Heteroarylureas with fused bicyclic diamine cores as inhibitors of fatty acid amide hydrolase

Bioorg Med Chem Lett. 2020 Oct 15;30(20):127463. doi: 10.1016/j.bmcl.2020.127463. Epub 2020 Aug 9.

Abstract

A series of mechanism-based heteroaryl urea fatty acid amide hydrolase (FAAH) inhibitors with fused bicyclic diamine cores is described. In contrast to compounds built around a piperazine core, most of the fused bicyclic diamine bearing analogs prepared exhibited greater potency against rFAAH than the human enzyme. Several compounds equipotent against both species were identified and profiled in vivo.

Keywords: Anandamide; Aryl urea; Covalent inhibitor; Endocannabinoid; Enzyme; FAAH; Inhibitors; Serine hydrolase.

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / metabolism
  • Animals
  • Diamines / chemistry
  • Diamines / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Structure
  • Rats
  • Structure-Activity Relationship
  • Urea / analogs & derivatives
  • Urea / chemistry
  • Urea / pharmacology*

Substances

  • Diamines
  • Enzyme Inhibitors
  • Urea
  • Amidohydrolases
  • fatty-acid amide hydrolase