Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan; Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan.
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Bioorg Med Chem Lett. 2020 Mar 1;30(5):126932. doi: 10.1016/j.bmcl.2019.126932. Epub 2019 Dec 30.
A novel unsymmetrical structural class of HCV NS5A inhibitors showing picomolar range antiviral activity has been identified. An unsymmetrical lead compound 2, generated from a substructure of a known symmetrical inhibitor 1, was optimized by extension of its substituents to interact with the hitherto unexplored site of the target protein. This approach afforded novel highly potent unsymmetrical inhibitor 20, which not only equally inhibited HCV genotypes1a, 1b, and 2a with EC values in the picomolar range, but also inhibited the 1a Q30K mutant induced by a launched symmetrical inhibitor daclatasvir with an EC in the low nanomolar range.
已鉴定出具有皮摩尔级抗病毒活性的新型 HCV NS5A 抑制剂非对称结构类别。通过扩展其取代基与目标蛋白 hitherto unexplored 位点相互作用，从已知对称抑制剂 1 的一个亚结构生成了非对称先导化合物 2。该方法提供了新型的高活性非对称抑制剂 20，它不仅以皮摩尔级的 EC 值同等抑制 HCV 基因型 1a、1b 和 2a，而且以低纳摩尔级的 EC 值抑制由已上市的对称抑制剂达卡他韦诱导的 1a Q30K 突变体。
