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

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

  • ACS Med Chem Lett. 2016 Feb 8;7(4):379-84. doi: 10.1021/acsmedchemlett.5b00389.
Hongfeng Deng 1,  Jingye Zhou 1,  Flora Sundersingh 1,  Jeffrey A Messer 1,  Donald O Somers 2,  Myriam Ajakane 3,  Christopher C Arico-Muendel 1,  Arthur Beljean 2,  Svetlana L Belyanskaya 1,  Ryan Bingham 2,  Emily Blazensky 4,  Anne-Benedicte Boullay 3,  Eric Boursier 3,  Jing Chai 1,  Paul Carter 2,  Chun-Wa Chung 2,  Alain Daugan 3,  Yun Ding 1,  Kenny Herry 3,  Clare Hobbs 2,  Eric Humphries 4,  Christopher Kollmann 1,  Van Loc Nguyen 3,  Edwige Nicodeme 3,  Sarah E Smith 2,  Nerina Dodic 3,  Nicolas Ancellin 3
Affiliations

Affiliations

  • 1 Platform of Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
  • 2 Medicines Research Centre, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Herts, SG1 2NY, U.K.
  • 3 Centre de Recherche, GlaxoSmithKline , Les Ulis, 25,27 Avenue du Québec, 91140 Villebon sur Yvette, France.
  • 4 Chemistry Department, Northeastern University , Boston, Massachusetts 02115, United States.
PMID: 27096045 DOI: 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.

Keywords

2-aryl benzimidazole; BCATm; DNA Encoded Library; ELT; branched chain amino acids (BCAAs).

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