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DIRECT RENIN INHIBITORS AS ANTIHYPERTENSIVE DRUGS

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?.

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DIRECT RENIN INHIBITORS AS ANTIHYPERTENSIVE DRUGS

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  1. www.pharmaxchange.info DIRECT RENIN INHIBITORS AS ANTIHYPERTENSIVE DRUGS DATE – OCTOBER 23rd, 2009 PRESENTED BY – AKUL MEHTA VIRGINIA COMMONWEALTH UNIVERSITYSCHOOL OF PHARMACY DEPARTMENT OF MEDICINAL CHEMISTRY

  2. www.pharmaxchange.info 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 Chobanian, A. V. et al.Hypertension2003,42, 1206-1252

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

  4. www.pharmaxchange.info CURRENT DRUGS TARGETING THE RENIN-ANGIOTENSIN SYSTEM FOR HYPERTENSION IS THERE REALLY A NEED FOR ANOTHER ANTIHYPERTENSIVE DRUG?

  5. www.pharmaxchange.info NEED FOR ANOTHER ANTIHYPERTENSIVE • Hypertension needs modulation Li, Y. C. Curr. Opin. Invest. Drugs 2007, 8, 750-757. Image from - http://blog.wineenthusiast.com/wp-content/uploads/2008/12/balance.jpg

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

  7. www.pharmaxchange.info 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 IS THERE REALLY A NEED FOR ANOTHER ANTIHYPERTENSIVE DRUG? YES THERE IS DEFINITELY A NEED Yokokawa, F. et al. Expert Opin. Ther. Patents 2008,18(6), 581-602.

  8. www.pharmaxchange.info CURRENT INTEREST IN INHIBITION OF RENIN ANGIOTENSIN SYSTEM Yokokawa, F. et al.Expert Opin. Ther. Patents 2008,18(6), 581-602.

  9. www.pharmaxchange.info INTRODUCING RENIN • History • Structure • Function • Mechanism PDB ID – 2v0z

  10. www.pharmaxchange.info 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

  11. www.pharmaxchange.info RENIN - HISTORY • 1934- Harry Goldblatt • Induced experimental hypertension in dogs • 1st to prove that renin system blockade would reduce hypertension Basso, N. et al. Hypertension2001,38, 1246-1249.

  12. www.pharmaxchange.info 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

  13. www.pharmaxchange.info RENIN - STRUCTURE • 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 ASP32 ASP215 Eder, J. et al. Current Pharmaceutical Design, 2007,13, 271-285. PDB ID- 2v0z

  14. www.pharmaxchange.info RENIN - FUNCTION Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu10--Val11-Ile-His-Asn--- Angiotensinogen (480 amino acid long) Renin cleaves peptide bond between Leu10-Val11 Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu10 + Val11-Ile-His-Asn--- Angiotensin I

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

  16. www.pharmaxchange.info HOW DOES ONE MEASURE RENIN INHIBITION? • In Vitro • Human renin is incubated with inhibitor • Angiotensinogen is added. • Angiotensin I produced is measured by radioimmunoassay • 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

  17. www.pharmaxchange.info INHIBITORS OF RENIN

  18. www.pharmaxchange.info INHIBITORS OF RENIN • Early Inhibitors of Renin • Antibodies • Transition State Analogs • Peptide Mimetic Inhibitors • Non-Peptide Inhibitors • Recently developed Inhibitors

  19. www.pharmaxchange.info INHIBITORS OF RENIN • Early Inhibitors of Renin • Antibodies • Transition State Analogs • Peptide Mimetic Inhibitors • Non-Peptide Inhibitors • Recently developed Inhibitors

  20. www.pharmaxchange.info EARLY INHIBITORS OF RENIN • Monoclonal Antibodies Against Renin • Excellent tools to study enzyme and its hypertensive effects • However – • parenteral administration • immunogenecitytherefore less application in medicine. Galen, F. X. J. Clin. Invest. 1984,74, 723-735.

  21. www.pharmaxchange.info INHIBITORS OF RENIN • Early Inhibitors of Renin • Antibodies • Transition State Analogs • Peptide Mimetic Inhibitors • Non-Peptide Inhibitors • Recently developed Inhibitors

  22. www.pharmaxchange.info SCHECHTER AND BERGER NOMENCLATURE FOR PROTEASES Mitti, P. R. Curr. Opin. Struct. Biol.2006, 16, 769-775.

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

  24. www.pharmaxchange.info PEPTIDE MIMETIC INHIBITORS • 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-NH2 Normal Peptide IC50 – 190nM Boger, J. et al. J. Med. Chem. 1985,28, 1779-1790.

