Dataset Information

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

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.

SUBMITTER: Deng H

PROVIDER: S-EPMC4834658 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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

Deng Hongfeng H Zhou Jingye J Sundersingh Flora F Messer Jeffrey A JA Somers Donald O DO Ajakane Myriam M Arico-Muendel Christopher C CC Beljean Arthur A Belyanskaya Svetlana L SL Bingham Ryan R Blazensky Emily E Boullay Anne-Benedicte AB Boursier Eric E Chai Jing J Carter Paul P Chung Chun-Wa CW Daugan Alain A Ding Yun Y Herry Kenny K Hobbs Clare C Humphries Eric E Kollmann Christopher C Nguyen Van Loc VL Nicodeme Edwige E Smith Sarah E SE Dodic Nerina N Ancellin Nicolas N

ACS medicinal chemistry letters 20160208 4

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. ...[more]

PMID: 27096045

Dataset Information

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

Publications

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

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