. Hypertension 2003, 42, 1206-1252
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RENIN ANGIOTENSIN SYSTEM
AngII
ACE
AngI = Angiotensin I ACE = Angiotensin converting enzyme AngII = Angiotensin II
Image adapted from - Li, Y. C. Curr. Opin. Invest. Drugs 2007, 8, 750-757.
Angiotensinogen AngI
Renin
Rate DeterminingStep INCREASE IN BLOOD
PRESSURE
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CURRENT DRUGS TARGETING THE RENIN-ANGIOTENSIN SYSTEM FOR HYPERTENSION
IS THERE REALLY A NEED FOR ANOTHER ANTIHYPERTENSIVE DRUG?
•Angiotensin Converting Enzyme Inhibitors
•Angiotensin II Receptor Blockers
•Aldosterone Antagonists
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NEED FOR ANOTHER ANTIHYPERTENSIVE
Li, Y. C. Curr. Opin. Invest. Drugs 2007, 8, 750-757.Image from - http://blog.wineenthusiast.com/wp-content/uploads/2008/12/balance.jpg
Hypertension needs modulation
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NEED FOR ANOTHER ANTIHYPERTENSIVE
Li, Y. C. Curr. Opin. Invest. Drugs 2007, 8, 750-757.
Angiotensinogen AngI AngII Ang II RECEPTORSAT1
Renin
Rate DeterminingStep
ACE
Ang II RECEPTORSAT2
ChymaseAT1 RECEPTOR BLOCKER (ARB)
ACE INHIBITOR
INVOLVED INBRADYKININMETABOLISM
Limitations of current drugs targeting the system
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NEED FOR ANOTHER ANTIHYPERTENSIVE Hypertension 1° risk factor in cardiovascular
diseases
Worldwide prevalance of ≈ 1 billion people (almost 1/6th of the human population)
United States of America > 60 million people
< 30% of patients achieve treatment goals
Yokokawa, F. et al. Expert Opin. Ther. Patents 2008, 18(6), 581-602.
IS THERE REALLY A NEED FOR ANOTHER ANTIHYPERTENSIVEDRUG?YES THERE IS DEFINITELY A NEED
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CURRENT INTEREST IN INHIBITION OF RENIN ANGIOTENSIN SYSTEM
1985-1989 1990-1994 1995-1999 2000-2004 2005-20080
2040
6080
100120
140160
138 135
12 12
75
Patent Applications from 1985-2008 for Renin Inhibitors
Yokokawa, F. et al. Expert Opin. Ther. Patents 2008, 18(6), 581-602.
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INTRODUCING RENIN
History
Structure
Function
Mechanism
PDB ID – 2v0z
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RENIN - HISTORY 1898- Tigerstedt and
Bergman
Kidney extracts produce pressor effects- coined the term ‘renin’
Phillips, M. I. News Physiol. Sci. 1999, 14, 271-274
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RENIN - HISTORY 1934- Harry Goldblatt
Induced experimental hypertension in dogs
1st to prove that renin system blockade would reduce hypertension
11Basso, N. et al. Hypertension 2001, 38, 1246-1249.
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RENIN - HISTORY 1970- Tadashi Inigami
Isolated pure renin from hog kidney
This was followed by isolation from rat and human kidney.
Currently working Vanderbilt University School of Medicine
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RENIN - STRUCTUREHighly Species Specific
340 amino acids
Two beta pleated sheets make two lobes
Active site between the two lobes
Aspartates for the active site provided by each lobe – i.e. Asp 32 and Asp. 215
Eder, J. et al. Current Pharmaceutical Design, 2007, 13, 271-285.PDB ID- 2v0z
ASP32
ASP215
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RENIN - FUNCTION
Renin cleaves peptide bondbetween Leu10-Val11
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu10 + Val11-Ile-His-Asn---
Angiotensin I
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu10--Val11-Ile-His-Asn---Angiotensinogen (480 amino acid long)
Angiotensinogen AngI
Renin
Rate DeterminingStep
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RENIN - MECHANISM
Asp
O
O
H
Asp
O-
O
HO
H
NH
HN
O
OP1
P1'
ENZYMEACTIVE SITE
Asp
O-
O Asp
O
O
NH
HN
O
OP1
P1'O
H H
H
Asp
OH
O Asp
O-
O
NH
HN
O
OP1
P1'
OH+ H
Eder, J. et al. Current Pharmaceutical Design, 2007, 13, 271-285.
