Study on chemical modification and analgesic activity of N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl) piperazine-1-carboxamide.

N-(4-Tert-butylphenyl)-4-(3-chloropyridin-2-yl) piperazine-1-carboxamide (BCTC) is a potent and extensively studied urea-based TRPV1 antagonist. Although BCTC was effective in alleviating chronic pain in rats, it showed obvious hyperthermia side-effect and unsatisfactory pharmacokinetic profile, therefore, it was not developed further. In order to enrich the structural types of urea-based TRPV1 antagonists, two series of novel analogs, in which the pyridine ring of BCTC was replaced with a mildly basic pyrimidine ring or 1,2,3,4-tetrahydro-ß-carboline scaffold, were designed and synthesized. Advancing the structure-activity relationship of these two series led to the discovery of N-(4-methoxyphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxamide (7o), with an improved pharmacological and tolerability profile compared with the lead compound BCTC.

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

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-b]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 µM) 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.

Design, synthesis and biological evaluation of N1-(isoquinolin-5-yl)-N2-phenylpyrrolidine-1,2-dicarboxamide derivatives as potent TRPV1 antagonists.

Reported herein is the design, synthesis, and pharmacologic evaluation of a class of TRPV1 antagonists constructed on a N1-(isoquinolin-5-yl)-N2-phenylpyrrolidine-1,2-dicarboxamide platform that evolved from a 5-aminoisoquinoline urea lead. Advancing the SAR of this series led to the eventual identification of 3b, comprising a p-Br substituted phenyl. In a TRPV1 functional assay, using cells expressing recombinant human TRPV1 channels, 3b displayed potent antagonism activated by capsaicin (IC50 = 0.084 µM) and protons (IC50 = 0.313 µM). In the preliminary analgesic and body temperature tests, 3b exhibited good efficacy in capsaicin-induced and heat-induced pain models and without hyperthermia side-effect. On the basis of its superior profiles, 3b could be considered as the lead candidate for the further development of antinociceptive drugs.

Design, synthesis and biological evaluation of novel hydrogen sulfide releasing capsaicin derivatives.

Capsaicin (CAP), the prototypical TRPV1 agonist, is the major active component in chili peppers with health-promoting benefits. However, its use is limited by the low bioavailability and irritating quality. In this study, for improving the activity of CAP and alleviating its irritating effects, a series of H2S-releasing CAPs were designed and synthesized by combining capsaicin and dihydro capsaicin with various hydrogen sulfide donors. The resulting compounds were evaluated their TRPV1 agonist activity, analgesic activity, anticancer activities, H2S-releasing ability, and gastric mucosa irritation. Biological evaluation indicated that the most active compound B9, containing 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione moiety as H2S donor, had better analgesic activity and displayed more potent cytotoxic effects on the test cell lines than the lead compound CAP. Furthermore, the preferred compound, B9 reduced rat gastric mucosa irritation caused by CAP. Notably, the improved properties of this derivative are associated with its H2S-releasing capability.