2-Alkyl/alkenyl substituted pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists

Bioorg Med Chem Lett. 2014 Aug 15;24(16):4039-43. doi: 10.1016/j.bmcl.2014.05.074. Epub 2014 Jun 2.

Abstract

A series of 2-alkyl/alkenyl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed excellent and stereospecific TRPV1 antagonism with better potency than previous lead 2. Among them, compound 15f demonstrated a strong analgesic profile in a rat neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of (S)-15f with our hTRPV1 homology model provided insight into its specific binding mode.

Keywords: Capsaicin; Molecular modeling; Resiniferatoxin; TRPV1 antagonist; Vanilloid receptor 1.

Publication types

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

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Hydrocarbons, Fluorinated / chemical synthesis
  • Hydrocarbons, Fluorinated / chemistry
  • Hydrocarbons, Fluorinated / pharmacology*
  • Molecular Structure
  • Phenylpropionates / chemical synthesis
  • Phenylpropionates / chemistry
  • Phenylpropionates / pharmacology*
  • Pyridines / chemistry*
  • Structure-Activity Relationship
  • TRPV Cation Channels / antagonists & inhibitors*

Substances

  • Hydrocarbons, Fluorinated
  • Phenylpropionates
  • Pyridines
  • TRPV Cation Channels
  • TRPV1 protein, human
  • pyridine