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HOW DOES ONE MEASURE RENIN INHIBITION?
In Vitro Human renin is
incubated with inhibitor
Angiotensinogen is added.
Angiotensin I produced is measured by radioimmunoassay
16
In Vivo Animal testing was
done on sodium depleted marmosets
Now even transgenic rats are used
Changes in blood pressure and heart rate is measured telemetrically.
Image from - http://www.bukisa.com/articles/50597_marmoset-monkeys-and-their-habitats
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INHIBITORS OF RENIN
OHN
H
OHN
O
NH
HN
O
HN
N
O
O
Cl CH3
Cl
OH
H2NHN
O
NH2
O
O
O
O
HN
O
O
Cl
N
HN
O
O
N
HN
O
O
O
O
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INHIBITORS OF RENIN
Early Inhibitors of Renin Antibodies
Transition State Analogs Peptide Mimetic Inhibitors Non-Peptide Inhibitors
▪ Recently developed Inhibitors
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INHIBITORS OF RENIN
Early Inhibitors of Renin Antibodies
Transition State Analogs Peptide Mimetic Inhibitors Non-Peptide Inhibitors
▪ Recently developed Inhibitors
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EARLY INHIBITORS OF RENIN
Monoclonal Antibodies Against Renin
Excellent tools to study enzyme and its hypertensive effects
However – ▪ parenteral administration ▪ immunogenecity
therefore less application in medicine.
Galen, F. X. J. Clin. Invest. 1984, 74, 723-735.
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INHIBITORS OF RENIN
Early Inhibitors of Renin Antibodies
Transition State Analogs Peptide Mimetic Inhibitors Non-Peptide Inhibitors
▪ Recently developed Inhibitors
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SCHECHTER AND BERGER NOMENCLATURE FOR PROTEASES
Mitti, P. R. Curr. Opin. Struct. Biol. 2006, 16, 769-775.
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THEORY OF TRANSITION STATE ANALOGS
SubstrateProduct
TransitionState
Enzyme Active Site
Schramm, V. L. Annu. Rev. Biochem. 1998, 67, 693-720.
Reaction Co-ordinate
En
erg
y
I
Inhibitor withstructure similar to transition statewill have highaffinity.
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PEPTIDE MIMETIC INHIBITORS
Modification of scissile bond with statine and its variants
Normal Substrate: AngiotensinogenAsp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Asn-]
Statine Analog:Boc-Phe-His-Stat-Leu-Phe-NH2
IC50 – 190nM Normal Peptide
Boger, J. et al. J. Med. Chem. 1985, 28, 1779-1790.
NH
HN
R1 H
H OH
HH
O
O
R2H
NH
HN
O
OR1
H
H
R2
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PEPTIDE MIMETIC INHIBITORS
Statine Analog:Boc-Phe-His-Stat-Leu-Phe-NH2
ACHPA Analog:Boc-Phe-His-ACHPA-Leu-Phe-NH2
IC50 – 49nM
O
NH
OHHN
(3S,4S)-4-amino-3-hydroxy-5-cyclohexylpentanoic acid
O
R2H
O
NH
R1 H
NH
HN
R1 H
H OH
HH
O
O
R2H
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NON-PEPTIDE INHIBITORS OF RENIN STORY OF ALISKIREN
(DEVELOPED BY NOVARTIS)
DEVELOPMENT OF PIPERIDINE CLASS OF RENIN INHIBITORS (DEVELOPED BY HOFFMAN LA ROCHE AND OTHERS)
OH
H2NHN
O
O
O
O
O
NH2
HN
O
O
Cl
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NON-PEPTIDE INHIBITORS OF RENIN
STORY OF ALISKIREN
OH
H2NHN
O
O
O
O
O
NH2
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STORY OF ALISKIRENBoc-Phe-His-ACHPA-Leu-Phe-NH2
OHHN
HN
O
NH
O
N
HN
O
SOO
CGP38560
IC50 = 1nMThe Renin-Angiotensin System; Robertson, J. I. S., Nicholls, M. G., Eds.; Mosby: London, 1993.
O
NH
OHHN
(3S,4S)-4-amino-3-hydroxy-5-cyclohexylpentanoic acid
O
R2H
O
NH
R1 H
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STORY OF ALISKIREN
OHHN
HN
O
NH
O
N
HN
O
SOO
S3 S1
CGP38560
S3 S1
IC50 = 1nM
Goshke, R. et al. Bioorg. Med. Chem. Lett. 1997, 7, 2735-2740.
