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-l-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-beta-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-blindole-2-carboxamide (70), with an improved pharmacological and tolerability profile compared with the lead compound BCTC. (C) 2020 Elsevier Masson SAS. All rights reserved.