Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists

Bioorg Med Chem. 2015 Nov 1;23(21):6844-54. doi: 10.1016/j.bmc.2015.10.001. Epub 2015 Oct 9.

Abstract

A series of 2-substituted 4-(trifluoromethyl)benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis indicated that the phenyl C-region derivatives exhibited better antagonism than those of the corresponding pyridine surrogates for most of the series examined. Among the phenyl C-region derivatives, the two best compounds 43 and 44S antagonized capsaicin selectively relative to their antagonism of other activators and showed excellent potencies with K(i(CAP))=0.3 nM. These two compounds blocked capsaicin-induced hypothermia, consistent with TRPV1 as their site of action, and they demonstrated promising analgesic activities in a neuropathic pain model without hyperthermia. The docking study of 44S in our hTRPV1 homology model indicated that its binding mode was similar with that of its pyridine surrogate in the A- and B-regions but displayed a flipped configuration in the C-region.

Keywords: Analgesic; TRPV1 antagonists; Vanilloid receptor 1.

Publication types

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

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / therapeutic use
  • Analgesics / chemical synthesis
  • Analgesics / chemistry*
  • Animals
  • Binding Sites
  • Capsaicin / toxicity
  • Humans
  • Hypothermia / chemically induced
  • Hypothermia / drug therapy
  • Mice
  • Molecular Conformation
  • Molecular Docking Simulation
  • Structure-Activity Relationship
  • TRPV Cation Channels / antagonists & inhibitors*
  • TRPV Cation Channels / metabolism

Substances

  • Amides
  • Analgesics
  • TRPV Cation Channels
  • Capsaicin