Zhen Le, Dai Liang, Wen Xiaoan, Yao Lan, Jin Xiaoliang, Yang Xiao-Wen, Zhao Wenfeng, Yu Sheng-Qi, Yuan Haoliang, Wang Guangji, Sun Hongbin
Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease and State Key Laboratory of Natural Medicines, China Pharmaceutical University , 24 Tongjia Xiang, Nanjing 210009, China.
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , 24 Tongjia Xiang, Nanjing, 210009 Jiangsu, China.
J Med Chem. 2017 Jul 27;60(14):6077-6088. doi: 10.1021/acs.jmedchem.7b00262. Epub 2017 Jul 10.
Resistant HCV variants carrying NS5B S282T mutation confer reduced sensitivity to sofosbuvir, the sole marketed NS5B polymerase inhibitor. On the basis of the finding that 2'-α-F-2'-β-C-methylcytidine 5'-triphosphate (8) was more potent than sofosbuvir's active metabolite on inhibition of both wild-type and S282T mutant polymerase, a dual-prodrug approach has been established. Twenty-nine phosphoramidates with N-modified cytosine were designed, synthesized, and evaluated for anti-HCV activity. The results showed that compounds 4c-4e and 4m (EC = 0.19-0.25 μM) exhibited comparable potency to that of sofosbuvir (EC = 0.15 μM) on inhibition of wild-type replicons. Notably, 4c (EC = 0.366 μM) was 1.5-fold more potent than sofosbuvir (EC = 0.589 μM) on inhibition of S282T mutant replicons. In vitro metabolic studies disclosed the possible metabolic pathways of 4c. The toxicity study results indicated a good safety profile of 4c. Together, 4c-4e and 4m hold promise for drug development for the treatment of HCV infection, especially the resistant variants with NS5B S282T mutation.
携带NS5B S282T突变的抗丙型肝炎病毒（HCV）变体对索磷布韦（唯一上市的NS5B聚合酶抑制剂）的敏感性降低。基于2'-α-F-2'-β-C-甲基胞苷5'-三磷酸（8）在抑制野生型和S282T突变型聚合酶方面比索磷布韦的活性代谢物更有效的发现，已建立了一种双前药方法。设计、合成了29种具有N-修饰胞嘧啶的氨基磷酸酯，并对其抗HCV活性进行了评估。结果表明，化合物4c-4e和4m（EC = 0.19-0.25 μM）在抑制野生型复制子方面表现出与索磷布韦（EC = 0.15 μM）相当的效力。值得注意的是，4c（EC = 0.366 μM）在抑制S282T突变型复制子方面比索磷布韦（EC = 0.589 μM）效力高1.5倍。体外代谢研究揭示了4c可能的代谢途径。毒性研究结果表明4c具有良好的安全性。总之，4c-4e和4m在治疗HCV感染，尤其是携带NS5B S282T突变的耐药变体的药物开发方面具有前景。
