Structure-based design of novel heterocyclesubstituted ATDP analogs as non-nucleoside reverse transcriptase inhibitors with improved selectivity and solubility  

作　　者：Li-Min Zhao Christophe Pannecouque Erik De Clerc Shuai Wang Fen-Er Chen 

机构地区：[1]Key Laboratory of Natural Resources of Changbai Mountain&Functional Molecules,Ministry of Education,Yanbian University College of Pharmacy,Yanbian University,Yanji 133002,China [2]Engineering Center of Catalysis and Synthesis for Chiral Molecules,Department of Chemistry,Fudan University,Shanghai 200433,China [3]Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs,Shanghai 200433,China [4]Rega Institute for Medical Research,KU Leuven,Leuven B-3000,Belgium

出　　处：《Acta Pharmaceutica Sinica B》2023年第12期4906-4917,共12页药学学报（英文版）

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

摘　　要：Following on our recently developed biphenyl-ATDP non-nucleoside reverse transcriptase inhibitor ZLM-66(SI=2019.80,S=1.9μg/mL),a series of novel heterocycle-substituted ATDP derivatives with significantly improved selectivity and solubility were identified by replacement of the biphenyl moiety of ZLM-66 with heterocyclic group with lower lipophilicity.Evidently,the representative analog 7w in this series exhibited dramatically enhanced selectivity and solubility(SI=12,497.73,S=4472μg/mL)in comparison with ZLM-66(SI=2019.80,S=1.9μg/mL).This new NNRTI conferred low nanomolar inhibition of wild-type HIV-1 strain and tested mutant strains(K103N,L1001,Y181C,E138K,and K103N+Y181C).The analog also demonstrated favorable safety and pharmacokinetic profiles,as evidenced by its insensitivity to CYP and hERG,lack of mortality and pathological damage,and good oral bioavailability in rats(F=27.1%).Further development of 7w for HIV therapy will be facilitated by this valuable information.

关 键 词：HIV-1 RT NNRTIS ATDP PYRIDONE 

分 类 号：R914[医药卫生—药物化学]