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
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DOI：
10.1021/acsmedchemlett.5b00389
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发表时间：
2016-04-01
影响因子：
4.2
通讯作者：
Ancellin, Nicolas
中科院分区：
文献类型：
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作者：
Deng, Hongfeng;Zhou, Jingye;Ancellin, Nicolas
为了鉴定适合于体内研究的BCATm抑制剂，使用编码文库技术（ELT）来亲和筛选1.17亿成员的基于苯并咪唑的DNA编码文库，其鉴定了具有生物化学和细胞活性的抑制剂系列。随后的SAR研究发现了一种高效和选择性的化合物，1-（3（5-溴噻吩-2-甲酰胺基）环己基）-N-甲基-2-（吡啶-2-基）-1H-苯并[d]咪唑-5-甲酰胺（8b），其PK特性大大改善。X-射线结构分析表明，8 b通过多重氢键和货车范德华力作用与BACTm的活性位点以独特的方式结合。口服给药后，由于BCATm抑制，8b升高了小鼠血液中所有三种支链氨基酸的水平。
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.