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DATE – OCTOBER 23 rd, 2009 PRESENTED BY – AKUL MEHTA VIRGINIA COMMONWEALTH UNIVERSITY SCHOOL OF PHARMACY DEPARTMENT OF MEDICINAL CHEMISTRY www.pharmaxchange.info.

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Presentation on theme: "DATE – OCTOBER 23 rd, 2009 PRESENTED BY – AKUL MEHTA VIRGINIA COMMONWEALTH UNIVERSITY SCHOOL OF PHARMACY DEPARTMENT OF MEDICINAL CHEMISTRY www.pharmaxchange.info."— Presentation transcript:

1 DATE – OCTOBER 23 rd, 2009 PRESENTED BY – AKUL MEHTA VIRGINIA COMMONWEALTH UNIVERSITY SCHOOL OF PHARMACY DEPARTMENT OF MEDICINAL CHEMISTRY

2  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 2 Chobanian, A. V. et al. Hypertension 2003, 42,

3 3  AngI = Angiotensin I  ACE = Angiotensin converting enzyme  AngII = Angiotensin II Image adapted from - Li, Y. C. Curr. Opin. Invest. Drugs 2007, 8,

4 4 IS THERE REALLY A NEED FOR ANOTHER ANTIHYPERTENSIVE DRUG? Angiotensin Converting Enzyme Inhibitors Angiotensin II Receptor BlockersAldosterone Antagonists

5 5 Li, Y. C. Curr. Opin. Invest. Drugs 2007, 8, Image from -  Hypertension needs modulation

6 6 Li, Y. C. Curr. Opin. Invest. Drugs 2007, 8,  Limitations of current drugs targeting the system

7  Hypertension  1° risk factor in cardiovascular diseases  Worldwide prevalance of ≈ 1 billion people (almost 1/6 th of the human population)  United States of America > 60 million people  < 30% of patients achieve treatment goals 7 Yokokawa, F. et al. Expert Opin. Ther. Patents 2008, 18(6), IS THERE REALLY A NEED FOR ANOTHER ANTIHYPERTENSIVE DRUG? YES THERE IS DEFINITELY A NEED

8 8 Yokokawa, F. et al. Expert Opin. Ther. Patents 2008, 18(6),

9 9  History  Structure  Function  Mechanism PDB ID – 2v0z

10  Tigerstedt and Bergman  Kidney extracts produce pressor effects- coined the term ‘renin’ 10 Phillips, M. I. News Physiol. Sci. 1999, 14,

11  Harry Goldblatt  Induced experimental hypertension in dogs  1 st to prove that renin system blockade would reduce hypertension 11 Basso, N. et al. Hypertension 2001, 38,

12  Tadashi Inigami  Isolated pure renin from hog kidney  This was followed by isolation from rat and human kidney. 12 Currently working Vanderbilt University School of Medicine

13 13  Highly 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, PDB ID- 2v0z ASP32 ASP215

14 14 Renin cleaves peptide bond between Leu 10 -Val 11 Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu 10 + Val 11 -Ile-His-Asn--- Angiotensin I Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu 10 --Val 11 -Ile-His-Asn--- Angiotensinogen (480 amino acid long)

15 15 ENZYME ACTIVE SITE Eder, J. et al. Current Pharmaceutical Design, 2007, 13,

16  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 -

17 17

18  Early Inhibitors of Renin  Antibodies  Transition State Analogs  Peptide Mimetic Inhibitors  Non-Peptide Inhibitors ▪Recently developed Inhibitors 18

19  Early Inhibitors of Renin  Antibodies  Transition State Analogs  Peptide Mimetic Inhibitors  Non-Peptide Inhibitors ▪Recently developed Inhibitors 19

20  Monoclonal Antibodies Against Renin  Excellent tools to study enzyme and its hypertensive effects  However – ▪parenteral administration ▪immunogenecity therefore less application in medicine. 20 Galen, F. X. J. Clin. Invest. 1984, 74,

21  Early Inhibitors of Renin  Antibodies  Transition State Analogs  Peptide Mimetic Inhibitors  Non-Peptide Inhibitors ▪Recently developed Inhibitors 21

22 22 Mitti, P. R. Curr. Opin. Struct. Biol. 2006, 16,

23 23 Substrate Product Transition State Enzyme Active Site Schramm, V. L. Annu. Rev. Biochem. 1998, 67, Reaction Co-ordinate Energy I I Inhibitor with structure similar to transition state will have high affinity.

