INHIBITORS OF HUMAN RENIN WITH C-TERMINI DERIVED FROM AMIDES AND ESTERS OF ALPHA-MERCAPTOALKANOIC ACIDS

被引：15

作者：

ASHTON, WT ^{[1
]}

CANTONE, CL ^{[1
]}

TOLMAN, RL ^{[1
]}

GREENLEE, WJ ^{[1
]}

LYNCH, RJ ^{[1
]}

SCHORN, TW ^{[1
]}

STROUSE, JF ^{[1
]}

SIEGL, PKS ^{[1
]}

机构：

[1] MERCK SHARP & DOHME LTD,W POINT,PA 19486

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1992年 / 35卷 / 15期

关键词：

D O I：

10.1021/jm00093a009

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

New transition-state analogues bearing C-termini derived from alpha-mercaptoalkanoic acids, esters, and amides were prepared and evaluated as inhibitors of human renin. Addition of alpha-mercaptoalkanoate esters to a chiral Boc-amino epoxide intermediate led ultimately to the target [(2R,3S)-3-(BocPheHis-amino)-4-cyclohexyl-2-hydroxy-1-butyl]thio derivatives. The corresponding sulfoxide and sulfone analogues were also investigated. Some of these derivatives, including one with a stable BocPhe replacement, were relatively potent inhibitors of human plasma renin, having IC50 values below 10 nM. When selected compounds were administered intravenously to sodium-deficient rhesus monkeys (Macaca mulatta) at 0.06-1 mg/kg, they reduced plasma renin activity by 87-94%. However, the accompanying drop in blood pressure was of short duration.

引用

页码：2772 / 2781

页数：10

共 31 条

[11]

FEDER J, 1986, Patent No. 149593

[12] RENIN INHIBITORS [J].