Results from recently completed studies suggested that the NH₂-naphthyl-diarylpyrimidine JX-7 displayed remarkable inhibitory activity against wild-type HIV-1 (EC₅₀ = 5 nM) and numerous clinically observed variants in MT-4 cells; however, its high cytotoxicity (CC₅₀ = 19 μM) precluded its further development as a clinical candidate. One approach we took to improve the safety involved replacing the naphthyl of JX-7 with biphenyl to provide a series of novel NH₂-biphenyl-DAPYs. Investigation of the structure–activity relationships (SARs) led to the identification of 4ab, a potent NNRTI with significantly reduced cytotoxicity (CC₅₀ = 120 μM), approximately 6-fold lower than JX-7, which maintained remarkable anti-HIV-1 activity against wild-type HIV-1 (EC₅₀ = 1.9 nM) and multiple mutant strains simultaneously. Also, 4ab displayed weak CYP sensitivity, little inhibition of hERG, and no apparent in vivo acute toxicity. These promising results demonstrate that 4ab can be used as a drug candidate for HIV-1 therapy.

中文翻译：

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基于结构的新型 NH2-联苯-二芳基嘧啶作为有效的非核苷类逆转录酶抑制剂的发现，安全性显着提高：从 NH2-萘基-二芳基嘧啶到 NH2-联苯-二芳基嘧啶

最近完成的研究结果表明，NH ₂ -萘基-二芳基嘧啶JX-7对野生型 HIV-1 (EC ₅₀ = 5 nM) 和许多临床观察到的 MT-4 细胞变异体表现出显着的抑制活性；然而，其高细胞毒性（CC ₅₀ = 19 μM）阻碍了其作为临床候选者的进一步发展。我们采取的一种提高安全性的方法涉及用联苯代替JX-7的萘基，以提供一系列新型 NH ₂ -联苯-DAPY。对构效关系 (SAR) 的研究导致了4ab的鉴定，这是一种有效的 NNRTI，具有显着降低的细胞毒性 (CC ₅₀= 120 μM)，比JX-7低约 6 倍，同时对野生型 HIV-1 (EC ₅₀ = 1.9 nM) 和多个突变株保持显着的抗 HIV-1 活性。此外，4ab对 CYP 的敏感性较弱，对 hERG 的抑制作用很小，并且没有明显的体内急性毒性。这些有希望的结果表明，4ab可用作 HIV-1 治疗的候选药物。