TRPV1 antagonist with high analgesic efficacy: 2-Thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides

Bioorg Med Chem. 2013 Nov 1;21(21):6657-64. doi: 10.1016/j.bmc.2013.08.015. Epub 2013 Aug 13.

Abstract

A series of 2-thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Among them, compound 24S showed stereospecific and excellent TRPV1 antagonism of capsaicin-induced activation. Further, it demonstrated strong anti-allodynic in a rat neuropathic pain model. Consistent with its action in vitro being through TRPV1, compound 24S blocked capsaicin-induced hypothermia in mice. Docking analysis of 24S with our hTRPV1 homology model was performed to identify its binding mode.

Keywords: Analgesic; Capsaicin; Resiniferatoxin; TRPV1 antagonists.

Publication types

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

MeSH terms

  • Amides / chemistry*
  • Amides / metabolism
  • Amides / therapeutic use
  • Analgesics / chemistry*
  • Analgesics / metabolism
  • Analgesics / therapeutic use
  • Animals
  • Benzeneacetamides / chemistry*
  • Benzeneacetamides / metabolism
  • Benzeneacetamides / therapeutic use
  • Binding Sites
  • Disease Models, Animal
  • Humans
  • Mice
  • Molecular Docking Simulation
  • Neuralgia / drug therapy
  • Protein Binding
  • Protein Structure, Tertiary
  • Pyridines / chemistry*
  • Rats
  • Structure-Activity Relationship
  • Sulfonamides / chemistry*
  • Sulfonamides / metabolism
  • Sulfonamides / therapeutic use
  • TRPV Cation Channels / antagonists & inhibitors*
  • TRPV Cation Channels / metabolism

Substances

  • Amides
  • Analgesics
  • Benzeneacetamides
  • N-((2-(cyclohexylthio)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(3-fluoro-4-(methylsulfonamido)phenyl)propanamide
  • Pyridines
  • Sulfonamides
  • TRPV Cation Channels
  • TRPV1 protein, human
  • pyridine