Bis(dialkylaminethiocarbonyl)disulfides as Potent and Selective Monoglyceride Lipase Inhibitors

J Med Chem. 2009 Nov 26;52(22):7310-4. doi: 10.1021/jm901323s.

Abstract

Monoglyceride lipase (MGL) inhibition may offer an approach in treating diseases in which higher 2-arachidonoyglycerol activity would be beneficial. We report here the synthesis and pharmacological evaluation of bis(dialkylaminethiocarbonyl)disulfide derivatives as irreversible MGL inhibitors. Inhibition occurs through interactions with MGL C208 and C242 residues, and these derivatives exhibit high inhibition selectivity over fatty acid amide hydrolase, another endocannabinoid-hydrolyzing enzyme.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors
  • Disulfides / chemical synthesis
  • Disulfides / chemistry*
  • Disulfides / pharmacology*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Monoacylglycerol Lipases / antagonists & inhibitors*
  • Monoacylglycerol Lipases / chemistry
  • Monoacylglycerol Lipases / genetics
  • Monoacylglycerol Lipases / metabolism
  • Mutation
  • Nitrogen / chemistry
  • Oxidation-Reduction
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • Disulfides
  • Enzyme Inhibitors
  • Monoacylglycerol Lipases
  • Amidohydrolases
  • fatty-acid amide hydrolase
  • Nitrogen