Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC.
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC.
Eur J Med Chem. 2019 Apr 1;167:245-268. doi: 10.1016/j.ejmech.2019.02.016. Epub 2019 Feb 6.
A medicinal chemistry program based on the small-molecule HCV NS5A inhibitor daclatasvir has led to the discovery of dimeric phenylthiazole compound 8, a novel and potent HCV NS5A inhibitor. The subsequent SAR studies and optimization revealed that the cycloalkyl amide derivatives 27a-29a exhibited superior potency against GT1b with GT1b EC values at picomolar concentration. Interestingly, high diastereospecificity for HCV inhibition was observed in this class with the (1R,2S,1'R,2'S) diastereomer displaying the highest GT1b inhibitory activity. The best inhibitor 27a was found to be 3-fold more potent (GT1b EC = 0.003 nM) than daclatasvir (GT1b EC = 0.009 nM) against GT1b, and no detectable in vitro cytotoxicity was observed (CC > 50 μM). Pharmacokinetic studies demonstrated that compound 27a had an excellent pharmacokinetic profiles with a superior oral exposure and desired bioavailability after oral administration in both rats and dogs, and therefore it was selected as a developmental candidate for the treatment of HCV infection.
基于小分子 HCV NS5A 抑制剂达拉他韦的药物化学项目导致了二芳基噻唑化合物 8 的发现，这是一种新型有效的 HCV NS5A 抑制剂。随后的 SAR 研究和优化表明，环烷基酰胺衍生物 27a-29a 对 GT1b 的活性更高，GT1b 的 EC 值达到皮摩尔浓度。有趣的是，该类化合物对 HCV 抑制具有很高的对映体选择性，其中（1R,2S,1'R,2'S）非对映异构体显示出最高的 GT1b 抑制活性。发现最佳抑制剂 27a 对 GT1b 的活性比达拉他韦（GT1b EC = 0.009 nM）强 3 倍（GT1b EC = 0.003 nM），并且在体外没有观察到可检测的细胞毒性（CC > 50 μM）。药代动力学研究表明，化合物 27a 具有优异的药代动力学特性，在大鼠和狗体内口服给药后具有卓越的口服暴露量和所需的生物利用度，因此被选为治疗 HCV 感染的候选药物。
