Pyrazole phenylcyclohexylcarbamates as inhibitors of human fatty acid amide hydrolases (FAAH)

Eur J Med Chem. 2015 Jun 5:97:289-305. doi: 10.1016/j.ejmech.2015.04.064. Epub 2015 May 5.

Abstract

Fatty acid amide hydrolase (FAAH) inhibitors have gained attention as potential therapeutic targets in the management of neuropathic pain. Here, we report a series of pyrazole phenylcyclohexylcarbamate derivatives standing on the known carbamoyl FAAH inhibitor URB597. Structural modifications led to the recognition of compound 22 that inhibited human recombinant FAAH (hrFAAH) in the low nanomolar range (IC50 = 11 nM). The most active compounds of this series showed significant selectivity toward monoacylglycerol lipase (MAGL) enzyme. In addition, molecular modeling and reversibility behavior of the new class of FAAH inhibitors are presented in this article.

Keywords: FAAH inhibitors; Molecular modeling; Pyrazole phenylcyclohexylcarbamate; Reversibility.

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Structure
  • Pyrazoles / chemistry*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Pyrazoles
  • pyrazole
  • Amidohydrolases
  • fatty-acid amide hydrolase