  25. www.pharmaxchange.info PEPTIDE MIMETIC INHIBITORS Statine Analog: Boc-Phe-His-Stat-Leu-Phe-NH2 ACHPA Analog: Boc-Phe-His-ACHPA-Leu-Phe-NH2 IC50 – 49nM

  26. www.pharmaxchange.info 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)

  27. www.pharmaxchange.info NON-PEPTIDE INHIBITORS OF RENINSTORY OF ALISKIREN

  28. www.pharmaxchange.info STORY OF ALISKIREN Boc-Phe-His-ACHPA-Leu-Phe-NH2 CGP38560 IC50 = 1nM • The Renin-Angiotensin System; Robertson, J. I. S., Nicholls, M. G., Eds.; Mosby: London, 1993.

  29. www.pharmaxchange.info STORY OF ALISKIREN CGP38560 S1 S3 IC50 = 1nM S3 S1 Goshke, R. et al. Bioorg. Med. Chem. Lett.1997, 7, 2735-2740.

  30. www.pharmaxchange.info STORY OF ALISKIREN Can be changed to methyl -OCH2COOCH3 > -OCH2CONH2 > -OCH2COOH -isopropyl was found optimum Increase or decrease in substituent size caused decrease in activity S1 S3 -phenyl substituent equipotent to -t-butyl R-epimer showed significant drop in activity

  31. www.pharmaxchange.info STORY OF ALISKIREN Most IC50 in μM range IC50 = 20nM

  32. www.pharmaxchange.info STORY OF ALISKIREN To improve physicochemical properties

  33. www.pharmaxchange.info STORY OF ALISKIREN When R2 = -CH2CONH2 R3= -Me R4= -n-butyl Goshke, R. et al. J. Med. Chem. 2007, 50, 4818-4831.

  34. www.pharmaxchange.info STORY OF ALISKIREN

  35. www.pharmaxchange.info STORY OF ALISKIREN Maibaum, J. et. al. J. Med. Chem. 2007,50, 4832-4844.

  36. www.pharmaxchange.info STORY OF ALISKIREN

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

  38. www.pharmaxchange.info SUMMARY OF ALISKIREN CGP38560 Aliskiren

  39. www.pharmaxchange.info NON-PEPTIDE INHIBITORS OF RENIN-PIPERIDINE CLASS OF INHIBITORS

  40. PIPERIDINE CLASS OF INHIBITORS www.pharmaxchange.info Screening of the Roche Compound Library IC50 = 50 μM Highly selective for renin. Vieira, E. et al. Bioorg. Med. Chem. Lett. 1999, 9, 1397-1402.

  41. PIPERIDINE CLASS OF INHIBITORS www.pharmaxchange.info • X-Ray Structure Interpretation Asp32-COOH HOOC-Asp215 S4 S3 S1

  42. www.pharmaxchange.info PIPERIDINE CLASS OF INHIBITORS S4 S3 S1

  43. www.pharmaxchange.info PIPERIDINE CLASS OF INHIBITORS • X-Ray Analysis Asp32-COOH HOOC-Asp215 Asp32-COOH HOOC-Asp215 S3sp S4 S1 S3 Lifts a whole flap region fromThr72 to Ser81 S3 S1

  44. PIPERIDINE CLASS OF INHIBITORS www.pharmaxchange.info * Indicates point of attachment to piperidine ring S3sp S3 S1 Guller, R. et al. Bioorg. Med. Chem. Lett. 1999, 9, 1403-1408.

  45. PIPERIDINE CLASS OF INHIBITORS www.pharmaxchange.info S3sp S1 S3 Story for these molecules in literature ends here Marki, H. P. et al. Il Farmaco2001, 56, 21-27.

  46. www.pharmaxchange.info PIPERIDINE CLASS OF INHIBITORS-KETOPIPERAZINES IC50 = 2nM IC50 = 180nM IC50 = 54nM SAR studies Holsworth, D. D. et al.Bioorg. Med. Chem.2005, 13, 2657-2664.

  47. www.pharmaxchange.info PIPERIDINE CLASS OF INHIBITORS-KETOPIPERAZINES S3sp S3 S1 Found to inhibit CYP3A4 * Indicates point of attachment to O.

  48. www.pharmaxchange.info PIPERIDINE CLASS OF INHIBITORS-KETOPYRAZINES S3sp S3 S1 * Indicates point of attachment to N of tetrahydroquinoline * Indicates point of attachment to N of tetrahydroquinoline Holsworth, D. D. et al. Bioorg. Med. Chem. Lett. 2006, 16, 2500-2504.

  49. www.pharmaxchange.info PIPERIDINE CLASS OF INHIBITORS-KETOPIPERAZINES S3sp S3 S1 * Indicates point of attachment to N of tetrahydroquinoline * Indicates point of attachment to N of tetrahydroquinoline Holsworth, D. D. et al.Bioorg. Med. Chem. Lett. 2006, 16, 2500-2504.

  50. www.pharmaxchange.info PIPERIDINE CLASS OF INHIBITORS-KETOPIPERAZINES Tyr14 Tyr 14 H2O Crystal Structure Schematic View Holsworth, D. D. et al. Bioorg. Med. Chem. Lett. 2006, 16, 2500-2504. PDB ID – 2fs4

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