Mercaptoacyl dipeptides as orally active dual inhibitors of angiotensin- converting enzyme and neutral endopeptidase

Journal of Medicinal Chemistry

Volumn 39, Issue 16, 1996, Pages 3158-3168

  Fink, Cynthia A ^a   Carlson, J Eric ^a   McTaggart, Patricia A ^a   Qiao, Ying ^a   Webb, Randy ^a   Chatelain, Ricardo ^a   Jeng, Arco Y ^a   Trapani, Angelo J ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

DIPEPTIDE; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; MEMBRANE METALLOENDOPEPTIDASE;

ALDOSTERONE BLOOD LEVEL; ALDOSTERONE RELEASE; ARTICLE; CONGESTIVE HEART FAILURE; DRUG SYNTHESIS; ENZYME ACTIVITY; ENZYME INHIBITION; HUMAN; HYPERTENSION; MEMBRANE BINDING; NATRIURESIS; ORAL DRUG ADMINISTRATION; PLASMA RENIN ACTIVITY;

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; ANIMALS; ANTIHYPERTENSIVE AGENTS; ATRIAL NATRIURETIC FACTOR; BENZAZEPINES; BLOOD PRESSURE; CAPTOPRIL; DIPEPTIDES; MAGNETIC RESONANCE SPECTROSCOPY; MALE; MOLECULAR STRUCTURE; NEPRILYSIN; PROTEASE INHIBITORS; RATS; RATS, INBRED SHR; TYROSINE;

EID: 0029742344     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm960323z     Document Type: Article

References (43)

