1-Aryl-2-((6-aryl)pyrimidin-4-yl)amino)ethanols as competitive inhibitors of fatty acid amide hydrolase

Bioorg Med Chem Lett. 2014 Mar 1;24(5):1280-4. doi: 10.1016/j.bmcl.2014.01.064. Epub 2014 Jan 31.

Abstract

A series of 1-aryl-2-(((6-aryl)pyrimidin-4-yl)amino)ethanols have been found to be competitive inhibitors of fatty acid amide hydrolase (FAAH). One member of this class, JNJ-40413269, was found to have excellent pharmacokinetic properties, demonstrated robust central target engagement, and was efficacious in a rat model of neuropathic pain.

Keywords: Analgesia; Crystal structure; Endo-cannabinoids; Enzymes; Fatty acid amide hydrolase (FAAH).

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / metabolism
  • Amino Alcohols / chemistry*
  • Amino Alcohols / pharmacokinetics
  • Amino Alcohols / therapeutic use
  • Analgesics / chemistry*
  • Analgesics / pharmacokinetics
  • Analgesics / therapeutic use
  • Animals
  • Binding Sites
  • Brain / metabolism
  • Catalytic Domain
  • Disease Models, Animal
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / therapeutic use
  • Half-Life
  • Humans
  • Molecular Docking Simulation
  • Neuralgia / drug therapy
  • Protein Binding
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / therapeutic use
  • Rats
  • Structure-Activity Relationship

Substances

  • Amino Alcohols
  • Analgesics
  • Enzyme Inhibitors
  • JNJ-40413269
  • Pyrimidines
  • Amidohydrolases
  • fatty-acid amide hydrolase
  • pyrimidine