Dual metalloprotease inhibitors: mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase.
J Med Chem
; 40(11): 1570-7, 1997 May 23.
Article
en En
| MEDLINE
| ID: mdl-9171867
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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Bases de datos:
MEDLINE
Asunto principal:
Piridinas
/
Tiazepinas
/
Inhibidores de la Enzima Convertidora de Angiotensina
/
Fármacos Cardiovasculares
/
Neprilisina
/
Inhibidores Enzimáticos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
1997
Tipo del documento:
Article
País de afiliación:
Estados Unidos