Discovery of potent orally active thrombin receptor (protease activated receptor 1) antagonists as novel antithrombotic agents
Discovery of potent orally active thrombin receptor (protease activated receptor 1) antagonists as novel antithrombotic agents
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DOI：
10.1021/jm0502236
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发表时间：
2005-09-22
影响因子：
7.3
通讯作者：
Chintala, M
中科院分区：
文献类型：
--
作者：
Chackalamannil, S;Xia, Y;Chintala, M
描述了基于天然产物himbacine的结构新颖的凝血酶受体（蛋白酶激活受体1，PAR-1）拮抗剂。原型PAR-1拮抗剂55在结合测定中显示2.7 nM的Ki，使其成为报道的最有效的PAR-1拮抗剂。55在几种功能测定中具有高度活性，在大鼠和猴模型中显示出优异的口服生物利用度，并显示出对激动剂诱导的ex.食蟹猴经口给药后的体内血小板聚集。
Structurally novel thrombin receptor (protease activated receptor 1, PAR-1) antagonists based on the natural product himbacine are described. The prototypical PAR-1 antagonist 55 showed a K-i of 2.7 nM in the binding assay, making it the most potent PAR-1 antagonist reported. 55 was highly active in several functional assays, showed excellent oral bioavailability in rat and monkey models, and showed complete inhibition of agonist-induced ex. vivo platelet aggregation in cynomolgus monkeys after oral administration.