Novel phenylalanine derived diamides as Factor XIa inhibitors
详细信息 查看全文
- 作者：Leon M. Smith II ; leon.smith@bms.com" class="auth_mail" title="E-mail the corresponding author ; Michael J. Orwat ; Zilun Hu ; Wei Han ; Cailan Wang ; Karen A. Rossi ; Paul J. Gilligan ; Kumar B. Pabbisetty ; Honey Osuna ; James R. Corte ; Alan R. Rendina ; Joseph M. Luettgen ; Pancras C. Wong ; Ranga Narayanan ; Timothy W. Harper ; Jeffrey M. Bozarth ; Earl J. Crain ; Anzhi Wei ; Vidhyashankar Ramamurthy ; Paul E. Morin ; Baomin Xin ; Joanna Zheng ; Dietmar A. Seiffert ; Mimi L. Quan ; Patrick Y.S. Lam ; Ruth R. Wexler ; Donald J.P. Pinto
- 关键词：Factor XIa ; FXIa ; Anticoagulant ; Thrombosis ; Serine protease ; aPTT
- 刊名：Bioorganic & Medicinal Chemistry Letters
- 出版年：2016
- 出版时间：15 January 2016
- 年：2016
- 卷：26
- 期：2
- 页码：472-478
- 全文大小：3635 K
文摘
The synthesis, structural activity relationships (SAR), and selectivity profile of a potent series of phenylalanine diamide FXIa inhibitors will be discussed. Exploration of P1 prime and P2 prime groups led to the discovery of compounds with high FXIa affinity, good potency in our clotting assay (aPPT), and high selectivity against a panel of relevant serine proteases as exemplified by compound 21. Compound 21 demonstrated good in vivo efficacy (EC50 = 2.8 μM) in the rabbit electrically induced carotid arterial thrombosis model (ECAT).