Discovery of potent, soluble and orally active TRPV1 antagonists. Structure-activity relationships of a series of isoxazoles

Bioorg Med Chem Lett. 2011 Aug 1;21(15):4652-7. doi: 10.1016/j.bmcl.2011.01.051. Epub 2011 Jan 26.

Abstract

Systematic optimisation of a poorly soluble lead series of isoxazole-3-carboxamides was conducted. Substitution of the 4-position with specific polar functionality afforded the requisite balance of potency, solubility and physicochemical properties. Compound 21a was found to be efficacious in the rat Capsaicin Hargreaves assay following oral administration.

MeSH terms

  • Administration, Oral
  • Amides / chemistry
  • Amides / pharmacokinetics
  • Amides / therapeutic use
  • Animals
  • Capsaicin / toxicity
  • Cyclohexanols / chemistry*
  • Cyclohexanols / pharmacokinetics
  • Cyclohexanols / therapeutic use
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Humans
  • Hyperalgesia / chemically induced
  • Hyperalgesia / drug therapy
  • Isoxazoles / chemistry*
  • Isoxazoles / pharmacokinetics
  • Isoxazoles / therapeutic use
  • Microsomes, Liver / metabolism
  • Rats
  • Structure-Activity Relationship
  • TRPV Cation Channels / antagonists & inhibitors*
  • TRPV Cation Channels / metabolism

Substances

  • Amides
  • Cyclohexanols
  • Isoxazoles
  • TRPV Cation Channels
  • Capsaicin