Selective CB2 agonists with anti-pruritic activity: discovery of potent and orally available bicyclic 2-pyridones

Bioorg Med Chem. 2013 Jun 1;21(11):3154-63. doi: 10.1016/j.bmc.2013.03.030. Epub 2013 Mar 30.

Abstract

The CB2 receptor has emerged as a potential target for the treatment of pruritus as well as pain without CB1-mediated side effects. We previously identified 2-pyridone derivatives 1 and 2 as potent CB2 agonists; however, this series of compounds was found to have unacceptable pharmacokinetic profiles with no significant effect in vivo. To improve these profiles, we performed further structural optimization of 1 and 2, which led to the discovery of bicyclic 2-pyridone 18e with improved CB2 affinity and selectivity over CB1. In a mouse pruritus model, 18e inhibited compound 48/80 induced scratching behavior at a dose of 100 mg/kg. In addition, the docking model of 18e with an active-state CB2 homology model indicated the structural basis of its high affinity and selectivity over CB1.

MeSH terms

  • Administration, Oral
  • Animals
  • Antipruritics / chemical synthesis*
  • Antipruritics / pharmacokinetics
  • Antipruritics / pharmacology
  • Behavior, Animal / drug effects
  • Bridged Bicyclo Compounds / chemical synthesis*
  • Bridged Bicyclo Compounds / pharmacokinetics
  • Bridged Bicyclo Compounds / pharmacology
  • CHO Cells
  • Cricetulus
  • Disease Models, Animal
  • Drug Discovery
  • Mice
  • Mice, Inbred ICR
  • Molecular Docking Simulation
  • Pruritus / drug therapy*
  • Pruritus / metabolism
  • Pruritus / physiopathology
  • Pyridones / chemical synthesis*
  • Pyridones / pharmacokinetics
  • Pyridones / pharmacology
  • Receptor, Cannabinoid, CB1 / chemistry
  • Receptor, Cannabinoid, CB2 / agonists*
  • Receptor, Cannabinoid, CB2 / chemistry
  • Receptor, Cannabinoid, CB2 / metabolism
  • Structure-Activity Relationship

Substances

  • Antipruritics
  • Bridged Bicyclo Compounds
  • Pyridones
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2