24  Modification of scissile bond with statine and its variants Normal Substrate: Angiotensinogen Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Asn-] Statine Analog: Boc-Phe-His-Stat-Leu-Phe-NH 2 24 IC 50 – 190nMNormal Peptide Boger, J. et al. J. Med. Chem. 1985, 28,

25 25 Statine Analog: Boc-Phe-His-Stat-Leu-Phe-NH 2 ACHPA Analog: Boc-Phe-His-ACHPA-Leu-Phe-NH 2 IC 50 – 49nM

26  STORY OF ALISKIREN (DEVELOPED BY NOVARTIS)  DEVELOPMENT OF PIPERIDINE CLASS OF RENIN INHIBITORS (DEVELOPED BY HOFFMAN LA ROCHE AND OTHERS) 26

27 27

28 28 Boc-Phe-His-ACHPA-Leu-Phe-NH 2 CGP38560 IC 50 = 1nM The Renin-Angiotensin System; Robertson, J. I. S., Nicholls, M. G., Eds.; Mosby: London,

29 29 S3 S1 CGP38560 S3 S1 IC 50 = 1nM Goshke, R. et al. Bioorg. Med. Chem. Lett. 1997, 7,

30 30 S3 S1 -phenyl substituent equipotent to -t-butyl -OCH 2 COOCH 3 > -OCH 2 CONH 2 > -OCH 2 COOH -isopropyl was found optimum Increase or decrease in substituent size caused decrease in activity R-epimer showed significant drop in activity Can be changed to methyl

31 31 Most IC 50 in μM range IC 50 = 20nM

32 32 To improve physicochemical properties

33 33 R1R1 -t-butyl -O-CH 3 When R 2 = -CH 2 CONH 2 R 3 = -Me R 4 = -n-butyl Goshke, R. et al. J. Med. Chem. 2007, 50,

34 34 R 2 (R 3 = Me, R 4 = n-butyl) IC 50 Human Renin Purified (nM) IC 50 Plasma Renin (nM) -CH 2 CONHMe CH 2 CH 2 OMe 432 -CH 2 CH 2 CH 2 OMe 11 -CH 2 CH 2 CH 2 OEt 320 -CH 2 CH 2 CH 2 OH 636 -CH 2 CH 2 CH 2 CH 2 OMe 222 -(CH 2 ) 4 CH

35 35 R 3 R 4 =n-butyl IC 50 Human Renin Purified (nM) IC 50 Plasma Renin (nM) -CH isopropyl Maibaum, J. et. al. J. Med. Chem. 2007, 50,

36 36 R4R4 IC 50 Human Renin Purified (nM) IC 50 Plasma Renin (nM) -CH 2 CONH CHMeCONH (CH 2 ) 2 CONHMe CH 2 CH 2 CH 2 -morpholine33

37 37 Aliskiren Green= CGP38560 Purple= Aliskiren Wood, J. M. et al. Biochem. Biophys. Res. Comm. 2003, 308, PDB ID – 2v0z

38 38 CGP38560 Aliskiren

39 39

40 Screening of the Roche Compound Library 40 IC 50 = 50 μM Highly selective for renin. Vieira, E. et al. Bioorg. Med. Chem. Lett. 1999, 9,

41  X-Ray Structure Interpretation 41 Asp32-COOHHOOC-Asp215 S4 S1 S3

42 42 R 1 R2R2 IC 50 (nM) H 26 H 5.8x10 2 H 2.6x10 3 H 41 H 53 H 8 H 1.5 OCH S4 S1 S3

43  X-Ray Analysis 43 Lifts a whole flap region fromThr72 to Ser81 S3 sp S1 S3 Asp32-COOHHOOC-Asp215 S4 S1 S3 Asp32-COOHHOOC-Asp215

44 S3 sp 44 Guller, R. et al. Bioorg. Med. Chem. Lett. 1999, 9, YZR1R1 R2R2 IC 50 (nM) Rec. Renin IC 50 (nM) Plasma renin CH H x10 2 CH OCH NCH H 5.9x x10 3 N N H8.2x x10 3 S1 S3 * Indicates point of attachment to piperidine ring

45 45 Marki, H. P. et al. Il Farmaco 2001, 56, R IC 50 (nM) Rec. Renin IC 50 (nM) Plasma Renin -CH 2 -CH 2 -OH CH 2 -CH 2 -NH-CO-CH CH 2 -CH 2 -CH 2 -NH n.d -CH 2 -CH 2 -CH 2 -NH-CO-CH n.d S3 sp S1S3 Story for these molecules in literature ends here

