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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 www.pharmaxchange.info

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, 1206-1252 www.pharmaxchange.info

3 3  AngI = Angiotensin I  ACE = Angiotensin converting enzyme  AngII = Angiotensin II Image adapted from - Li, Y. C. Curr. Opin. Invest. Drugs 2007, 8, 750-757. www.pharmaxchange.info

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

5 5 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 www.pharmaxchange.info

6 6 Li, Y. C. Curr. Opin. Invest. Drugs 2007, 8, 750-757.  Limitations of current drugs targeting the system www.pharmaxchange.info

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), 581-602. IS THERE REALLY A NEED FOR ANOTHER ANTIHYPERTENSIVE DRUG? YES THERE IS DEFINITELY A NEED www.pharmaxchange.info

8 8 Yokokawa, F. et al. Expert Opin. Ther. Patents 2008, 18(6), 581-602. www.pharmaxchange.info

9 9  History  Structure  Function  Mechanism PDB ID – 2v0z www.pharmaxchange.info

10  1898- Tigerstedt and Bergman  Kidney extracts produce pressor effects- coined the term ‘renin’ 10 Phillips, M. I. News Physiol. Sci. 1999, 14, 271-274 www.pharmaxchange.info

11  1934- 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, 1246-1249. www.pharmaxchange.info

12  1970- 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 www.pharmaxchange.info

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, 271-285. PDB ID- 2v0z ASP32 ASP215 www.pharmaxchange.info

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) www.pharmaxchange.info

15 15 ENZYME ACTIVE SITE Eder, J. et al. Current Pharmaceutical Design, 2007, 13, 271-285. www.pharmaxchange.info

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 - http://www.bukisa.com/articles/50597_marmoset-monkeys-and-their-habitats www.pharmaxchange.info

17 17 www.pharmaxchange.info

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

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

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, 723-735. www.pharmaxchange.info

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

22 22 Mitti, P. R. Curr. Opin. Struct. Biol. 2006, 16, 769-775. www.pharmaxchange.info

23 23 Substrate Product Transition State Enzyme Active Site Schramm, V. L. Annu. Rev. Biochem. 1998, 67, 693-720. Reaction Co-ordinate Energy I I Inhibitor with structure similar to transition state will have high affinity. www.pharmaxchange.info

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, 1779-1790. www.pharmaxchange.info

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 www.pharmaxchange.info

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

27 27 www.pharmaxchange.info

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, 1993. www.pharmaxchange.info

29 29 S3 S1 CGP38560 S3 S1 IC 50 = 1nM Goshke, R. et al. Bioorg. Med. Chem. Lett. 1997, 7, 2735-2740. www.pharmaxchange.info

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 www.pharmaxchange.info

31 31 Most IC 50 in μM range IC 50 = 20nM www.pharmaxchange.info

32 32 To improve physicochemical properties www.pharmaxchange.info

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, 4818-4831. www.pharmaxchange.info

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 1138 -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 3 470 www.pharmaxchange.info

35 35 R 3 R 4 =n-butyl IC 50 Human Renin Purified (nM) IC 50 Plasma Renin (nM) -CH 3 13 -isopropyl0.70.9 Maibaum, J. et. al. J. Med. Chem. 2007, 50, 4832-4844. www.pharmaxchange.info

36 36 R4R4 IC 50 Human Renin Purified (nM) IC 50 Plasma Renin (nM) -CH 2 CONH 2 310 -CHMeCONH 2 412 -(CH 2 ) 2 CONHMe37 0.6 -CH 2 CH 2 CH 2 -morpholine33 www.pharmaxchange.info

37 37 Aliskiren Green= CGP38560 Purple= Aliskiren Wood, J. M. et al. Biochem. Biophys. Res. Comm. 2003, 308, 698-705. PDB ID – 2v0z www.pharmaxchange.info

38 38 CGP38560 Aliskiren www.pharmaxchange.info

39 39 www.pharmaxchange.info

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, 1397-1402. www.pharmaxchange.info

41  X-Ray Structure Interpretation 41 Asp32-COOHHOOC-Asp215 S4 S1 S3 www.pharmaxchange.info

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 3 0.060 S4 S1 S3 www.pharmaxchange.info

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 www.pharmaxchange.info

44 S3 sp 44 Guller, R. et al. Bioorg. Med. Chem. Lett. 1999, 9, 1403-1408. YZR1R1 R2R2 IC 50 (nM) Rec. Renin IC 50 (nM) Plasma renin CH H 5.13.3x10 2 CH OCH 3 0.6737 NCH H 5.9x10 2 7.1x10 3 N N H8.2x10 2 8.2x10 3 S1 S3 * Indicates point of attachment to piperidine ring www.pharmaxchange.info

