N-aryl 2-aryloxyacetamides as a new class of fatty acid amide hydrolase (FAAH) inhibitors

J Enzyme Inhib Med Chem. 2017 Dec;32(1):513-521. doi: 10.1080/14756366.2016.1265520.

Abstract

Fatty acid amide hydrolase (FAAH) is a promising target for the development of drugs to treat neurological diseases. In search of new FAAH inhibitors, we identified 2-(4-cyclohexylphenoxy)-N-(3-(oxazolo[4,5-b]pyridin-2-yl)phenyl)acetamide, 4g, with an IC50 of 2.6 µM as a chemical starting point for the development of potent FAAH inhibitors. Preliminary hit-to-lead optimisation resulted in 2-(4-phenylphenoxy)-N-(3-(oxazolo[4,5-b]pyridin-2-yl)phenyl)acetamide, 4i, with an IC50 of 0.35 µM.

Keywords: 1H-imidazo[4,5-b]pyridine anilines; Fatty acid amide hydrolase inhibitors; endocannabinoid system; oxazolo[4,5-b]pyridine anilines.

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / chemistry
  • Acetamides / pharmacology*
  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / metabolism
  • Animals
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Rats
  • Structure-Activity Relationship

Substances

  • Acetamides
  • Enzyme Inhibitors
  • Amidohydrolases
  • fatty-acid amide hydrolase

Grants and funding

Knut och Alice Wallenbergs Stiftelse, 10.13039/501100004063 [2008.0064]; Vetenskapsrådet, 10.13039/501100004359 [521-2012-2802].