t-Butyl pyridine and phenyl C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists

Bioorg Med Chem. 2017 Apr 15;25(8):2451-2462. doi: 10.1016/j.bmc.2017.03.004. Epub 2017 Mar 6.

Abstract

A series of 2-substituted 6-t-butylpyridine and 4-t-butylphenyl C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis of structure activity relationships indicated that the pyridine derivatives generally exhibited a little better antagonism than did the corresponding phenyl surrogates for most of the series. Among the compounds, compound 7 showed excellent antagonism toward capsaicin activation with Ki=0.1nM and compound 60S demonstrated a strong antiallodynic effect with 83% MPE at 10mg/kg in the neuropathic pain model. The docking study of 7S in our hTRPV1 homology model indicated that the interactions between the A/B-regions of 7S with Tyr511 and the interactions between the t-butyl and ethyl groups in the C-region of 7S with the two hydrophobic binding pockets of hTRPV1 contributed to the high potency.

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 / chemistry
  • Amides / pharmacology*
  • Animals
  • Humans
  • Molecular Docking Simulation
  • Pyridines / chemistry*
  • Structure-Activity Relationship
  • TRPV Cation Channels / antagonists & inhibitors*

Substances

  • Amides
  • Pyridines
  • TRPV Cation Channels
  • TRPV1 protein, human