N-4-t-Butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamide TRPV1 antagonists: Structure-activity relationships in the A-region

Bioorg Med Chem. 2012 Jan 1;20(1):215-24. doi: 10.1016/j.bmc.2011.11.008. Epub 2011 Nov 22.

Abstract

Structure-activity relationships for the A-region in a series of N-4-t-butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamides as TRPV1 antagonists have been investigated. Among them, the 3-fluoro analogue 54 showed high binding affinity and potent antagonism for both rTRPV1 and hTRPV1 in CHO cells. Its stereospecific activity was demonstrated with marked selectivity for the (S)-configuration (54S versus 54R). A docking study of 54S with our hTRPV1 homology model highlighted crucial hydrogen bonds between the ligand and the receptor contributing to its potency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / pharmacology*
  • Animals
  • Binding Sites
  • CHO Cells
  • Computer Simulation
  • Cricetinae
  • Cricetulus
  • Humans
  • Hydrogen Bonding
  • Protein Binding / drug effects
  • Protein Structure, Tertiary
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship
  • TRPV Cation Channels / antagonists & inhibitors*
  • TRPV Cation Channels / metabolism

Substances

  • Amides
  • TRPV Cation Channels
  • TRPV1 protein, human