Development of a Series of (1-Benzyl-3-(6-methoxypyrimidin-3-yl)-5-(trifluoromethoxy)-1H-indol-2-yl)methanols as Selective Protease Activated Receptor 4 (PAR4) Antagonists with in Vivo Utility and Activity Against γ-Thrombin

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• 作者：Kayla J. Temple ; Matthew T. Duvernay ; Summer E. Young ; Wandong Wen ; Wenjun Wu ; Jae G. Maeng ; Anna L. Blobaum ; Shaun R. Stauffer ; Heidi E. Hamm ; Craig W. Lindsley
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：August 25, 2016
• 年：2016
• 卷：59
• 期：16
• 页码：7690-7695
• 全文大小：383K
• 年卷期：0
• ISSN：1520-4804

文摘

Here, we describe the development of a series of highly selective PAR4 antagonists with nanomolar potency and selectivity versus PAR1, derived from the indole-based 3. Of these, 9j (PAR4 IC₅₀ = 445 nM, PAR1 response IC₅₀ > 30 μM) and 10h (PAR4 IC₅₀ = 179 nM, PAR1 response IC₅₀ > 30 μM) maintained an overall favorable in vitro DMPK profile, encouraging rat/mouse in vivo pharmacokinetics (PK) and activity against γ-thrombin.