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.
MeSH terms
-
Angiotensin-Converting Enzyme Inhibitors / chemical synthesis*
-
Animals
-
Antihypertensive Agents / chemical synthesis
-
Antihypertensive Agents / therapeutic use
-
Atrial Natriuretic Factor / urine
-
Cardiovascular Agents / chemical synthesis*
-
Cardiovascular Agents / therapeutic use
-
Cyclic GMP / urine
-
Enzyme Inhibitors / chemical synthesis*
-
Heart Failure / drug therapy
-
Hypertension / drug therapy
-
Macaca fascicularis
-
Neprilysin / antagonists & inhibitors*
-
Pyridines / chemical synthesis*
-
Pyridines / therapeutic use
-
Rats
-
Renin / blood
-
Sodium / urine
-
Thiazepines / chemical synthesis*
-
Thiazepines / therapeutic use
Substances
-
Angiotensin-Converting Enzyme Inhibitors
-
Antihypertensive Agents
-
Cardiovascular Agents
-
Enzyme Inhibitors
-
Pyridines
-
Thiazepines
-
omapatrilat
-
Atrial Natriuretic Factor
-
Sodium
-
Renin
-
Neprilysin
-
Cyclic GMP