Discovery and Optimization of Potent, Selective, and in Vivo Efficacious 2-Aryl Benzimidazole BCATm Inhibitors
| Autor: | Svetlana L. Belyanskaya, Chun-wa Chung, Eric Humphries, Christopher S. Kollmann, Nicolas Ancellin, Christopher C. Arico-Muendel, Hongfeng Deng, Ryan P. Bingham, Van Loc Nguyen, Jeffrey A. Messer, Yun Ding, Emily Blazensky, Arthur Beljean, Anne-Benedicte Boullay, Sarah E. Smith, Jingye Zhou, Edwige Nicodeme, Jing Chai, Flora S. Sundersingh, Clare I. Hobbs, Alain Claude-Marie Daugan, Myriam Ajakane, Donald O. Somers, Nerina Dodic, Kenny Herry, Paul S. Carter, Eric Boursier |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Benzimidazole biology Stereochemistry Aryl Organic Chemistry Active site Biochemistry Amino acid 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology chemistry In vivo Drug Discovery biology.protein Transferase DNA |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|