Design and synthesis of bicyclic pyrazinone and pyrimidinone amides as potent TF-FVIIa inhibitors
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- 作者：Xiaojun Zhang ; xiaojun.zhang@bms.com ; Peter W. Glunz ; Wen Jiang ; Aaron Schmitt ; Makenzie Newman ; Frank A. Barbera ; Jeffery M. Bozarth ; Alan R. Rendina ; Anzhi Wei ; Xiao Wen ; Karen A. Rossi ; Joseph M. Luettgen ; Pancras C. Wong ; Robert M. Knabb ; Ruth R. Wexler ; E. Scott Priestley
- 关键词：TF&ndash ; FVIIa inhibitor ; Bicyclic pyrazinone ; Bicyclic pyrimidinone
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：15 March, 2013
- 年：2013
- 卷：23
- 期：6
- 页码：1604-1607
- 全文大小：1057 K
文摘
Bicyclic pyrazinone and pyrimidinone amides were designed and synthesized as potent TF-FVIIa inhibitors. SAR demonstrated that the S2 and S3 pockets of FVIIa prefer to bind small, lipophilic groups. An X-ray crystal structure of optimized compound boldFont"">9b bound in the active site of FVIIa showed that the bicyclic scaffold provides 5 hydrogen bonding interactions in addition to projecting groups for interactions within the S1, S2 and S3 pockets. Compound boldFont"">9b showed excellent FVIIa potency, good selectivity against FIXa, Xa, XIa and chymotrypsin, and good clotting activity.