Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.
J Med Chem. 2022 Feb 10;65(3):2122-2138. doi: 10.1021/acs.jmedchem.1c01676. Epub 2022 Jan 24.
A series of novel heteroaromatic biphenyl-methyl-pyrimidine analogues were designed via hybridization of privileged structures of two HIV-1 inhibitors. Among them, compound containing 4-pyridinyl-phenyl and methyl-pyrimidine fragments revealed excellent wild-type HIV-1 inhibitory activity with low cytotoxicity. had favorable solubility and liver microsome stability; moreover, no apparent CYP enzymatic inhibitory activity or acute toxicity was observed. However, its inhibitory activity toward mutant strains and the pharmacokinetic (PK) profiles were still unsatisfactory. Further optimizations resulted in a highly potent compound without methyl on the pyrimidine but a heteroaromatic dimethyl-biphenyl on the left rings of difluoro-pyridinyl-diarylpyrimidines (DAPYs). A broad-spectrum activity (EC = 2.0-57 nM) of against resistant strains was revealed. This compound also exhibited good solubility and safety profiles and a good PK profile with an oral bioavailability of 59% in rats. Collectively, these novel heteroaromatic dimethyl-biphenyl-DAPYs represent promising drug candidates for HIV clinical therapy.
设计了一系列新型杂芳基联苯-嘧啶类似物，方法是将两种 HIV-1 抑制剂的优势结构进行杂交。其中，含有 4-吡啶基-苯基和甲基嘧啶片段的化合物 对野生型 HIV-1 具有优异的抑制活性，同时细胞毒性低。 具有良好的溶解度和肝微粒体稳定性；此外，没有观察到明显的 CYP 酶抑制活性或急性毒性。然而，其对突变株的抑制活性和药代动力学（PK）特征仍然不理想。进一步的优化导致一种高度有效的化合物 ，其嘧啶上没有甲基，但在二氟吡啶基二芳基嘧啶（DAPY）的左侧环上有一个杂芳基二甲基联苯。 对耐药株具有广谱活性（EC = 2.0-57 nM）。该化合物还表现出良好的溶解度和安全性特征，以及良好的 PK 特征，在大鼠中的口服生物利用度为 59%。总的来说，这些新型杂芳基二甲基联苯-DAPY 代表了用于 HIV 临床治疗的有前途的药物候选物。
