Chemical Diversity Research Institute, Rabochaya St. 2a, Khimki, Moscow Region 141401, Russia; ChemDiv, 6605 Nancy Ridge Drive San Diego, CA 92121, United States; Moscow Institute of Physics and Technology (State University), 9 Institutskiy lane, Dolgoprudny City, Moscow Region 141700, Russia.
ChemDiv, 6605 Nancy Ridge Drive San Diego, CA 92121, United States; Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Ufa, Russia.
Bioorg Med Chem. 2020 Oct 15;28(20):115716. doi: 10.1016/j.bmc.2020.115716. Epub 2020 Aug 20.
A series of novel small-molecule pan-genotypic hepatitis C virus (HCV) NS5A inhibitors with picomolar activity containing 2-[(2S)-pyrrolidin-2-yl]-5-[4-(4-{2-[(2S)-pyrrolidin-2-yl]-1H-imidazol-5-yl}buta-1,3-diyn-1-yl)phenyl]-1H-imidazole core was designed based on molecular modeling study and SAR analysis. The constructed in silico model and docking study provide a deep insight into the binding mode of this type of NS5A inhibitors. Based on the predicted binding interface we have prioritized the most crucial diversity points responsible for improving antiviral activity. The synthesized molecules were tested in a cell-based assay, and compound 1.12 showed an EC value in the range of 2.9-34 pM against six genotypes of NS5A HCV, including gT3a, and demonstrated favorable pharmacokinetic profile in rats. This lead compound can be considered as an attractive candidate for further clinical evaluation.
设计了一系列新型含纳摩尔活性的小分子泛基因型丙型肝炎病毒 (HCV) NS5A 抑制剂，该抑制剂含有 2-[(2S)-吡咯烷-2-基]-5-[4-(4-{2-[(2S)-吡咯烷-2-基]-1H-咪唑-5-基}丁-1,3-二炔-1-基)苯基]-1H-咪唑核心，基于分子建模研究和 SAR 分析。构建的计算机模型和对接研究深入了解了这类 NS5A 抑制剂的结合模式。基于预测的结合界面，我们确定了对提高抗病毒活性最重要的关键多样性点。合成的分子在基于细胞的测定中进行了测试，化合物 1.12 对包括 gT3a 在内的六种基因型的 NS5A HCV 的 EC 值在 2.9-34 pM 范围内，并在大鼠中表现出良好的药代动力学特征。该先导化合物可被视为进一步临床评估的有吸引力的候选物。
