PHARMACOLOGICAL PROPERTIES OF YM-21095, A POTENT AND HIGHLY SPECIFIC RENIN INHIBITOR

被引：7

作者：

SHIBASAKI, M

ASANO, M

FUKUNAGA, Y

USUI, T

ICHIHARA, M

MURAKAMI, Y

NAKANO, K

FUJIKURA, T

机构：

[1] Central Research Laboratories, Applied Pharmacology Development Laboratories Yamanouchi Pharmaceutical Co Ltd.

来源：

AMERICAN JOURNAL OF HYPERTENSION | 1991年 / 4卷 / 12期

关键词：

HUMAN RENIN INHIBITOR; HYPOTENSION; SQUIRREL MONKEY;

D O I：

10.1093/ajh/4.12.932

中图分类号：

R6 [外科学];

学科分类号：

1002 ; 100210 ;

摘要：

A novel renin inhibitor, YM-21095 ((2RS), (3S)-3-[N-alpha[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)-buthyl]-L-histidil-amino]-4-cyclohexyl-1-[(1-methyl-5-tetrazolyl)thio]-2-butanol), has been synthesized in our laboratories. The aim of this study was to evaluate the pharmacological properties of YM-21095 in in vitro and in vivo experiments. YM-21095 inhibited human renin with an IC-50 value of 4.7 x 10(-10) mol/L. YM-21095 was also a potent inhibitor against squirrel monkey renin, but less effective against renins from dog, rabbit, and rat. The effect of YM-21095 is highly specific for renin, since it did not inhibit cathepsin D, pepsin, or angiotensin converting enzyme up to a concentration of 10(-4) mol/L. YM-21095 was resistant to proteolytic actions of the enzymes (pepsin, chymotrypsin, trypsin) and squirrel monkey tissue homogenates (liver, kidney, small intestine). Intravenous infusion of YM-21095 (0.1 to 100-mu-g/kg/min) decreased mean blood pressure and inhibited plasma renin activity in a dose-dependent manner with no effect on heart rate in anesthetized sodium-depleted and sodium-replete squirrel monkeys. The hypotensive effect of YM-21095 in sodium-depleted squirrel monkeys was about ten times as potent as that in sodium-replete squirrel monkeys. Oral administration of YM-21095 to conscious sodium-depleted squirrel monkeys produced dose-related decreases of systolic blood pressure. We conclude that YM-21095 is a potent and highly specific inhibitor of primate renin and produces a blood pressure lowering effect.

引用

页码：932 / 938

页数：7

共 15 条

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