6,6-Fused heterocyclic ureas as highly potent TRPV1 antagonists

Bioorg Med Chem Lett. 2015 Feb 15;25(4):803-6. doi: 10.1016/j.bmcl.2014.12.086. Epub 2015 Jan 5.

Abstract

A series of N-[{2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)-pyridin-3-yl}methyl] N'-(6,6-fused heterocyclic) ureas have been investigated as hTRPV1 antagonists. Among them, compound 15 showed highly potent TRPV1 antagonism to capsaicin, with Ki(ant)=0.2nM, as well as antagonism to other activators, and it was efficacious in a pain model. A docking study of 15 with our hTRPV1 homology model indicates that there is crucial hydrogen bonding between the ring nitrogen and the receptor, contributing to its potency.

Keywords: Analgesic; Molecular modeling; TRPV1 antagonist; Vanilloid receptor 1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Humans
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • TRPV Cation Channels / antagonists & inhibitors*
  • TRPV Cation Channels / chemistry
  • Urea / analogs & derivatives*
  • Urea / chemistry
  • Urea / pharmacology

Substances

  • Isoquinolines
  • TRPV Cation Channels
  • TRPV1 protein, human
  • Urea