Loratadine analogues as MAGL inhibitors

Bioorg Med Chem Lett. 2015 Apr 1;25(7):1436-42. doi: 10.1016/j.bmcl.2015.02.037. Epub 2015 Feb 24.

Abstract

Compound 12a (JZP-361) acted as a potent and reversible inhibitor of human recombinant MAGL (hMAGL, IC50=46 nM), and was found to have almost 150-fold higher selectivity over human recombinant fatty acid amide hydrolase (hFAAH, IC50=7.24 μM) and 35-fold higher selectivity over human α/β-hydrolase-6 (hABHD6, IC50=1.79 μM). Additionally, compound 12a retained H1 antagonistic affinity (pA2=6.81) but did not show cannabinoid receptor activity, when tested at concentrations ⩽ 10 μM. Hence, compound 12a represents a novel dual-acting pharmacological tool possessing both MAGL-inhibitory and antihistaminergic activities.

Keywords: 2-Arachidonoyl glycerol; Fatty acid amide hydrolase; Loratadine; Monoacylglycerol lipase; α/β hydrolase-6.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors
  • Amidohydrolases / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Loratadine / chemical synthesis
  • Loratadine / chemistry
  • Loratadine / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Monoacylglycerol Lipases / antagonists & inhibitors*
  • Monoacylglycerol Lipases / metabolism
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Recombinant Proteins
  • Loratadine
  • Monoacylglycerol Lipases
  • Amidohydrolases
  • fatty-acid amide hydrolase