2,6 - 二苯氧基吡啶衍生的凝血因子Xa抑制剂的设计、合成及活性

Design, synthesis, and activity of 2,6-diphenoxypyridine-derived factor Xa inhibitors.

作者信息

Phillips G, Davey D D, Eagen K A, Koovakkat S K, Liang A, Ng H P, Pinkerton M, Trinh L, Whitlow M, Beatty A M, Morrissey M M

机构信息

Discovery Research, Berlex Biosciences, 15049 San Pablo Avenue, P.O. Box 4099, Richmond, California 94804-0099, USA.

出版信息

J Med Chem. 1999 May 20;42(10):1749-56. doi: 10.1021/jm980667k.

DOI:10.1021/jm980667k

PMID:10346927

Abstract

A novel series of 2,6-diphenoxypyridines has been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. The evolution from the photochemically unstable bisamidine (Z,Z)-BABCH to potent bisamidine compounds with a pyridine heterocycle as the core scaffold has been achieved. The most potent compound in the series, 6h, has a Ki for human factor Xa of 12 nM. The selectivity of 6h against bovine trypsin and human thrombin was greater than 90- and 1000-fold, respectively. Two proposed modes of binding of 6h to factor Xa are made based on the crystal structures of 6h by itself and of 6h bound to bovine trypsin.

摘要

设计了一系列新型的2,6 - 二苯氧基吡啶以抑制凝血因子Xa，这是一种在凝血级联反应中处于关键位置的丝氨酸蛋白酶。已经实现了从光化学不稳定的双脒（Z,Z）-BABCH到以吡啶杂环为核心骨架的强效双脒化合物的演变。该系列中最有效的化合物6h对人凝血因子Xa的Ki为12 nM。6h对牛胰蛋白酶和人凝血酶的选择性分别大于90倍和1000倍。基于6h自身以及6h与牛胰蛋白酶结合的晶体结构，提出了6h与凝血因子Xa结合的两种模式。