Discovery of potent orally active thrombin receptor (protease activated receptor 1) antagonists as novel antithrombotic agents

被引：111

作者：

Chackalamannil, S ^{[1
]}

Xia, Y ^{[1
]}

Greenlee, WJ ^{[1
]}

Clasby, M ^{[1
]}

Doller, D ^{[1
]}

Tsai, H ^{[1
]}

Asberom, T ^{[1
]}

Czarniecki, M ^{[1
]}

Ahn, HS ^{[1
]}

Boykow, G ^{[1
]}

Foster, C ^{[1
]}

Agans-Fantuzzi, J ^{[1
]}

Bryant, M ^{[1
]}

Lau, J ^{[1
]}

Chintala, M ^{[1
]}

机构：

[1] Schering Plough Corp, Res Inst, Kenilworth, NJ 07033 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2005年 / 48卷 / 19期

关键词：

D O I：

10.1021/jm0502236

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：5884 / 5887

页数：4

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