Discovery and Optimization of Potent, Selective, and in Vivo Efficacious 2-Aryl Benzimidazole BCATm Inhibitors

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• 作者：Hongfeng Deng ; Jingye Zhou ; Flora Sundersingh ; Jeffrey A. Messer ; Donald O. Somers ; Myriam Ajakane ; Christopher C. Arico-Muendel ; Arthur Beljean ; Svetlana L. Belyanskaya ; Ryan Bingham ; Emily Blazensky ; Anne-Benedicte Boullay ; Eric Boursier ; Jing Chai ; Paul Carter ; Chun-Wa Chung ; Alain Daugan ; Yun Ding ; Kenny Herry ; Clare Hobbs ; Eric Humphries ; Christopher Kollmann ; Van Loc Nguyen ; Edwige Nicodeme ; Sarah E. Smith ; Nerina Dodic ; Nicolas Ancellin
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：7
• 期：4
• 页码：379-384
• 全文大小：427K
• 年卷期：0
• ISSN：1948-5875

文摘

To identify BCATm inhibitors suitable for in vivo study, Encoded Library Technology (ELT) was used to affinity screen a 117 million member benzimidazole based DNA encoded library, which identified an inhibitor series with both biochemical and cellular activities. Subsequent SAR studies led to the discovery of a highly potent and selective compound, 1-(3-(5-bromothiophene-2-carboxamido)cyclohexyl)-N-methyl-2-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamide (8b) with much improved PK properties. X-ray structure revealed that 8b binds to the active site of BACTm in a unique mode via multiple H-bond and van der Waals interactions. After oral administration, 8b raised mouse blood levels of all three branched chain amino acids as a consequence of BCATm inhibition.