OH
H2NHN
O
R2R1R3
R4
OHHN
HN
O
NH
O
N
HN
O
SOO
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STORY OF ALISKIREN
OH
H2NHN
O
R2R1R3
R4
S3S1
-phenyl substituent equipotent to -t-butyl
-OCH2COOCH3 > -OCH2CONH2 > -OCH2COOH
-isopropyl was found optimumIncrease or decrease in substituent size caused decrease in activity
R-epimer showed significant drop in activity
Can be changed to methyl
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OH
H2NHN
OO
O
H2N
STORY OF ALISKIRENOH
H2NHN
O
R2R1R3
R4
Most IC50 in μM range
IC50 = 20nM
OH
H2NHN
OO
O
H2N
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STORY OF ALISKIRENOH
H2NHN
OO
O
H2N
OH
H2NHN
O
R1
O
R3
R2 R4
To improve physicochemical properties
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STORY OF ALISKIREN
R1
-t-butyl
-O-CH3
OH
H2NHN
O
R1
O
R3
R2 R4
When R2 = -CH2CONH2
R3= -MeR4= -n-butyl
Goshke, R. et al. J. Med. Chem. 2007, 50, 4818-4831.
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OH
H2NHN
O
O
O
R3
R2 R4
STORY OF ALISKIREN
R2
(R3= Me, R4= n-butyl)IC50 Human Renin
Purified (nM)IC50 Plasma Renin (nM)
-CH2CONHMe 11 38
-CH2CH2OMe 4 32
-CH2CH2CH2OMe 1 1
-CH2CH2CH2OEt 3 20
-CH2CH2CH2OH 6 36
-CH2CH2CH2CH2OMe 2 22
-(CH2)4CH3 4 70
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STORY OF ALISKIREN
R3
R4=n-butylIC50 Human Renin
Purified (nM)IC50 Plasma Renin (nM)
-CH3 1 3
-isopropyl 0.7 0.9
OH
H2NHN
O
O
O
R3
R4
O
Maibaum, J. et. al. J. Med. Chem. 2007, 50, 4832-4844.
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STORY OF ALISKIREN
R4 IC50 Human Renin Purified (nM)
IC50 Plasma Renin (nM)
-CH2CONH2 3 10
-CHMeCONH2 4 12
-(CH2)2CONHMe 3 7
0.6 0.6
-CH2CH2CH2-morpholine 3 3
OH
H2NHN
O
O
O
R4
O
CH2
H3C CH3
O
NH2
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STORY OF ALISKIREN
OH
H2NHN
O
O
O
O
O
NH2
Aliskiren
Green= CGP38560Purple= Aliskiren
Wood, J. M. et al. Biochem. Biophys. Res. Comm. 2003, 308, 698-705.PDB ID – 2v0z
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SUMMARY OF ALISKIREN
OHHN
HN
O
NH
O
N
HN
O
SOO
CGP38560
OH
H2NHN
O
O
O
O
O
NH2
Aliskiren
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NON-PEPTIDE INHIBITORS OF RENIN-
PIPERIDINE CLASS OF INHIBITORS
HN
O
O
Cl
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Screening of the Roche Compound Library
IC50 = 50 μMHighly selective forrenin.
HN
O
O
Cl
Vieira, E. et al. Bioorg. Med. Chem. Lett. 1999, 9, 1397-1402.
PIPERIDINE CLASS OF INHIBITORS
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X-Ray Structure Interpretation
HN
O
O
Cl
Asp32-COOH HOOC-Asp215
S4
S1 S3
PIPERIDINE CLASS OF INHIBITORS
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PIPERIDINE CLASS OF INHIBITORS
HN
O
R2
R1
R1
R1 R2 IC50 (nM)
H 26
H
5.8x102
H
2.6x103
H 41
H 53
H 8
H 1.5
OCH3
0.060
NH
OO
N
O
OO
O
OO
NO
NO
OO
OO
O
OO
O
OO
S4
S1 S3
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X-Ray Analysis
Lifts a whole flap region fromThr72 to Ser81
PIPERIDINE CLASS OF INHIBITORS
HN
O
OCH3
OCH3
O
O
O
S3sp
S1 S3
HN
O
O
Cl
Asp32-COOH HOOC-Asp215
S4
S1 S3
Asp32-COOH HOOC-Asp215
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S3sp
HN
R1
Y Z
O O
R2
Guller, R. et al. Bioorg. Med. Chem. Lett. 1999, 9, 1403-1408.
