beta-Lactams derived from a carbapenem chiron are selective inhibitors of human fatty acid amide hydrolase versus human monoacylglycerol lipase

J Med Chem. 2009 Nov 26;52(22):7054-68. doi: 10.1021/jm9008532.

Abstract

A library of 30 beta-lactams has been prepared from (3R,4R)-3-[(R)-1'-(tbutyldimethylsilyloxy)-ethyl]-4-acetoxy-2-azetidinone, and the corresponding deacetoxy derivative, by sequential N- and O-functionalizations with various omega-alkenoyl and omega-arylalkanoyl chains. All compounds were selective inhibitors of hFAAH versus hMGL, and IC(50) values in the nanomolar range (5-14 nM) were recorded for the best representatives. From time-dependent preincubation and rapid dilution studies, and from docking analyses in a homology model of the target enzyme, a reversible mechanism of inhibition of hFAAH is proposed.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / chemistry
  • Amidohydrolases / metabolism
  • Carbapenems / chemical synthesis
  • Carbapenems / chemistry*
  • Carbapenems / metabolism
  • Carbapenems / pharmacology*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Conformation
  • Monoacylglycerol Lipases / antagonists & inhibitors*
  • Monoacylglycerol Lipases / chemistry
  • Monoacylglycerol Lipases / metabolism

Substances

  • Carbapenems
  • Enzyme Inhibitors
  • Monoacylglycerol Lipases
  • Amidohydrolases
  • fatty-acid amide hydrolase