RENIN INHIBITORS .2. SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF N-TERMINUS MODIFIED INHIBITORS CONTAINING A HOMOSTATINE ANALOG

被引：3

作者：

ATSUUMI, S

NAKANO, M

KOIKE, Y

TANAKA, S

FUNABASHI, H

MATSUYAMA, K

NAKANO, M

SAWASAKI, Y

FUNABASHI, K

MORISHIMA, H

机构：

[1] BANYU PHARMACEUT CO LTD, BIOCHEM CENT RES LABS, MEGURO KU, TOKYO 153, JAPAN

[2] BANYU PHARMACEUT CO LTD, PHARMACOL CENT RES LABS, MEGURO KU, TOKYO 153, JAPAN

来源：

CHEMICAL & PHARMACEUTICAL BULLETIN | 1992年 / 40卷 / 12期

关键词：

RENIN INHIBITOR; ANTIHYPERTENSIVE AGENT; HOMOSTATINE ANALOG; SULFONEMETHYLENE ISOSTERE; STRUCTURE ACTIVITY RELATIONSHIP;

D O I：

10.1248/cpb.40.3214

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The synthesis and structure-activity relationships of N-terminus modified renin inhibitors containing the homostatine analogue, (2RS,4S,5S)-5-amino-2-ethyl-4-hydroxy-7-methyloctanoic acid, are described. The compounds having a 3-alkyl (or aryl)sulfonylpropionyl residue at the N-terminus are found to be potent inhibitors which contain two amino acids. (2RS,4S,5S)-N-Isobutyl-5-[N-[(2S)-3-ethylsulfonyl-2-(1-naphthylmethyl)propionyl]-L-norleucyl]-amino-2-ethyl-4-hydroxy-7-methyloctanamide (20) has an IC50 of 0.5 nm against human plasma renin and die oral bioavailability of 20 is 0.73% in rats. Interaction between renin and the N-terminus of 1 and 20 is discussed in molecular modeling studies.

引用

页码：3214 / 3221

页数：8

共 30 条

[1]

ABOLA EE, 1987, CRYSTALLOGRAPHIC DAT, P107

[2] AN EFFICIENT ENANTIOSELECTIVE PREPARATION OF 2-SUBSTITUTED-3-HYDROXYPROPIONIC ACIDS VIA CHEMOENZYMATIC REACTION [J].