Y Z R1 R2 IC50 (nM)Rec.
Renin
IC50 (nM)
Plasma renin
CH CH
H
5.1 3.3x102
CH CH OCH3
0.67 37
N CH
H
5.9x102 7.1x103
N
N
H 8.2x102 8.2x103
O*
O*
HN
O*
HN
O*
PIPERIDINE CLASS OF INHIBITORS
S1 S3
* Indicates point of attachmentto piperidine ring
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45Marki, H. P. et al. Il Farmaco 2001, 56, 21-27.
PIPERIDINE CLASS OF INHIBITORSHN
O
ONR
O
O
R IC50 (nM) Rec. Renin
IC50 (nM) Plasma Renin
-CH2-CH2-OH 0.30 18
-CH2-CH2-NH-CO-CH3 0.039 0.60
-CH2-CH2-CH2-NH2 8.0 n.d
-CH2-CH2-CH2-NH-CO-CH3 2.5 n.d
S3sp
S1 S3
Story for these molecules in literature ends here
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PIPERIDINE CLASS OF INHIBITORS-KETOPIPERAZINES
Holsworth, D. D. et al. Bioorg. Med. Chem. 2005, 13, 2657-2664.
N
HN
O
O
O
O
ON
HN
O
O
O
O
HN
O
O
O
O
IC50 = 2nM IC50 = 180nM IC50 = 54nM
SAR studies
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PIPERIDINE CLASS OF INHIBITORS-KETOPIPERAZINES
N
HN
O O
O
OR
R IC50(nM)
1700
1020
440
0.50
*
N*
NH
ON
NH
O
N
HN
O O
O
OO
* Indicates point of attachment to O.
CH2
*
CH2
*
S3sp
S1S3
Found to inhibit CYP3A4
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PIPERIDINE CLASS OF INHIBITORS-KETOPYRAZINES
Holsworth, D. D. et al. Bioorg. Med. Chem. Lett. 2006, 16, 2500-2504.
N
HN
O O
O
OO
N
R
R
IC50 RENIN (nM) 0.29 4.0
IC50 CYP3A4 (nM) 82 18
*NH
O
*N
O
R
IC50 RENIN (nM) 606 >10,000 0.42
IC50 CYP3A4 (nM) 42 3790 n.d
N*
O
NO
*O
*O
O
* Indicates point of attachment to N of tetrahydroquinoline
S3sp
S1 S3* Indicates point of attachment to N of tetrahydroquinoline
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PIPERIDINE CLASS OF INHIBITORS-KETOPIPERAZINES
Holsworth, D. D. et al. Bioorg. Med. Chem. Lett. 2006, 16, 2500-2504.
N
HN
O O
O
OO
N
R
R
IC50 RENIN (nM) 9.0 550
IC50 CYP3A4 (nM) n.d 54
R
IC50 RENIN (nM) 3.2 37 450
IC50 CYP3A4 (nM) 12 455 10,000
*O
O
*O
O
* O * OH* OH
O
* Indicates point of attachment to N of tetrahydroquinoline
S3sp
S1 S3* Indicates point of attachment to N of tetrahydroquinoline
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PIPERIDINE CLASS OF INHIBITORS-KETOPIPERAZINES
Holsworth, D. D. et al. Bioorg. Med. Chem. Lett. 2006, 16, 2500-2504.PDB ID – 2fs4
Tyr 14 Tyr14
H2O
Crystal Structure
N
O
H
Schematic View
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R
IC50 RENIN (nM) 0.18 364 1,200
IC50 CYP3A4 (nM) 14 25,000 15,000
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PIPERIDINE CLASS OF INHIBITORS-KETOPIPERAZINES
N
HN
O O
O
RO
R
IC50 RENIN (nM) 7 0.68
IC50 CYP3A4 (nM) 35 n.d
N*O
O
O
O
N*O
O
O
O
N*S
O
O
O
N*O O
HO
O
O
N*S O
HO
O
* Indicates point of attachment to C of Methyl
S3sp
S1
S3
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SUMMARY OF PIPERIDINE CLASS
HN
O
ON
O
O
NH
O
HN
O
O
Cl
HN
O
O N
O
O
O
O
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RECENTLY DEVELOPED INHIBITORS OF RENIN 3,9-diazobicyclo [3.3.1] nonene derivatives
Bezencon, O. et al. J. Med. Chem. 2009, 52, 3689-3702.