1. Robl, J. A.; Cimarusti, M. P.; Simpkins, L. M.; Brown, B.; Ryono, D. E.; Bird, J. E.; Asaad, M. M.; Schaeffer, T. R.; Trippodo, N. C. Dual Metalloprotease Inhibitors, 6. Incorporation of Bicyclic and Substituted Monocyclic Azepinones as Dipeptide Surrogates in Angiotensin-Converting Enzyme/Neutral Endopeptidase Inhibitors. J. Med. Chem. 1996, 39, 494-502.
2. De Lombaert, S.; Tan, J.; Stamford, L.; Sakane, Y.; Berry, C.; Ghai, R. D. Dual Inhibition of Neutral Endopeptidase and Angiotensin-Converting Enzyme by N-Phosphonomethyl and N-Carboxyalkyl Dipeptides. Bioorg. Med. Chem. Lett. 1994, 4, 2715-2720.
3. Mac Pherson, L. J.; Baybert, E. K.; Capparelli, M. P.; Bohacek, R. S.; Clarke, F. H.; Ghai, R. D.; Sakane, Y.; Berry, C. J.; Peppard, J. V.; Trapani, A. Design and Synthesis of an Orally Active Macrocyclic Neutral Endopeptidase 24.11 Inhibitor. J. Med. Chem. 1993, 36, 3821-3828.
4. Bhagwat, S. S.; Fink, C. A.; Gude, C.; Chan, K.; Qiao, Y.; Sakane, Y.; Berry, C.; Ghai, R. D. 4-Substituted Proline Derivatives that Inhibit Angiotensin Converting Enzyme and Neutral Endopeptidase 24.11. Bioorg. Med. Chem. Lett. 1994, 4, 2673-2676.
5. Turcaud, S.; Gonzalez, W.; Michel, J.; Roques, B. P.; Fournie-Zaluski, M. C. Diastereoselective Synthesis of Mixanpril, an Orally Active Dual Inhibitor of Neutral Endopeptidase and Angiotensin Converting Enzyme. Bioorg. Med. Chem. Lett. 1995, 5, 1893-1898.
6. Slusarchyk, W. A.; Robl, J. A.; Taunk, P. C.; Asaad, M. M.; Bird, J. E.; DiMarco, J.; Pan, Y. Dual Metalloprotease Inhibitors. V. Utilization of Bicyclic Azepinonethiazolidines and Azepinonetetrahydrothiazines in Constrained Peptidomimetics of Mercaptoacyl Dipeptides. Bioorg. Med. Chem. Lett. 1995, 5, 753-758.
7. Das, J.; Robl, J. A.; Reid, J. A.; Sun, C. Q.; Misra, R. N.; Brown, B. R.; Ryono, D. E.; Asaad, M. M.; Bird, J. E.; Trippodo, N. C.; Pritrillo, E. W.; Karanewsky, D. S. Dual Metalloprotease Inhibitors. IV. Utilization of Thiazepines and Thiazines as Constrained Peptidomimetic Surrogates in Mercaptoacyl Dipeptides. Bioorg. Med. Chem. Lett. 1994, 4, 2193-2198.
8. Robl, J. A.; Sun, C. Q.; Simpkins, L. M.; Ryono, D. E.; Barrish, J. C.; Karanewski, D. S.; Asaad, M. M.; Schaeffer, T. R.; Trippodo, N. C. Dual Metalloprotease Inhibitors. III. Utilization of Bicyclic and Monocyclic Diazepinone Based Mercaptoacetyls. Bioorg. Med. Chem. Lett. 1994, 4, 2055-2060.
9. Robl, J. A.; Simpkins, L. M.; Sulsky, R.; Sieber-McMaster, E.; Stevenson, J.; Kelly, Y. F.; Sun, C. Q.; Misra, R. N.; Ryono, D. E.; Asaad, M. M.; Bird, J. E.; Trippodo, N. C.; Karanewsky, D. S. Dual Metalloprotease Inhibitors II. Effect of Substitution and Stereochemistry Benzazepinone Based Mercaptoacetyls. Bioorg. Med. Chem. Lett. 1994, 4, 1795-1800.
10. Robl, J. A.; Simpkins, L. M.; Stevenson, J.; Kelly, Y. F.; Sun, C. Q.; Murugesan, N.; Barrish, J. C.; Asaad, M. M.; Bird, J. E.; Schaeffer, T. R.; Trippodo, N. C.; Petrillo, E. W.; Karanewsky, D. S. Dual Metalloprotease Inhibitors I. Constrained Peptidomimetics of Mercaptoacyl Dipeptides. Bioorg. Med. Chem. Lett. 1994, 4, 1789-1794.
