Discovery of 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-4-carboxamides as potent and selective CB2 receptor agonists

Bioorg Med Chem Lett. 2015 Jan 15;25(2):322-6. doi: 10.1016/j.bmcl.2014.11.040. Epub 2014 Nov 26.

Abstract

The design and synthesis of novel 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-4-carboxamide CB2 selective ligands for the potential treatment of pain is described. Compound (R,R)-25 has good balance between CB2 agonist potency and selectivity over CB1, and possesses overall favorable pharmaceutical properties. It also demonstrated robust in vivo efficacy mediated via CB2 activation in the rodent models of inflammatory and osteoarthritis pain after oral administration.

Keywords: CB2 agonist; Cannabinoid 2 receptor; Pain.

MeSH terms

  • Administration, Oral
  • Analgesics, Non-Narcotic / administration & dosage
  • Analgesics, Non-Narcotic / chemistry
  • Analgesics, Non-Narcotic / pharmacology*
  • Animals
  • Arthritis, Experimental / drug therapy
  • Arthritis, Experimental / metabolism
  • Heterocyclic Compounds, 3-Ring / administration & dosage
  • Heterocyclic Compounds, 3-Ring / chemistry
  • Heterocyclic Compounds, 3-Ring / pharmacology*
  • Humans
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Male
  • Microsomes, Liver / drug effects*
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Molecular Structure
  • Osteoarthritis / drug therapy*
  • Osteoarthritis / metabolism
  • Pain / drug therapy*
  • Pain / metabolism
  • Pyrazoles / administration & dosage
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB2 / agonists*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Analgesics, Non-Narcotic
  • Heterocyclic Compounds, 3-Ring
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2