Novel piperazine urea derivatives as highly potent transient receptor potential vanilloid 1 (TRPV1) antagonists.

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel with high permeability to Ca2+, which can be activated by low pH, noxious heat and vanilloid compounds such as capsaicin. TRPV1 has been proved to be very important in the process of pain production and is considered to be a highly effective analgesic target. In this work, three series of new piperazine urea TRPV1 antagonists were designed, synthesized and evaluated based on classical TRPV1 antagonists BCTC and GRT12360. Among them, N-(4,6-dimethylpyridin-2-yl)-4-(2-(pyrrolidin-1-yl)benzyl)piperazine-1-carboxamide (5ac) was finally identified, which had excellent TRPV1 antagonistic activity (IC50 (CAP) = 9.80 nM), good bioavailability and did not cause side effects of hyperthermia. In the study of molecular docking, the compound 5ac fitted well with the amino acid residues on rTRPV1 through hydrophobic interaction. Collectively, compound 5ac is an efficient TRPV1 antagonist and can be used as a candidate for the development of analgesic drugs.

A patent review of transient receptor potential vanilloid type 1 modulators (2014-present).

Introduction: Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel with high permeability to calcium, which is widely expressed in the central nervous system (CNS) and peripheral nervous system. Since the TRPV1 was molecularly cloned more than 20 years ago, a series of research activities have been carried out on the possibility of new drugs. Areas covered: This review summarizes the patents on TRPV1 regulators (including agonists and antagonists) that were published during 2014-present and predicts the development direction in the future. The patent description is organized according to the applicant company and focuses on the representative compounds and their in vitro and in vivo data. Expert opinion: At present, TRPV1 is considered to be a molecular integrator of a broad range of chemical and physical stimuli. The desensitization of nociceptive neurons caused by TRPV1 agonists and the pharmacological blockade of TRPV1 by powerful small molecular antagonists are different treatments, both of which have analgesic effects. Unfortunately, TRPV1 modulators have suffered from adverse effects related to the role of TRPV1 channel in body temperature regulation and noxious heat sensation. What we need to know is whether these adverse effects are on-target (unavoidable), and whether chemical modification can be used to avoid or reduce these adverse reactions in the process of designing drug molecules, so as to develop a TRPV1 regulator with potent analgesic effect and no obvious adverse effects. Despite the difficulties and roadblocks, TRPV1 modulators remain powerful tools in pain research and represent promising therapeutic agents.

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.