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
ACS Med. Chem. Lett., 2016, 7, 4, 379-384
https://doi.org/10.1021/acsmedchemlett.5b00389

Abstract

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.