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

In order to find new TRPV1 antagonists without obvious side effects, three series of piperazine urea derivatives were designed, synthesized and evaluated using classical TRPV1 ligands BCTC and GRT12360 as leading compounds. [Display omitted] •Three series of new piperazine urea TRPV1 antagonists were designed, synthesized and evaluated based on classical TRPV1 antagonists BCTC and GRT12360.•The most effective compound 5ac showed mode selective antagonism and avoided the side effects of hyperthermia.•Compound 5ac is more effective than positive control BCTC in CAP and heat-induced pain models. 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.