Shionogi Pharmaceutical Research Center, Shionogi & Company, Limited, 1-1, Futabacho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
Shionogi Pharmaceutical Research Center, Shionogi & Company, Limited, 1-1, Futabacho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
Bioorg Med Chem. 2020 Sep 1;28(17):115643. doi: 10.1016/j.bmc.2020.115643. Epub 2020 Jul 10.
We report herein the discovery of novel integrase-LEDGF/p75 allosteric inhibitors (INLAIs) based on a benzene scaffold 3. This scaffold can extend substituents from the C1 position unlike the common pyridine scaffolds 2. Structure-activity relationship studies showed that the sulfonamide linker at the C1 position was important for the antiviral activity. Interaction between sulfonamide and Q95 was observed by X-ray crystallography. Compound 31h showed more potent antiviral activity (EC (NL432) = 3.9 nM) than BI-224436 (EC (NL432) = 56 nM), suggesting the potential of the newly designed scaffold 3.
我们在此报告了基于苯环骨架 3 的新型整合酶 - LEDGF/p75 别构抑制剂 (INLAIs) 的发现。与常见的吡啶骨架 2 不同，该骨架可以从 C1 位置延伸取代基。构效关系研究表明，C1 位置的磺酰胺连接基对于抗病毒活性很重要。通过 X 射线晶体学观察到磺酰胺与 Q95 之间的相互作用。化合物 31h 显示出比 BI-224436（EC（NL432）= 56 nM）更强的抗病毒活性（EC（NL432）= 3.9 nM），这表明新设计的骨架 3 具有潜力。
