Selective CB2 receptor agonists. Part 3: the optimization of a piperidine-based series that demonstrated efficacy in an in vivo neuropathic pain model

Bioorg Med Chem Lett. 2015 Feb 1;25(3):587-92. doi: 10.1016/j.bmcl.2014.12.031. Epub 2014 Dec 17.

Abstract

A novel class of potent cannabinoid receptor 2 (CB2) agonists based on a (S)-piperidine scaffold was identified using ligand-based pharmacophore models. Optimization of solubility and metabolic stability led to the identification of several potent CB2 agonists (e.g., 30) that displayed selectivity over cannabinoid receptor 1 (CB1) and acceptable drug like properties. In rats, compound 30 demonstrated a favorable pharmacokinetic profile and efficacy in a Streptozotocin-induced diabetic neuropathy model, with full reversal of mechanical hyperalgesia.

Keywords: CB1; CB2; Cannabinoid receptor; Metabolic stability; Piperidine; Solubility.

MeSH terms

  • Animals
  • Diabetic Neuropathies / chemically induced
  • Diabetic Neuropathies / drug therapy
  • Half-Life
  • Humans
  • Ligands
  • Male
  • Microsomes, Liver / metabolism
  • Pain / drug therapy
  • Pipecolic Acids / chemistry*
  • Pipecolic Acids / pharmacokinetics
  • Pipecolic Acids / therapeutic use
  • Piperidines / chemistry*
  • Piperidines / pharmacokinetics
  • Piperidines / therapeutic use
  • Protein Binding
  • Rats
  • Rats, Wistar
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptor, Cannabinoid, CB2 / agonists*
  • Receptor, Cannabinoid, CB2 / metabolism
  • Solubility
  • Structure-Activity Relationship
  • Thiazines / chemistry*
  • Thiazines / pharmacokinetics
  • Thiazines / therapeutic use

Substances

  • Ligands
  • Pipecolic Acids
  • Piperidines
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Thiazines
  • piperidine