Tetrahydroquinoline Derivatives as Potent and Selective Factor XIa Inhibitors

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• 作者：Mimi L. Quan ; Pancras C. Wong ; Cailan Wang ; Francis Woerner ; Joanne M. Smallheer ; Frank A. Barbera ; Jeffrey M. Bozarth ; Randi L. Brown ; Mark R. Harpel ; Joseph M. Luettgen ; Paul E. Morin ; Tara Peterson ; Vidhyashankar Ramamurthy ; Alan R. Rendina ; Karen A. Rossi ; Carol A. Watson ; Anzhi Wei ; Ge Zhang ; Dietmar Seiffert ; Ruth R. Wexler
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 13, 2014
• 年：2014
• 卷：57
• 期：3
• 页码：955-969
• 全文大小：611K
• ISSN：1520-4804

文摘

Antithrombotic agents that are inhibitors of factor XIa (FXIa) have the potential to demonstrate robust efficacy with a low bleeding risk profile. Herein, we describe a series of tetrahydroquinoline (THQ) derivatives as FXIa inhibitors. Compound 1 was identified as a potent and selective tool compound for proof of concept studies. It exhibited excellent antithrombotic efficacy in rabbit thrombosis models and did not prolong bleeding times. This demonstrates proof of concept for the FXIa mechanism in animal models with a reversible, small molecule inhibitor.