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 se...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.展开更多
基金financially supported by National Natural Science Foundation of China(No.22077018).
文摘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.
