Exploring the chiral space within the active site of α-thrombin with a constrained mimic of D-Phe-Pro-Arg -: Design, synthesis, inhibitory activity, and x-ray structure of an enzyme-inhibitor complex

被引：46

作者：

Hanessian, S

Balaux, E

Musil, D

Olsson, LL

Nilsson, I

机构：

[1] Univ Montreal, Dept Chem, Montreal, PQ H3C 3J7, Canada

[2] AstraZeneca R&D, Struct Chem Lab, Molndal, Sweden

[3] Gothenburg Univ, Dept Inorgan Chem, Gothenburg, Sweden

[4] Gothenburg Univ, Ctr Struct Biol, Gothenburg, Sweden

[5] AstraZeneca R&D, Med Chem, Molndal, Sweden

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2000年 / 10卷 / 03期

关键词：

thrombin inhibitor; enzyme-inhibitor complex; X-ray;

D O I：

10.1016/S0960-894X(99)00669-1

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

An indolizidinone motif with strategically placed substitutents was designed and synthesized as a constrained mimic of D-Phe-Pro-Arg. Low nanomolar inhibition of a-thrombin validates the design elements in this inhibitor which also exhibits a 20-fold selectivity for thrombin versus trypsin. An X-ray crystal structure of the inhibitor with alpha-thrombin shows the expected interactions with key amino acids within the active site and some notable changes in positions. (C) 2000 Elsevier Science Ltd. All rights reserved.

引用

页码：243 / 247

页数：5

共 35 条

[31] Rational design, synthesis, and serine protease inhibitory activity of a novel P-1-argininal derivative featuring a conformationally constrained P-2-P-3-bicyclic lactam moiety [J].