Discovery of potent transient receptor potential vanilloid 1 antagonists: design and synthesis of phenoxyacetamide derivatives

Bioorg Med Chem Lett. 2013 Jun 1;23(11):3154-6. doi: 10.1016/j.bmcl.2013.04.016. Epub 2013 Apr 13.

Abstract

We aimed to discover a novel type of transient receptor potential vanilloid 1 (TRPV1) antagonist because such antagonists are possible drug candidates for treating various disorders. We modified the structure of hit compound 7 (human TRPV1 IC50=411 nM) and converted its pyrrolidino group to a (hydroxyethyl)methylamino group, which substantially improved inhibitory activity (15d; human TRPV1 IC50=33 nM). In addition, 15d ameliorated bladder overactivity in rats in vivo.

MeSH terms

  • Acetamides / chemistry*
  • Acetamides / metabolism
  • Acetamides / therapeutic use
  • Aminopyridines / chemistry*
  • Aminopyridines / metabolism
  • Aminopyridines / therapeutic use
  • Animals
  • Capsaicin / toxicity
  • Cystitis / chemically induced
  • Cystitis / drug therapy
  • Drug Design*
  • Drug Evaluation, Preclinical
  • Humans
  • Protein Binding
  • Rats
  • Structure-Activity Relationship
  • TRPV Cation Channels / antagonists & inhibitors*
  • TRPV Cation Channels / metabolism

Substances

  • Acetamides
  • Aminopyridines
  • TRPV Cation Channels
  • TRPV1 protein, human
  • acetamide
  • Capsaicin