Design, synthesis and biological evaluation of novel 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole triazole derivatives as potent TRPV1 antagonists

被引:15
作者
Li, Jinyu [1 ]
Nie, Cunbin [1 ]
Qiao, Yue [1 ]
Hu, Jing [1 ]
Li, Qifei [2 ]
Wang, Qiang [3 ]
Pu, Xiaohui [1 ]
Yan, Lin [1 ]
Qian, Hai [2 ]
机构
[1] Henan Univ, Sch Pharm, Inst Innovat Drug Design & Evaluat, N Jinming Ave, Kaifeng 475004, Henan, Peoples R China
[2] China Pharmaceut Univ, Ctr Drug Discovery, State Key Lab Nat Med, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, Peoples R China
[3] South Cent Univ Nationalities, Sch Pharmaceut Sci, 182 Minyuan Rd, Wuhan 430074, Hubei, Peoples R China
基金
中国国家自然科学基金;
关键词
Analgesic; Transient receptor potential vanilloid type 1; 2.3,4,9-Tetrahydro-1H-pyrido[3,4-b]indole; 1,2,3-Triazole; Hyperthermia; VANILLOID RECEPTOR TRPV1; CHANNELS; HYPERTHERMIA; PHARMACOLOGY; INHIBITION; ACTIVATION; CHEMISTRY;
D O I
10.1016/j.ejmech.2019.06.007
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Reported herein is the design, synthesis, and pharmacologic evaluation of a class of TRPV1 antagonists constructed on 2,3,4,9-tetrahydro-1H-pyrido[3,4-6]indole as A-region and triazole as B-region. The SAR analysis indicated that 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole analogues displayed excellent antagonism of hTRPV1 activation by capsaicin and showed better potency compared to the corresponding dihydroindole analogues. Optimization of this design led to the eventual identification of 2-((1-(2-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (6g), a potent TRPV1 antagonist. In vitro, using cells expressing recombinant human TRPV1 channels, 6g displayed potent antagonism activated by capsaicin (IC50 = 0.075 mu M) and only partially blocked acid activation of TRPV1. In vivo, 6g exhibited good efficacy in capsaicin-induced and heat-induced pain models and had almost no hyperthermia side-effect. Furthermore, pharmacokinetic studies revealed that compound 6g had a superior oral exposure after oral administration in rats. To understand its binding interactions with the receptor, the docking study of 6g was performed in rTRPV1 model and showed an excellent fit to the binding site. On the basis of its superior profiles, 6g could be considered as the lead candidate for the further development of antinociceptive drugs. (C) 2019 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:433 / 445
页数:13
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