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

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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

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

J Med Chem. 1997 May 23;40(11):1570-7.

PubMed ID

9171867 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Omapatrilat	Angiotensin-converting enzyme	IC 50 (nM)	5	N/A	N/A	Details