Metabolism-Based Identification of a Potent Thrombin Receptor Antagonist

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• 作者：Martin C. Clasby ; Samuel Chackalamannil ; Michael Czarniecki ; Dario Doller ; Keith Eagen ; William Greenlee ; Grace Kao ; Yan Lin ; Hsingan Tsai ; Yan Xia ; Ho-Sam Ahn ; Jacqueline Agans-Fantuzzi ; George Boyko
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：January 11, 2007
• 年：2007
• 卷：50
• 期：1
• 页码：129 - 138
• 全文大小：169K
• 年卷期：v.50,no.1(January 11, 2007)
• ISSN：1520-4804

文摘

The metabolism of our prototypical thrombin receptor antagonist 1, K_i = 2.7 nM, was studied and threemajor metabolites (2, 4, and 5) were found. The structures of the metabolites were verified independentlyby synthesis. Compound 4 was shown to be a potent antagonist of the thrombin receptor with a K_i = 11nM. Additionally, compound 4 showed a 3-fold improvement in potency with respect to 1 in an agonist-induced ex-vivo platelet aggregation assay in cynomolgus monkeys after oral administration; this activitywas sustained with 60% inhibition observed at 24 h post-dose. Compound 4 was highly active in functionalassays and showed excellent oral bioavailability in rats and monkeys. Compound 4 showed a superior ratenzyme induction profile relative to compound 1, allowing it to replace compound 1 as a developmentcandidate.