Structure-activity studies of a novel series of isoxazole-3-carboxamide derivatives as TRPV1 antagonists

Bioorg Med Chem Lett. 2011 Feb 1;21(3):892-8. doi: 10.1016/j.bmcl.2010.12.092. Epub 2010 Dec 23.

Abstract

Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / pharmacokinetics
  • Animals
  • Antihypertensive Agents / chemical synthesis
  • Antihypertensive Agents / chemistry*
  • Antihypertensive Agents / pharmacokinetics
  • Cyclohexanols / chemical synthesis
  • Cyclohexanols / chemistry*
  • Cyclohexanols / pharmacokinetics
  • Hyperthermia, Induced
  • Isoxazoles / chemical synthesis
  • Isoxazoles / chemistry*
  • Isoxazoles / pharmacokinetics
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship
  • TRPV Cation Channels / antagonists & inhibitors*
  • TRPV Cation Channels / metabolism

Substances

  • Amides
  • Antihypertensive Agents
  • Cyclohexanols
  • Isoxazoles
  • TRPV Cation Channels
  • Trpv1 protein, rat