Design,synthesis and preliminary evaluation of novel indole analogues bearing 1,2,3-triazole moiety as ATX/FXR dual regulators
Using previously reported ATX inhibitor LHR-144 and FXR agonist TERN-101 as the lead compounds,twelve indole-based compounds bearing 1,2,3-triazole moiety were designed as novel ATX/FXR dual regulators.With 5-nitroindole as the staring material,compounds C1-C7 were obtained through a sequential 9-step procedure including methylation,Friedel-Crafts acylation,reduction,azidation,1,3-dipolar cycloaddition,chlorination,N-alkylation,hydrolysis and Curtius rearrangement.Starting from intermediate 6,compounds C8-C12 were synthesized through N-alkylation,hydrolysis,esterification,Curtius rearrangement and hydrolysis reaction.The structures of target compounds were characterized by MS and NMR.The preliminary biological evaluation results showed that most compounds exerted strong ATX inhibitory potency,and compound C8 was the optimal compound with an IC50 value of 1.32 nmol·L-1.Meanwhile,compound C8 tended to serve as a modest FXR agonist with a primary EC50 value of 0.67 µmol·L-1,which was worthy of further study.
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