Discovery of a nonpeptidic small molecule antagonist of the human platelet thrombin receptor (PAR-1)

被引：39
|
作者：
Nantermet, PG [1 ]
Barrow, JC
Lundell, GF
Pellicore, JM
Rittle, KE
Young, M
Freidinger, RM
Connolly, TM
Condra, C
Karczewski, J
Bednar, RA
Gaul, SL
Gould, RJ
Prendergast, K
Selnick, HG
机构：
[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA
[2] Merck Res Labs, Dept Pharmacol, West Point, PA 19486 USA
[3] Merck Res Labs, Dept Mol Design & Divers, West Point, PA 19486 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2002年 / 12卷 / 03期
关键词：
D O I：
10.1016/S0960-894X(01)00745-4
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
The synthesis and biological evaluation of a series of nonpeptidic small molecule antagonists of the human platelet thrombin receptor (PAR-1) are described. Optimization of the 5-amino-3-arylisoxazole lead resulted in an approximate 100-fold increase in potency. The most potent of these compounds (54) inhibits platelet activation with IC50S of 90 nM against the thrombin receptor agonist peptide (TRAP) and 510 nM against thrombin as the agonist. Further, antagonist 54 fully blocks platelet aggregation stimulated by 1 nM thrombin for 10 min. (C) 2002 Published by Elsevier Science Ltd.
引用
收藏
页码：319 / 323
页数：5
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