Fatty acid amide hydrolase inhibitors. 3: tetra-substituted azetidine ureas with in vivo activity

Bioorg Med Chem Lett. 2012 Jan 15;22(2):901-6. doi: 10.1016/j.bmcl.2011.12.032. Epub 2011 Dec 13.

Abstract

We describe here our attempts to optimise the human fatty acid amide hydrolase (FAAH) inhibition and physicochemical properties of our previously reported tetrasubstituted azetidine urea FAAH inhibitor, VER-156084. We describe the SAR of a series of analogues and conclude with the demonstration of in vivo dose-dependant FAAH inhibition in an anandamide-loading study in rats.

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / metabolism
  • Animals
  • Azetidines / chemical synthesis
  • Azetidines / chemistry
  • Azetidines / pharmacology*
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism
  • Dose-Response Relationship, Drug
  • ERG1 Potassium Channel
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship
  • Urea / chemical synthesis
  • Urea / chemistry
  • Urea / pharmacology*

Substances

  • Azetidines
  • Cytochrome P-450 Enzyme Inhibitors
  • ERG1 Potassium Channel
  • Enzyme Inhibitors
  • Ether-A-Go-Go Potassium Channels
  • azetidine
  • Urea
  • Cytochrome P-450 Enzyme System
  • Amidohydrolases
  • fatty-acid amide hydrolase