Selective CB2 receptor agonists. Part 2: Structure-activity relationship studies and optimization of proline-based compounds

Bioorg Med Chem Lett. 2015 Feb 1;25(3):581-6. doi: 10.1016/j.bmcl.2014.12.019. Epub 2014 Dec 13.

Abstract

Through a ligand-based pharmacophore model (S)-proline based compounds were identified as potent cannabinoid receptor 2 (CB2) agonists with high selectivity over the cannabinoid receptor 1 (CB1). Structure-activity relationship investigations for this compound class lead to oxo-proline compounds 21 and 22 which combine an impressive CB1 selectivity profile with good pharmacokinetic properties. In a streptozotocin induced diabetic neuropathy model, 22 demonstrated a dose-dependent reversal of mechanical hyperalgesia.

Keywords: Cannabinoid receptor 2 (CB2); Metabolic stability; Pharmacokinetic properties; Proline; Solubility.

MeSH terms

  • Animals
  • Diabetic Neuropathies / chemically induced
  • Diabetic Neuropathies / drug therapy
  • Half-Life
  • Humans
  • Isoxazoles / chemistry*
  • Isoxazoles / pharmacokinetics
  • Isoxazoles / therapeutic use
  • Ligands
  • Male
  • Microsomes, Liver / metabolism
  • Proline / chemistry*
  • Proline / pharmacokinetics
  • Proline / therapeutic use
  • Protein Binding
  • Pyrrolidonecarboxylic Acid / analogs & derivatives*
  • Pyrrolidonecarboxylic Acid / chemistry
  • Pyrrolidonecarboxylic Acid / pharmacokinetics
  • Pyrrolidonecarboxylic Acid / therapeutic use
  • Rats
  • Rats, Wistar
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptor, Cannabinoid, CB2 / agonists*
  • Receptor, Cannabinoid, CB2 / metabolism
  • Solubility
  • Structure-Activity Relationship

Substances

  • Isoxazoles
  • Ligands
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Proline
  • Pyrrolidonecarboxylic Acid