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
  • 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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