45 45 Marki, H. P. et al. Il Farmaco 2001, 56, 21-27. R IC 50 (nM) Rec. Renin IC 50 (nM) Plasma Renin -CH 2 -CH 2 -OH0.30 18 -CH 2 -CH 2 -NH-CO-CH 3 0.039 0.60 -CH 2 -CH 2 -CH 2 -NH 2 8.0 n.d -CH 2 -CH 2 -CH 2 -NH-CO-CH 3 2.5 n.d S3 sp S1S3 Story for these molecules in literature ends here www.pharmaxchange.info

46 46 Holsworth, D. D. et al. Bioorg. Med. Chem. 2005, 13, 2657-2664. IC 50 = 2nM IC 50 = 180nMIC 50 = 54nM SAR studies www.pharmaxchange.info

47 47 RIC 50 (nM) 1700 1020 440 0.50 * Indicates point of attachment to O. S3 sp S1 S3 Found to inhibit CYP3A4 www.pharmaxchange.info

48 48 Holsworth, D. D. et al. Bioorg. Med. Chem. Lett. 2006, 16, 2500-2504. R IC 50 RENIN (nM)0.294.0 IC 50 CYP3A4 (nM)8218 R IC 50 RENIN (nM)606>10,0000.42 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 www.pharmaxchange.info

49 49 Holsworth, D. D. et al. Bioorg. Med. Chem. Lett. 2006, 16, 2500-2504. R IC 50 RENIN (nM)9.0550 IC 50 CYP3A4 (nM)n.d54 R IC 50 RENIN (nM)3.237450 IC 50 CYP3A4 (nM)1245510,000 * Indicates point of attachment to N of tetrahydroquinoline S3 sp S1 S3 * Indicates point of attachment to N of tetrahydroquinoline www.pharmaxchange.info

50 50 Holsworth, D. D. et al. Bioorg. Med. Chem. Lett. 2006, 16, 2500-2504. PDB ID – 2fs4 Tyr 14 H2OH2O Crystal StructureSchematic View www.pharmaxchange.info

51 R IC 50 RENIN (nM) 0.183641,200 IC 50 CYP3A4 (nM) 1425,00015,000 51 R IC 50 RENIN (nM) 70.68 IC 50 CYP3A4 (nM) 35n.d * Indicates point of attachment to C of Methyl S3 sp S1 S3 www.pharmaxchange.info

52 52 www.pharmaxchange.info

53 53  3,9-diazobicyclo [3.3.1] nonene derivatives Bezencon, O. et al. J. Med. Chem. 2009, 52, 3689-3702. Displaces H 2 O from active site aspartates www.pharmaxchange.info

54 54  3,9-diazobicyclo [3.3.1] nonene derivatives Bezencon, O. et al. J. Med. Chem. 2009, 52, 3689-3702. -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 www.pharmaxchange.info

55  Alkyl amines 55 Tice, C. M. et al. Bioorg. Med. Chem. Lett. 2009, 19, 3541-3545. S3 S1 S3 sp HOOC-Asp32 HOOC-Asp215 www.pharmaxchange.info

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, 3541-3545. -Me> -Et 3-Cl > 3-F > 2-Cl > 2,3-diCl 3 o alcohol would interact with Ser 219 γ Oxygen -Me > -H www.pharmaxchange.info

57  Orally bioavailable alkyl amines- crystal structure 57 Tice, C. M. et al. Bioorg. Med. Chem. Lett. 2009, 19, 3541-3545. PDB ID = 3gw5 www.pharmaxchange.info

58 58 www.pharmaxchange.info

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, 51-55. www.pharmaxchange.info

60 60 Image adapted from- http://tainano.com/Molecular%20Biology%20Glossary.files/image087.gif Nguyen, G. et al. Journ. Clin. Invest. 2002, 109, 1417-1427 www.pharmaxchange.info

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 www.pharmaxchange.info

62  Functionality of the receptor  Effect on ERK1/ERK2 activation 62 www.pharmaxchange.info

63  Immunofluorescence studies of receptors on cells of human:  Kidney  Placenta 63  Coronary Artery www.pharmaxchange.info

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, 1259-1264. www.pharmaxchange.info

65 PASTPRESENTFUTURE 65 Over 100 years since discovery of renin www.pharmaxchange.info

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


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