α-Ketoheterocycle inhibitors of fatty acid amide hydrolase: exploration of conformational constraints in the acyl side chain

Bioorg Med Chem. 2014 May 1;22(9):2763-70. doi: 10.1016/j.bmc.2014.03.013. Epub 2014 Mar 18.

Abstract

A series of α-ketooxazoles containing heteroatoms embedded within conformational constraints in the C2 acyl side chain of 2 (OL-135) were synthesized and evaluated as inhibitors of fatty acid amide hydrolase (FAAH). The studies reveal that the installation of a heteroatom (O) in the conformational constraint is achievable, although the potency of these novel derivatives is reduced slightly relative to 2 and the analogous 1,2,3,4-tetrahydronaphthalene series. Interestingly, both enantiomers (R and S) of the candidate inhibitors bearing a chiral center adjacent to the electrophilic carbonyl were found to effectively inhibit FAAH.

Keywords: Fatty acid amide hydrolase; α-Ketoheterocycles.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / metabolism
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Mice
  • Molecular Conformation
  • Oxazoles / chemical synthesis
  • Oxazoles / chemistry
  • Oxazoles / pharmacology
  • Proteome / drug effects
  • Stereoisomerism
  • Tetrahydronaphthalenes / chemical synthesis
  • Tetrahydronaphthalenes / chemistry
  • Tetrahydronaphthalenes / pharmacology

Substances

  • Enzyme Inhibitors
  • Oxazoles
  • Proteome
  • Tetrahydronaphthalenes
  • Amidohydrolases
  • fatty-acid amide hydrolase
  • tetralin