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

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

Affiliation

  • 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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