Discovery of 1-(1H-indazol-4-yl)-3-((1-phenyl-1H-pyrazol-5-yl)methyl) ureas as potent and thermoneutral TRPV1 antagonists

Bioorg Med Chem Lett. 2020 Dec 1;30(23):127548. doi: 10.1016/j.bmcl.2020.127548. Epub 2020 Sep 12.

Abstract

A series of 1-indazol-3-(1-phenylpyrazol-5-yl)methyl ureas were investigated as hTRPV1 antagonists. The structure-activity relationship study was conducted systematically for both the indazole A-region and the 3-trifluoromethyl/t-butyl pyrazole C-region to optimize the antagonism toward the activation by capsaicin. Among them, the antagonists 26, 50 and 51 displayed highly potent antagonism with Ki(CAP) = 0.4-0.5 nM. Further, in vivo studies in mice indicated that these derivatives both antagonized capsaicin induced hypothermia, consistent with their in vitro activity, and themselves did not induce hyperthermia. In the formalin model, 51 showed anti-nociceptive activity in a dose-dependent manner.

Keywords: Analgesic; TRPV1 Antagonist; Vanilloid Receptor 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / chemical synthesis
  • Analgesics / pharmacology
  • Animals
  • Body Temperature / drug effects
  • CHO Cells
  • Capsaicin / pharmacology
  • Cricetulus
  • Humans
  • Indazoles / chemical synthesis
  • Indazoles / pharmacology*
  • Methylurea Compounds / chemical synthesis
  • Methylurea Compounds / pharmacology*
  • Mice
  • Molecular Structure
  • Pyrazoles / chemical synthesis
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship
  • TRPV Cation Channels / agonists
  • TRPV Cation Channels / antagonists & inhibitors*

Substances

  • Analgesics
  • Indazoles
  • Methylurea Compounds
  • Pyrazoles
  • TRPV Cation Channels
  • TRPV1 protein, human
  • Capsaicin