肾素抑制剂。II. 含高同型半胱氨酸类似物的N端修饰抑制剂的合成及构效关系

Renin inhibitors. II. Synthesis and structure-activity relationships of N-terminus modified inhibitors containing a homostatine analogue.

作者信息

Atsuumi S, Nakano M, Koike Y, Tanaka S, Funabashi H, Matsuyama K, Nakano M, Sawasaki Y, Funabashi K, Morishima H

机构信息

Chemistry of Natural Products, Banyu Pharmaceutical Co., Ltd., Tokyo, Japan.

出版信息

Chem Pharm Bull (Tokyo). 1992 Dec;40(12):3214-21. doi: 10.1248/cpb.40.3214.

DOI:10.1248/cpb.40.3214

PMID:1294323

Abstract

The synthesis and structure-activity relationships of N-terminus modified renin inhibitors containing the homostatin 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 the 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.

摘要

本文描述了含高抑肽素类似物（2RS,4S,5S）-5-氨基-2-乙基-4-羟基-7-甲基辛酸的N端修饰肾素抑制剂的合成及其构效关系。发现N端带有3-烷基（或芳基）磺酰基丙酰基残基的化合物是有效的含两个氨基酸的抑制剂。（2RS,4S,5S）-N-异丁基-5-[N-[(2S)-3-乙基磺酰基-2-(1-萘基甲基)丙酰基]-L-正亮氨酰基]-氨基-2-乙基-4-羟基-7-甲基辛酰胺（20）对人血浆肾素的IC50为0.5 nM，在大鼠中的口服生物利用度为0.73%。分子模拟研究讨论了肾素与1和20的N端之间的相互作用。