α-Substituted 2-(3-fluoro-4-methylsulfonamidophenyl)acetamides as potent TRPV1 antagonists

Bioorg Med Chem Lett. 2015 Jun 1;25(11):2326-30. doi: 10.1016/j.bmcl.2015.04.024. Epub 2015 Apr 12.

Abstract

A series of α-substituted acetamide derivatives of previously reported 2-(3-fluoro-4-methylsulfonamidophenyl)propanamide leads (1, 2) were investigated for antagonism of hTRPV1 activation by capsaicin. Compound 34, which possesses an α-m-tolyl substituent, showed highly potent and selective antagonism of capsaicin with Ki(CAP)=0.1 nM. It thus reflected a 3-fold improvement in potency over parent 1. Docking analysis using our homology model indicated that the high potency of 34 might be attributed to a specific hydrophobic interaction of the m-tolyl group with the receptor.

Keywords: Analgesic; Capsaicin; Molecular modeling; TRPV1 antagonist.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / chemistry
  • Acetamides / pharmacology*
  • Animals
  • CHO Cells
  • Capsaicin / pharmacology
  • Cricetinae
  • Cricetulus
  • Molecular Structure
  • Structure-Activity Relationship
  • TRPV Cation Channels / antagonists & inhibitors*
  • TRPV Cation Channels / metabolism

Substances

  • Acetamides
  • TRPV Cation Channels
  • TRPV1 protein, human
  • Capsaicin