The discovery of azetidine-piperazine di-amides as potent, selective and reversible monoacylglycerol lipase (MAGL) inhibitors

Bioorg Med Chem Lett. 2020 Jul 15;30(14):127243. doi: 10.1016/j.bmcl.2020.127243. Epub 2020 May 7.

Abstract

Monoacylglycerol lipase (MAGL) is the enzyme that is primarily responsible for hydrolyzing the endocannabinoid 2-arachidononylglycerol (2-AG) to arachidonic acid (AA). It has emerged in recent years as a potential drug target for a number of diseases. Herein, we report the discovery of compound 6g from a series of azetidine-piperazine di-amide compounds as a potent, selective, and reversible inhibitor of MAGL. Oral administration of compound 6g increased 2-AG levels in rat brain and produced full efficacy in the rat complete Freund's adjuvant (CFA) model of inflammatory pain.

Keywords: 2-Arachidonoylglycerol (2-AG); MAGL inhibition; Monoacylglycerol lipase (MAGL); Reversible MAGL inhibitor.

MeSH terms

  • Amides / chemistry
  • Amides / pharmacology*
  • Azetidines / chemistry
  • Azetidines / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Monoacylglycerol Lipases / antagonists & inhibitors*
  • Monoacylglycerol Lipases / metabolism
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Amides
  • Azetidines
  • Enzyme Inhibitors
  • Piperazines
  • azetidine
  • Monoacylglycerol Lipases