Vasopeptidase inhibitors: incorporation of geminal and spirocyclic substituted azepinones in mercaptoacyl dipeptides.

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Robl JA, Sulsky R, Sieber-McMaster E, Ryono DE, Cimarusti MP, Simpkins LM, Karanewsky DS, Chao S, Asaad MM, Seymour AA, Fox M, Smith PL, Trippodo NC

Vasopeptidase inhibitors: incorporation of geminal and spirocyclic substituted azepinones in mercaptoacyl dipeptides.

J Med Chem. 1999 Jan 28;42(2):305-11.

PubMed ID

9925736 [ View in PubMed

]

Abstract

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.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Omapatrilat	Angiotensin-converting enzyme	IC 50 (nM)	5	N/A	N/A	Details