Phenylimidazoles as Potent and Selective Inhibitors of Coagulation Factor XIa with in Vivo Antithrombotic Activity

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• 作者：Jon J. Hangeland ; Todd J. Friends ; Karen A. Rossi ; Joanne M. Smallheer ; Cailan Wang ; Zhong Sun ; James R. Corte ; Tianan Fang ; Pancras C. Wong ; Alan R. Rendina ; Frank A. Barbera ; Jeffrey M. Bozarth ; Joseph M. Luettgen ; Carol A. Watson ; Ge Zhang ; Anzhi Wei ; Vidhyashankar Ramamurthy ; Paul E. Morin ; Gregory S. Bisacchi ; Srinath Subramaniam ; Piramanayagam Arunachalam ; Arvind Mathur ; Dietmar A. Seiffert ; Ruth R. Wexler ; Mimi L. Quan
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：December 11, 2014
• 年：2014
• 卷：57
• 期：23
• 页码：9915-9932
• 全文大小：720K
• ISSN：1520-4804

文摘

Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (K_i = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID₅₀ = 0.6 mg/kg + 1 mg kg^鈥? h^鈥?). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID₉₀ for thrombus inhibition.