Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.
Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China.
J Med Chem. 2022 Jun 23;65(12):8478-8492. doi: 10.1021/acs.jmedchem.2c00468. Epub 2022 Jun 1.
Results from recently completed studies suggested that the NH-naphthyl-diarylpyrimidine displayed remarkable inhibitory activity against wild-type HIV-1 (EC = 5 nM) and numerous clinically observed variants in MT-4 cells; however, its high cytotoxicity (CC = 19 μM) precluded its further development as a clinical candidate. One approach we took to improve the safety involved replacing the naphthyl of with biphenyl to provide a series of novel NH-biphenyl-DAPYs. Investigation of the structure-activity relationships (SARs) led to the identification of , a potent NNRTI with significantly reduced cytotoxicity (CC = 120 μM), approximately 6-fold lower than , which maintained remarkable anti-HIV-1 activity against wild-type HIV-1 (EC = 1.9 nM) and multiple mutant strains simultaneously. Also, displayed weak CYP sensitivity, little inhibition of hERG, and no apparent acute toxicity. These promising results demonstrate that can be used as a drug candidate for HIV-1 therapy.
最近完成的研究结果表明，NH-萘基-二芳基嘧啶对野生型 HIV-1（EC = 5 nM）和 MT-4 细胞中许多临床观察到的变异体表现出显著的抑制活性；然而，其高细胞毒性（CC = 19 μM）排除了其作为临床候选药物的进一步发展。我们采取的一种提高安全性的方法是用联苯取代 的萘基，提供了一系列新型 NH-联苯-DAPYs。对构效关系（SARs）的研究导致了 的鉴定，这是一种有效的 NNRTI，其细胞毒性显著降低（CC = 120 μM），大约比 低 6 倍，同时对野生型 HIV-1（EC = 1.9 nM）和多种突变株均保持显著的抗 HIV-1 活性。此外， 对 CYP 的敏感性较弱，对 hERG 的抑制作用较小，无明显的急性毒性。这些有希望的结果表明， 可以作为 HIV-1 治疗的候选药物。
