Discovery and Optimization of Imidazopyridine-Based Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2)
Discovery and Optimization of Imidazopyridine-Based Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2)
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DOI：
10.1021/acs.jmedchem.5b01006
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发表时间：
2015-09-24
影响因子：
7.3
通讯作者：
Goodwin, Bryan
中科院分区：
文献类型：
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作者：
Futatsugi, Kentaro;Kung, Daniel W.;Goodwin, Bryan
描述了基于咪唑吡啶的药物化学和临床前生物学的二酰基甘油酰基转移酶2（DGAT2）的抑制剂。通过两个关键的结构修饰优化了具有低亲脂性效率（LIPE）的筛查1：（1）鉴定吡咯烷酰胺酰胺基以显着改善，以及（2）插入Sp（3）插入SP（3） - 杂交碳中心分子同时改善N-葡萄糖醛酸化代谢责任和靶向药理学的核心。临床前候选者9（PF-06424439）在口服口服对血脂异常啮齿动物模型时表现出极好的ADMET特性，并且循环和肝脂质降低。
The medicinal chemistry and preclinical biology of imidazopyridine-based inhibitors of diacylglycerol acyltransferase 2 (DGAT2) is described. A screening hit 1 with low lipophilic efficiency (LipE) was optimized through two key structural modifications: (1) identification of the pyrrolidine amide group for a significant LipE improvement, and (2) insertion of a sp(3)-hybridized carbon center in the core of the molecule for simultaneous improvement of N-glucuronidation metabolic liability and off-target pharmacology. The preclinical candidate 9 (PF-06424439) demonstrated excellent ADMET properties and decreased circulating and hepatic lipids when orally administered to dyslipidemic rodent models.