HN
O
ON
O
O
NH
O
HN
O
HN
N
O
Ar1
OAr2
R1
Displaces H2O from active siteaspartates
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RECENTLY DEVELOPED INHIBITORS OF RENIN 3,9-diazobicyclo [3.3.1] nonene derivatives
Bezencon, O. et al. J. Med. Chem. 2009, 52, 3689-3702.
HN
O
HN
N
O
Ar1
OAr2
R1
HN
O
HN
N
O
O
Cl CH3
Cl
-H, -CH3, -cyclopropane
•short linker preferred•ortho, meta substituentsimproveaffinity.
•ortho di-halo substituents preferred•4-methyl group preferred
IC50 (nM) IC50 (nM)Rec. Renin= 0.20 Plasma Renin= 19
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RECENTLY DEVELOPED INHIBITORS OF RENIN Alkyl amines
Tice, C. M. et al. Bioorg. Med. Chem. Lett. 2009, 19, 3541-3545.
NHR2
HN
O
NOR1O
X
H
H
S3 S1
S3spHOOC-Asp32
HOOC-Asp215
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RECENTLY DEVELOPED INHIBITORS OF RENIN Alkyl amines
Human Renin = 0.47 nMPlasma Renin = 13 nMOral Bioavailability = 38%
(in dog)
Tice, C. M. et al. Bioorg. Med. Chem. Lett. 2009, 19, 3541-3545.
NHR2
HN
O
NOR1O
X
H
H-Me> -Et
3-Cl > 3-F > 2-Cl > 2,3-diCl
3o alcohol would interact with Ser 219 γ Oxygen
-Me > -H
NHMe
HN
O
NMeOOH
H
Cl
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RECENTLY DEVELOPED INHIBITORS OF RENIN Orally bioavailable alkyl amines- crystal structure
Tice, C. M. et al. Bioorg. Med. Chem. Lett. 2009, 19, 3541-3545.PDB ID = 3gw5
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FUTURE TARGET OF THE RENIN-ANGIOTENSIN
SYSTEM
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FUTURE TARGET OF RENIN ANGIOTENSIN SYSTEM
Renin Angiotensin
System
Remodeling
Development
Inflammation
Thrombosis
Involvement of Renin-Angiotensin System
Clearly not mediated by Ang II.
Is there a Renin Receptor?
Nguyen, G. et al. Curr. Opin. Nephrol. Hypertens. 2003, 12, 51-55.
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Organ of interest mRNA cDNA Cloning
Vector
Put into cellsCells are plated• 1 cell= 1 colony
Cells express cDNA
proteins
Screening of cells against
I125 Renin
Cells with receptors
emit radiation
Isolate the cDNA for receptor
Transfect Human cell lines with
cDNA
FUTURE TARGET OF RENIN ANGIOTENSIN SYSTEM
60Image adapted from- http://tainano.com/Molecular%20Biology%20Glossary.files/image087.gifNguyen, G. et al. Journ. Clin. Invest. 2002, 109, 1417-1427
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Functionality of the receptor Effect on Ang I generation in presence of renin
FUTURE TARGET OF RENIN ANGIOTENSIN SYSTEM
Membrane bound renin 1nM
Free renin 1nM
Membrane bound renin 0.5nM
Free renin 0.5nM
Agen = AngiotensinogenAng I = Angiotensin I
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Functionality of the receptor Effect on ERK1/ERK2 activation
FUTURE TARGET OF RENIN ANGIOTENSIN SYSTEM
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Immunofluorescence studies of receptors on cells of human: Kidney
Placenta
FUTURE TARGET OF RENIN ANGIOTENSIN SYSTEM
Coronary
Artery
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Characteristics of renin receptor: 350 amino-acid protein with no homology 45-kDa Multidomain
▪ Hydrophobic amino-terminal domainbinds renin and prorenin activates it
▪ Cytoplasmic tail= 20 amino acids activates ERK1/ERK2 intracellularly
▪ Single transmembrane domain
FUTURE TARGET OF RENIN ANGIOTENSIN SYSTEM
Campbell, D. J. Hypertension, 2008, 51, 1259-1264.
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CONCLUSION
PAST PRESENT FUTURE
Over 100 years since discovery of renin
OH
H2NHN
O
NH2
O
O
O
ON
HN
O
O
N
HN
O
O
O
O
OHN
H
OHN
O
NH
HN
O
HN
N
O
O
Cl CH3
Cl
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ACKNOWLEDGEMENTS
Dr. Umesh Desai
The Desai Group
Department of Medicinal Chemistry at VCU
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