Pyridine C-region analogs of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists

Eur J Med Chem. 2015 Mar 26:93:101-8. doi: 10.1016/j.ejmech.2015.02.001. Epub 2015 Feb 2.

Abstract

A series of pyridine derivatives in the C-region of N-((6-trifluoromethyl-pyridin-3-yl)methyl) 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. The SAR analysis indicated that 6-difluorochloromethyl pyridine derivatives were the best surrogates of the C-region for previous leads. Among them, compound 31 showed excellent antagonism to capsaicin as well as to multiple hTRPV1 activators. It demonstrated strong analgesic activity in the formalin test in mice with full efficacy and it blocked capsaicin-induced hypothermia in vivo.

Keywords: Analgesic; TRPV1 antagonists; Vanilloid receptor 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / chemical synthesis*
  • Analgesics / chemistry
  • Analgesics / pharmacology
  • Analgesics / therapeutic use
  • Animals
  • Benzeneacetamides / chemical synthesis*
  • Benzeneacetamides / chemistry
  • Benzeneacetamides / pharmacology
  • Benzeneacetamides / therapeutic use
  • Mice
  • Molecular Structure
  • Pain / drug therapy
  • Pain Measurement
  • Pyridines / chemistry*
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use
  • TRPV Cation Channels / antagonists & inhibitors*

Substances

  • Analgesics
  • Benzeneacetamides
  • Pyridines
  • Sulfonamides
  • TRPV Cation Channels
  • TRPV1 protein, human