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

被引：34

作者：

Hangeland, Jon J. ^{[1
]}

Friends, Todd J. ^{[1
]}

Rossi, Karen A. ^{[1
]}

Smallheer, Joanne M. ^{[1
]}

Wang, Cailan ^{[1
]}

Sun, Zhong ^{[1
]}

Corte, James R. ^{[1
]}

Fang, Tianan ^{[1
]}

Wong, Pancras C. ^{[1
]}

Rendina, Alan R. ^{[1
]}

Barbera, Frank A. ^{[1
]}

Bozarth, Jeffrey M. ^{[1
]}

Luettgen, Joseph M. ^{[1
]}

Watson, Carol A. ^{[1
]}

Zhang, Ge ^{[1
]}

Wei, Anzhi ^{[1
]}

Ramamurthy, Vidhyashankar ^{[1
]}

Morin, Paul E. ^{[1
]}

Bisacchi, Gregory S. ^{[1
]}

Subramaniam, Srinath ^{[1
]}

Arunachalam, Piramanayagam ^{[1
]}

Mathur, Arvind ^{[1
]}

Seiffert, Dietmar A. ^{[1
]}

Wexler, Ruth R. ^{[1
]}

Quan, Mimi L. ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Res & Dev, Princeton, NJ 08543 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 23期

关键词：

FACTOR XA INHIBITORS; BLEEDING-TIME PROLONGATION; BIOLOGICAL EVALUATION; ARTERIAL THROMBOSIS; DEFICIENCY; RABBITS; ACTIVATION; DISCOVERY; DISEASE; BINDING;

D O I：

10.1021/jm5010607

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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(-1) h(-1)). 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.

引用

页码：9915 / 9932

页数：18

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