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

被引：42

作者：

Robl, JA ^{[1
]}

Sulsky, R ^{[1
]}

Sieber-McMaster, E ^{[1
]}

Ryono, DE ^{[1
]}

Cimarusti, MP ^{[1
]}

Simpkins, LM ^{[1
]}

Karanewsky, DS ^{[1
]}

Chao, S ^{[1
]}

Asaad, MM ^{[1
]}

Seymour, AA ^{[1
]}

Fox, M ^{[1
]}

Smith, PL ^{[1
]}

Trippodo, NC ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Pharmaceut Res Inst, Princeton, NJ 08543 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1999年 / 42卷 / 02期

关键词：

D O I：

10.1021/jm980542f

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：305 / 311

页数：7

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