Discovery and Optimization of Potent, Selective, and in Vivo Efficacious 2-Aryl Benzimidazole BCATm Inhibitors
Hongfeng Deng, Jingye Zhou, Flora S. Sundersingh, Jeffrey A. Messer, Donald O'N Somers, Myriam Ajakane, Christopher C. Arico-Muendel, Arthur Beljean, Svetlana L. Belyanskaya, Ryan P. Bingham, Emily Blazensky, Anne-Bénédicte Boullay, Eric V. Boursier, Jing Chai, Paul Carter, Chun‐wa Chung, Alain Daugan, Yun Ding, Kenny Herry, Clare I. Hobbs · ACS Medicinal Chemistry Letters · 2016
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.