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

Basic Information

ID: ALA3808314

Journal: ACS Med Chem Lett

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

Authors: Deng H, Zhou J, Sundersingh F, Messer JA, Somers DO, Ajakane M, Arico-Muendel CC, Beljean A, Belyanskaya SL, Bingham R, Blazensky E, Boullay AB, Boursier E, Chai J, Carter P, Chung CW, Daugan A, Ding Y, Herry K, Hobbs C, Humphries E, Kollmann C, Nguyen VL, Nicodeme E, Smith SE, Dodic N, Ancellin N.

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.

CiteXplore: 27096045

DOI: 10.1021/acsmedchemlett.5b00389

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