Discovery of S-444823, a potent CB1/CB2 dual agonist as an antipruritic agent

Bioorg Med Chem Lett. 2012 Apr 15;22(8):2898-901. doi: 10.1016/j.bmcl.2012.02.050. Epub 2012 Feb 23.

Abstract

The optimization of a series of 3-carbamoyl 2-pyridone derivatives as CB agonists is reported. These efforts resulted in the discovery of 3-(2-(1-(cyclohexylmethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocycloocta[b]pyridine-3-carboxamido)thiazol-4-yl)propanoic acid (21), a potent dual CB1/CB2 agonist without CNS side effects induced by CB1 receptor activation. It exhibited strong inhibition of scratching as a 1.0% acetone solution in the pruritic model.

MeSH terms

  • Animals
  • Antipruritics / chemistry*
  • Antipruritics / pharmacology
  • CHO Cells
  • Cricetinae
  • Drug Discovery*
  • Humans
  • Mice
  • Protein Binding / drug effects
  • Pyridones / agonists*
  • Pyridones / chemistry
  • Pyridones / pharmacology
  • Receptor, Cannabinoid, CB1 / agonists*
  • Receptor, Cannabinoid, CB2 / agonists*
  • Thiazoles / agonists*
  • Thiazoles / chemistry
  • Thiazoles / pharmacology

Substances

  • Antipruritics
  • Pyridones
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • S-444823
  • Thiazoles