11. Delaney, N. G.; Barrish, J. C.; Neubeck, R.; Natarajan, S.; Cohen, M.; Rovnyak, G. C.; Huber, G.; Murugesan, N.; Girotra, R.; Sieber-McMaster, E.; Robl, J. A.; Asaad, M. M.; Cheung, H. S.; Bird, J. E.; Waldron, T.; Petrillo, E. W. Mercaptoacyl Dipeptides as Dual Inhibitors of Angiotensin Converting Enzyme and Neutral Endopeptidase. Preliminary Structure-Activity Studies. Bioorg. Med. Chem. Lett. 1994, 4, 1783-1788.
12. Gomez-Monterrey, I.; Beaumont, A.; Nemecek, P.; Roques, B. P.; Fournie-Zaluski, M. C. New Thiol Inhibitors of Neutral Endopeptidase EC 3.4.24.11: Synthesis and Enzyme Active Site Recognition. J. Med. Chem. 1994, 37, 1865-1873.
13. Fournie-Zaluski, M. C.; Coric, P.; Turcaud, S.; Rousselet, N.; Gonzalez, W.; Barbe, P.; Pham, I.; Jullian, N.; Michel, J.; Roques, B. P. New Dual Inhibitor of Neutral Endopeptidase and Angiotensin Converting Enzyme: Rational Design, Bioavailability, and Pharmacological Response in Experimental Hypertension. J. Med. Chem. 1994, 37, 1070-1083.
14. Stanton, J. L.; Sperbeck, D. M.; Trapani, A. J.; Cote, D.; Sakane, Y.; Berry, C. J.; Ghai, R. D. Heterocyclic Lactam Derivatives as Dual Angiotensin Converting Enzyme and Neutral Endopeptidase 24.11 Inhibitors. J. Med. Chem. 1993, 36, 3829-3833.
15. Flynn, G. A.; Beight, D. W.; Mehdi, S.; Koehl, J. R.; Giroux, E. L.; French, J. F.; Hake, P. W.; Dage, R. C. Application of a Conformationally Restricted Phe-Leu Dipeptide Mimetic to the Design of a Combined Inhibitor of Angiotensin-I Converting Enzyme and Neutral Endopeptidase 24.11 J. Med. Chem. 1993, 36, 2420-2423.
16. Bhagwat, S. S.; Fink, C. A.; Gude, C.; Chan, K.; Qiao, Y.; Sakane, Y.; Berry, C.; Ghai, R. D. α-Mercaptoacyl Dipeptides that Inhibit Angiotensin Converting Enzyme and Neutral Endopeptidase 24.11. Bioorg. Med. Chem. Lett. 1995, 5, 735-738.
17. Fink, C. A.; Qiao, Y.; Berry, C. J.; Sakane, Y.; Ghai, R. D.; Trapani, A. New α-Thiol Dipeptide Dual Inhibitors of Angiotensin-I Converting Enzyme and Neutral Endopeptidase EC 3.4.24.11. J. Med. Chem. 1995, 38, 5023-5030.
18. Sonnenberg, J. L.; Sakane, Y.; Jeng, A. Y.; Koehn, J. A.; Ansell, J. A.; Wennogle, L. P.; Ghai, R. D. Identification of Protease NEP 24.11 as the Major Atrial Natriuretic Factor Degrading Enzyme in the Rat Kidney. Peptides 1988, 9, 173-180.
19. Kenny, A. J.; Stephenson, S. L. Role of Endopeptidase-24.11 in the Inactivation of Atrial Natriuretic Peptide. FEBS Lett. 1988, 232, 1-8.
20. Roques, B. P.; Beaumont, A. Neutral Endopeptidase-24.11 Inhibitors: from Analgesics to Antihypertensives? Trends Pharmacol. Sci. 1990, 11, 245-250.
21. Winquist, R. J.; Hintze, T. H. Mechanism of Atrial Natriuretic Factor-Induced Vasodilation. Pharmacol. Ther. 1990, 48, 417-426.
22. Johnson, C. I.; Hodsman, P. G.; Kohzuki, M.; Casley, D. J.; Fabris, B.; Phillips, P. A. Interaction Between Atrial Natriuretic Peptide and the Renin Angiotensin Aldosterone System. Am. J. Med. 1989, 87, 24S-28S.
23. Chatterjee, K. Heart Dis. Stroke 1992, 1, 128.
24. Flynn, G. A.; French, J. F.; Dage, R. C. Dual Inhibitors of Angiotensin Converting Enzyme and Neutral Endopeptidase: Design and Therapeutic Rationale. In Hypertension: Pathophysiology, Diagnosis, and Management; Laragh, J. H., Brenner, B. M., Eds.; Raven Press: New York, 1995; pp 3099-3114.
25. Laragh, J. H. The Renin System and New Understanding of the Complications of Hypertension and Their Treatment. Arzneim.-Forsch. Drug Res. 1993, 43, 247-254.
