Discovery of indane propanamides as potent and selective TRPV1 antagonists

Bioorg Med Chem Lett. 2020 Feb 1;30(3):126838. doi: 10.1016/j.bmcl.2019.126838. Epub 2019 Dec 3.

Abstract

A series of indane-type acetamide and propanamide analogues were investigated as TRPV1 antagonists. The analysis of structure-activity relationship indicated that indane A-region analogues exhibited better antagonism than did the corresponding 2,3-dihydrobenzofuran and 1,3-benzodioxole surrogates. Among them, antagonist 36 exhibited potent and selective antagonism toward capsaicin for hTRPV1 and mTRPV1. Further, in vivo studies indicated that antagonist 36 showed excellent analgesic activity in both phases of the formalin mouse pain model and inhibited the pain behavior completely at a dose of 1 mg/kg in the 2nd phase.

Keywords: Analgesic; TRPV1 antagonist; Vanilloid receptor 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / chemistry
  • Acetamides / metabolism
  • Acetamides / therapeutic use
  • Amides / chemistry*
  • Amides / metabolism
  • Amides / therapeutic use
  • Analgesics / chemistry
  • Analgesics / therapeutic use
  • Animals
  • Capsaicin / chemistry
  • Capsaicin / metabolism
  • Drug Design
  • Drug Evaluation, Preclinical
  • Humans
  • Indans / chemistry*
  • Mice
  • Pain / chemically induced
  • Pain / drug therapy
  • Pyridines / chemistry
  • Structure-Activity Relationship
  • TRPV Cation Channels / antagonists & inhibitors*
  • TRPV Cation Channels / metabolism

Substances

  • Acetamides
  • Amides
  • Analgesics
  • Indans
  • Pyridines
  • TRPV Cation Channels
  • acetamide
  • indan
  • Capsaicin