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A series of 7-(di)alkyl and spirocyclic substituted azepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. Clear structure-activity relationships with respect to both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) activity in vitro were observed. The best in this series, compound 1g, a geminally dimethylated C-7-substituted azepinone, demonstrated excellent blood pressure lowering in animal models. Compound 1g (BMS-189921) is characterized by a good duration of activity and excellent oral efficacy in models relevant to ACE or NEP inhibition, and its activity is comparable to that of the clinically efficacious agent omapatrilat. Consequently this inhibitor has been advanced clinically for the treatment of hypertension and congestive heart failure.

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.

A series of substituted monocyclic and bicyclic azepinones were incorporated as dipeptide surrogates in mercaptoacetyl dipeptides with the desire to generate a single compound which would potently inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). Many of these compounds displayed excellent potency against both enzymes. Two of the most potent compounds, monocyclic azepinone 2n and bicyclic azepinone 3q, demonstrated a high level of activity versus ACE and NEP both in vitro and in vivo.

Investigations were directed toward inhibition of an aminopeptidase, isolated from rat brain, which has been implicated in the metabolic inactivation of enkephalins. The design rationale and synthesis of novel peptidyl diamino thiol inhibitors of rat brain aminopeptidase are presented, along with accompanying structure-activity analysis. Some of the reported compounds are highly active aminopeptidase inhibitors and possess enzyme inhibitory potency in the nanomolar range (62; I50 = 1 nM). Analysis of the data permits speculations on possible modes of binding of diamino thiols to aminopeptidase. Other investigations were directed toward understanding the mode of enzyme binding of the naturally occurring aminopeptidase inhibitor bestatin. On the basis of published models of enzyme binding, replacement of the C-2 hydroxyl group of bestatin by a sulfhydryl group was anticipated to lead to enhanced inhibition due to a strengthened interaction of this group with enzymic zinc. Contrary to expectations, "thiobestatin" inhibited rat brain aminopeptidase with only the same degree of effectiveness as the corresponding alcohol. Speculations on the possible mode of enzyme-inhibitor binding of bestatin are offered.