Document Report Card

ID: ALA1130034

Journal: J Med Chem

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

Authors: Robl JA, Sun CQ, Stevenson J, Ryono DE, Simpkins LM, Cimarusti MP, Dejneka T, Slusarchyk WA, Chao S, Stratton L, Misra RN, Bednarz MS, Asaad MM, Cheung HS, Abboa-Offei BE, Smith PL, Mathers PD, Fox M, Schaeffer TR, Seymour AA, Trippodo NC.

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.

CiteXplore: 9171867

DOI: 10.1021/jm970041e