Sang Ya-Li, Pannecouque Christophe, De Clercq Erik, Wang Shuai, Chen Fen-Er
Department of Chemistry, Engineering Center of Catalysis and Synthesis for Chiral Molecules, Fudan University, Shanghai 200433, China.
Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China.
Acta Pharm Sin B. 2023 Jul;13(7):3054-3066. doi: 10.1016/j.apsb.2023.03.022. Epub 2023 Mar 29.
Considering the undesirable metabolic stability of our recently identified NNRTI ( = 96 min) in human liver microsomes, we directed our efforts to improve its metabolic stability by introducing a new favorable hydroxymethyl side chain to the C-5 position of pyrimidine. This strategy provided a series of novel methylol-biphenyl-diarylpyrimidines with excellent anti-HIV-1 activity. The best compound was endowed with remarkably improved metabolic stability in human liver microsomes ( = 2754 min), which was about 29-fold longer than that of ( = 96 min). This compound conferred picomolar inhibition of WT HIV-1 (EC = 0.9 nmol/L) and low nanomolar activity against five clinically drug-resistant mutant strains. It maintained particularly low cytotoxicity (CC = 264 μmol/L) and good selectivity (SI = 256,438). Molecular docking studies revealed that compound exhibited a more stable conformation than due to the newly constructed hydrogen bond of the hydroxymethyl group with E138. Also, compound was characterized by good safety profiles. It displayed no apparent inhibition of CYP enzymes and hERG. The acute toxicity assay did not cause death and pathological damage in mice at a single dose of 2 g/kg. These findings paved the way for the discovery and development of new-generation anti-HIV-1 drugs.
考虑到我们最近鉴定出的非核苷类逆转录酶抑制剂（半衰期 = 96分钟）在人肝微粒体中不良的代谢稳定性，我们致力于通过在嘧啶的C-5位引入一个新的有利羟甲基侧链来提高其代谢稳定性。这一策略提供了一系列具有优异抗HIV-1活性的新型羟甲基联苯二芳基嘧啶。最佳化合物在人肝微粒体中的代谢稳定性得到显著提高（半衰期 = 2754分钟），比前者（半衰期 = 96分钟）长约29倍。该化合物对野生型HIV-1具有皮摩尔级别的抑制作用（半数有效浓度 = 0.9纳摩尔/升），对五种临床耐药突变株具有低纳摩尔活性。它的细胞毒性特别低（半数细胞毒性浓度 = 264微摩尔/升），选择性良好（选择性指数 = 256,438）。分子对接研究表明，由于羟甲基与E138新形成的氢键，化合物表现出比更稳定的构象。此外，化合物具有良好的安全性。它对CYP酶和人乙醚相关基因没有明显抑制作用。急性毒性试验表明，在2克/千克的单剂量下，小鼠未出现死亡和病理损伤。这些发现为新一代抗HIV-1药物的发现和开发铺平了道路。
