Dual metalloprotease inhibitors: mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase

Journal of Medicinal Chemistry
J A RoblN C Trippodo

Abstract

A series of 7,6- and 7,5-fused bicyclic thiazepinones and oxazepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. These compounds are potent inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) both in vitro and in vivo. Compound 1a, a 7,6-fused bicyclic thiazepinone, demonstrated excellent blood pressure lowering in a variety of animal models characterized by various levels of plasma renin activity and significantly potentiated urinary sodium, ANP, and cGMP excretion in a cynomolgus monkey assay. On the basis of its potency and duration of action, compound 1a (BMS-186716) was advanced into clinical development for the treatment of hypertension and congestive heart failure.

References

Dec 1, 1990·Drugs·A Salvetti
May 1, 1994·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·F J Stare

❮ Previous
Next ❯

Citations

Sep 12, 2000·Current Hypertension Reports·J R Asher, A J Naftilan
Nov 4, 2010·Current Hypertension Reports·Julian Segura, Luis M Ruilope
Feb 18, 2004·Journal of Cardiac Failure·Jiang XuXiao-Ping Yang
May 15, 2002·Progress in Cardiovascular Diseases·Martin R Cowie, Gustavo F Mendez
Mar 7, 2001·The American Journal of Cardiology·D R McCleanI G Crozier
Jun 27, 2002·Journal of the American College of Cardiology·Dougal R McCleanUNKNOWN Omapatrilat Hemodynamic Study Group
Feb 19, 2002·Current Opinion in Biotechnology·R N Patel
Mar 4, 2000·Bioorganic & Medicinal Chemistry Letters·J A RoblM M Asaad
Dec 1, 1999·Bioorganic & Medicinal Chemistry·R L HansonL J Szarka
Apr 16, 2002·Current Opinion in Pharmacology·Giuseppe MolinaroAlbert Adam
Feb 28, 2002·British Journal of Pharmacology·G F Baxter, Z Ebrahim
Apr 10, 2002·Diabetes, Obesity & Metabolism·T A Chowdhury, T Khan
Jun 5, 2002·The Journal of Clinical Hypertension·R Guthrie, R A Reeves
Aug 16, 2001·Journal of Clinical Pharmacology·B K MalhotraC A Knupp
Jan 5, 2002·Journal of Clinical Pharmacology·J B KostisW C Liao
Nov 14, 2001·Lancet·M A Weber
Jan 5, 2002·Expert Opinion on Investigational Drugs·M Burnier
Feb 1, 2008·Expert Opinion on Drug Discovery·Ramesh N Patel
Jul 6, 2006·Clinical and Experimental Hypertension : CHE·David LochLindsay Brown
Mar 9, 2007·European Journal of Pharmacology·Simon W Rabkin, Shaun S Klassen
Dec 18, 2003·British Journal of Clinical Pharmacology·Matthew I WorthleyStephen G Worthley
Jul 26, 2015·Journal of Cardiac Failure·Jonathan BuggeyEric J Velazquez
May 9, 2015·Naunyn-Schmiedeberg's Archives of Pharmacology·Wenke Schmedt Auf der GünneJuraj Culman
May 1, 2010·Biochimie·Neil D Rawlings
Jun 3, 2017·Chemical Communications : Chem Comm·Katharina J HockRene M Koenigs
Jun 17, 2003·Journal of Cardiovascular Pharmacology and Therapeutics·Jasmina VaragicEdward D Frohlich
Dec 19, 2002·Journal of Peptide Science : an Official Publication of the European Peptide Society·Olivier HeudiFadi Abou-Shakra
Nov 11, 2003·Journal of the Renin-angiotensin-aldosterone System : JRAAS·Kok H CheeChim C Lang
Apr 23, 2002·Journal of the Renin-angiotensin-aldosterone System : JRAAS·G A Sagnella
Oct 5, 2002·Hypertension·Calin V ManiuMargaret M Redfield
Mar 8, 2003·Hypertension·Duncan John Campbell
Sep 7, 2006·Nature Reviews. Drug Discovery·Boris Turk

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antihypertensive Agents: Mechanisms of Action

Antihypertensive drugs are used to treat hypertension (high blood pressure) which aims to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Discover the latest research on antihypertensive drugs and their mechanism of action here.