Heterotricyclic Himbacine Analogs as Potent, Orally Active Thrombin Receptor (Protease Activated Receptor-1) Antagonists

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• 作者：Mariappan V. Chelliah ; Samuel Chackalamannil ; Yan Xia ; Keith Eagen ; Martin C. Clasby ; Xiaobang Gao ; William Greenlee ; Ho-Sam Ahn ; Jacqueline Agans-Fantuzzi ; George Boykow ; Yunsheng Hsieh ; Matthew Brya
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：October 18, 2007
• 年：2007
• 卷：50
• 期：21
• 页码：5147 - 5160
• 全文大小：225K
• 年卷期：v.50,no.21(October 18, 2007)
• ISSN：1520-4804

文摘

Pursuing our earlier efforts in the himbacine-based thrombin receptor antagonist area, we have synthesizeda series of compounds that incorporate heteroatoms in the C-ring of the tricyclic motif. This effort hasresulted in the identification of several potent heterocyclic analogs with excellent affinity for the thrombinreceptor. Several of these compounds demonstrated robust inhibition of platelet aggregation in an ex vivomodel in cynomolgus monkeys following oral administration. A detailed profile of 28b, a benchmarkcompound in this series, with a K_i of 4.3 nM, is presented.