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. doi: 10.1021/jm970041e.
J A Robl  1 ,  C Q Sun ,  J Stevenson ,  D E Ryono ,  L M Simpkins ,  M P Cimarusti ,  T Dejneka ,  W A Slusarchyk ,  S Chao ,  L Stratton ,  R N Misra ,  M S Bednarz ,  M M Asaad ,  H S Cheung ,  B E Abboa-Offei ,  P L Smith ,  P D Mathers ,  M Fox ,  T R Schaeffer ,  A A Seymour ,  N C Trippodo
Affiliations
  • 1. Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
PMID: 9171867 DOI: 10.1021/jm970041e
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.

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