Picomolar inhibitor of reverse transcriptase featuring significantly improved metabolic stability  

作　　者：Ya-Li Sang Christophe Pannecouque Erik De Clercq Shuai Wang Fen-Er Chen 

机构地区：[1]Department of Chemistry,Engineering Center of Catalysis and Synthesis for Chiral Molecules,Fudan University,Shanghai 200433,China [2]Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs,Shanghai 200433,China [3]School of Science,Harbin Institute of Technology(Shenzhen),Shenzhen 518055,China [4]Rega Institute for Medical Research,KU Leuven,Leuven B-3000,Belgium

出　　处：《Acta Pharmaceutica Sinica B》2023年第7期3054-3066,共13页药学学报（英文版）

基　　金：financially supported by National Natural Science Foundation of China(No.22077018)。

摘　　要：Considering the undesirable metabolic stability of our recently identified NNRTI 5(t1/2=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 9g was endowed with remarkably improved metabolic stability in human liver microsomes(t1/2=2754 min),which was about 29-fold longer than that of 5(t1/2=96 min).This compound conferred picomolar inhibition of WT HIV-1(EC50=0.9 nmol/L)and low nanomolar activity against five clinically drug-resistant mutant strains.It maintained particularly low cytotoxicity(CC50=264μmol/L)and good selectivity(SI=256,438).Molecular docking studies revealed that compound 9g exhibited a more stable conformation than 5 due to the newly constructed hydrogen bond of the hydroxymethyl group with E138.Also,compound 9g was characterized by good safety profiles.It displayed no apparent inhibition of CYP enzymes and h ERG.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.

关 键 词：NNRTI HIV-1 DAPYs Picomolar Metabolic stability 

分 类 号：R914[医药卫生—药物化学]