46 46 Holsworth, D. D. et al. Bioorg. Med. Chem. 2005, 13, IC 50 = 2nM IC 50 = 180nMIC 50 = 54nM SAR studies

47 47 RIC 50 (nM) * Indicates point of attachment to O. S3 sp S1 S3 Found to inhibit CYP3A4

48 48 Holsworth, D. D. et al. Bioorg. Med. Chem. Lett. 2006, 16, R IC 50 RENIN (nM) IC 50 CYP3A4 (nM)8218 R IC 50 RENIN (nM)606>10, IC 50 CYP3A4 (nM)423790n.d * Indicates point of attachment to N of tetrahydroquinoline S3 sp S1 S3 * Indicates point of attachment to N of tetrahydroquinoline

49 49 Holsworth, D. D. et al. Bioorg. Med. Chem. Lett. 2006, 16, R IC 50 RENIN (nM) IC 50 CYP3A4 (nM)n.d54 R IC 50 RENIN (nM) IC 50 CYP3A4 (nM) ,000 * Indicates point of attachment to N of tetrahydroquinoline S3 sp S1 S3 * Indicates point of attachment to N of tetrahydroquinoline

50 50 Holsworth, D. D. et al. Bioorg. Med. Chem. Lett. 2006, 16, PDB ID – 2fs4 Tyr 14 H2OH2O Crystal StructureSchematic View

51 R IC 50 RENIN (nM) ,200 IC 50 CYP3A4 (nM) 1425,00015, R IC 50 RENIN (nM) IC 50 CYP3A4 (nM) 35n.d * Indicates point of attachment to C of Methyl S3 sp S1 S3

52 52

53 53  3,9-diazobicyclo [3.3.1] nonene derivatives Bezencon, O. et al. J. Med. Chem. 2009, 52, Displaces H 2 O from active site aspartates

54 54  3,9-diazobicyclo [3.3.1] nonene derivatives Bezencon, O. et al. J. Med. Chem. 2009, 52, H, -CH 3, -cyclopropane short linker preferred ortho, meta substituents improve affinity. ortho di-halo substituents preferred 4-methyl group preferred IC 50 (nM) Rec. Renin= 0.20 Plasma Renin= 19

55  Alkyl amines 55 Tice, C. M. et al. Bioorg. Med. Chem. Lett. 2009, 19, S3 S1 S3 sp HOOC-Asp32 HOOC-Asp215

56  Alkyl amines 56 Human Renin = 0.47 nM Plasma Renin = 13 nM Oral Bioavailability = 38% (in dog) Tice, C. M. et al. Bioorg. Med. Chem. Lett. 2009, 19, Me> -Et 3-Cl > 3-F > 2-Cl > 2,3-diCl 3 o alcohol would interact with Ser 219 γ Oxygen -Me > -H

57  Orally bioavailable alkyl amines- crystal structure 57 Tice, C. M. et al. Bioorg. Med. Chem. Lett. 2009, 19, PDB ID = 3gw5

58 58

59 Renin Angiotensin System RemodelingDevelopmentInflammation Thrombosis 59 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,

60 60 Image adapted from- Nguyen, G. et al. Journ. Clin. Invest. 2002, 109,

61  Functionality of the receptor  Effect on Ang I generation in presence of renin 61 Membrane bound renin 1nM Free renin 1nM Membrane bound renin 0.5nM Free renin 0.5nM Agen = Angiotensinogen Ang I = Angiotensin I

62  Functionality of the receptor  Effect on ERK1/ERK2 activation 62

63  Immunofluorescence studies of receptors on cells of human:  Kidney  Placenta 63  Coronary Artery

64  Characteristics of renin receptor:  350 amino-acid protein with no homology  45-kDa  Multidomain ▪Hydrophobic amino-terminal domain  binds renin and prorenin  activates it ▪Cytoplasmic tail= 20 amino acids  activates ERK1/ERK2 intracellularly ▪Single transmembrane domain 64 Campbell, D. J. Hypertension, 2008, 51,

65 PASTPRESENTFUTURE 65 Over 100 years since discovery of renin

66  Dr. Umesh Desai  The Desai Group  Department of Medicinal Chemistry at VCU 66


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