26. Townsend, R. R.; Holland, O. B. Combination of Converting Enzyme Inhibitor with Diuretic for the Treatment of Hypertension. Arch. Intern. Med. 1990, 150, 1175-1183.
27. Waeber, B.; Nussberger, J.; Brunner, H. In Hypertension; Laragh, J. H., Brenner, B. M., Eds.; Raven Press: New York, 1990; Vol. 2, pp 2209-2232.
28. Friedman, P. A. Biochemistry and Pharmacology of Diuretics. Semin. Nephrol. 1988, 8, 198-212.
29. Roques, B. P.; Noble, F.; Dauge, V.; Fornie-Zaluski, M. C.; Beaumont, A. Neutral Endopeptidase 24.11 Structure, Inhibition and Experimental and Clinical Pharmacology. Pharmacol. Rev. 1993, 45, 87-146.
30. Seymour, A. A.; Asaad, M. M.; Lanoce, V. M.; Langenbacher, K. M.; Fennell, S. A.; Rogers, W. L. Systemic Hemodynamics, Renal Function and Hormonal Levels during Inhibition of Neutral Endopeptidase 3.4.24.11 and Angiotensin-Converting Enzyme in Conscious Dogs with Pacing-Induced Heart Failure. J. Pharmacol. Exp. Ther. 1993, 266, 872-883.
31. Pham, I.; Gonzalez, W.; El Amraani, A. I.; Fournie-Zaluski, M. C.; Philippe, M.; Laboulandine, I.; Roques, B. P.; Michel, J. B. Effects of Converting Enzyme Inhibitor and Neutral Endopeptidase Inhibitor on Blood Pressure and Renal Function in Experimental Hypertension. J. Pharmacol. Exp. Ther. 1993, 265, 1339-1347.
32. Trippodo, N. C.; Robl, J. A.; Asaad, M. M.; Bird, J. E.; Panchal, B. C.; Schaeffer, T. R.; Fox, M.; Giancarli, M. R.; Cheung, H. S. Cardiovascular Effects of the Novel Dual Inhibitor of Neutral Endopeptidase and Angiotensin-Converting Enzyme BMS 182657 in Experimental Hypertension and Heart Failure. J. Pharmacol. Exp. Ther. 1995, 275, 745-752.
33. French, J. F.; Anderson, B. A.; Downs, T. R.; Dage, R. C. Dual Inhibition of Angiotensin-Converting Enzyme and Neutral Endopeptidase in Rats with Hypertension. J. Cardiovasc. Pharmacol. 1995, 26, 107-113.
34. Gonzalez Vera, W.; Fournie-Zaluski, M. C.; Pham, I.; Laboulandine, I.; Roques, B. P.; Michel, J. B. Hypotensive and Natriuretic Effects of RB 105, a New Dual Inhibitor of Angiotensin Converting Enzyme and Neutral Endopeptidase in Hypertensive Rats. J. Pharmacol. Exp. Ther. 1995, 272, 343-351.
35. Konig, W.; Geiger, R. New Method for Peptide Synthesis: Activation of the Carboxylic Acid with Dicyclohexylcarbodiimide with the Addition of 1-Hydroxybenzotriazole. Chem. Ber. 1970, 103, 2034-2040.
36. Konig, W.; Geiger R. Racemization in Peptide Synthesis. Chem. Ber. 1970, 103, 2024-2033.
37. Carpino, L. A. 1-Hydroxy-7-azabensotriazole, An Efficient Peptide Coupling Additive. J. Am. Chem. Soc. 1993, 115, 4397-4398.
38. n2 Substitution Using Cesium Thiocarboxylates. J. Org. Chem. 1986, 51, 3663.
39. Wyvratt, M. J.; Patchett, A. A. Med. Res. Rev. 1985, 5, 483-531.
40. Fournie-Zaluski, M. C.; Lucas, E.; Waksman, G.; Roques, B. P. Differences in the Structural Requirements for Selective Interaction With Neutral Metalloendopeptidase (Enkephalinase) or Angiotensin-Converting Enzyme. Eur. J. Biochem. 1984, 139, 267-274.
41. 50 = 1940 ± 140 nM (n = 3) for ACE. Of the compounds tested, compound 48 was the most active against these enzymes.
42. 50 = 1940 ± 140 nM (n = 3) for ACE. Of the compounds tested, compound 48 was the most active against these enzymes.
43. Rojo-Ortega, J. M.; Genest, J. A Method for Production of Experimental Hypertension in Rats. Can. J. Physiol. Pharmacol. 1969, 46, 883-885.