2-(Halogenated Phenyl) acetamides and propanamides as potent TRPV1 antagonists

Bioorg Med Chem Lett. 2021 Sep 15:48:128266. doi: 10.1016/j.bmcl.2021.128266. Epub 2021 Jul 14.

Abstract

A series consisting of 117 2-(halogenated phenyl) acetamide and propanamide analogs were investigated as TRPV1 antagonists. The structure-activity analysis targeting their three pharmacophoric regions indicated that halogenated phenyl A-region analogs exhibited a broad functional profile ranging from agonism to antagonism. Among the compounds, antagonists 28 and 92 exhibited potent antagonism toward capsaicin for hTRPV1 with Ki[CAP] = 2.6 and 6.9 nM, respectively. Further, antagonist 92 displayed promising analgesic activity in vivo in both phases of the formalin mouse pain model. A molecular modeling study of 92 indicated that the two fluoro groups in the A-region made hydrophobic interactions with the receptor.

Keywords: Analgesic; TRPV1 Antagonist; Vanilloid Receptor 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / chemistry
  • Acetamides / pharmacology*
  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Animals
  • Dose-Response Relationship, Drug
  • Humans
  • Mice
  • Molecular Structure
  • Structure-Activity Relationship
  • TRPV Cation Channels / antagonists & inhibitors*
  • TRPV Cation Channels / metabolism

Substances

  • Acetamides
  • Amides
  • TRPV Cation Channels
  • TRPV1 protein, human
  • TRPV1 protein, mouse
  • acetamide