Imidazopyridine CB2 agonists: optimization of CB2/CB1 selectivity and implications for in vivo analgesic efficacy

B Wesley Trotter; Kausik K Nanda; Christopher S Burgey; Craig M Potteiger; James Z Deng; Ahren I Green; John C Hartnett; Nathan R Kett; Zhicai Wu; Darrell A Henze; Kimberly Della Penna; Reshma Desai; Michael D Leitl; Wei Lemaire; Rebecca B White; Suzie Yeh; Mark O Urban; Stefanie A Kane; George D Hartman; Mark T Bilodeau

doi:10.1016/j.bmcl.2011.02.082

Imidazopyridine CB2 agonists: optimization of CB2/CB1 selectivity and implications for in vivo analgesic efficacy

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2354-8. doi: 10.1016/j.bmcl.2011.02.082. Epub 2011 Mar 1.

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Boston, MA, USA. bwesley_trotter@merck.com

PMID: 21420860
DOI: 10.1016/j.bmcl.2011.02.082

Abstract

A new series of imidazopyridine CB2 agonists is described. Structural optimization improved CB2/CB1 selectivity in this series and conferred physical properties that facilitated high in vivo exposure, both centrally and peripherally. Administration of a highly selective CB2 agonist in a rat model of analgesia was ineffective despite substantial CNS exposure, while administration of a moderately selective CB2/CB1 agonist exhibited significant analgesic effects.

MeSH terms

Analgesics / chemical synthesis
Analgesics / chemistry*
Analgesics / therapeutic use
Animals
Disease Models, Animal
Freund's Adjuvant / pharmacology
Humans
Hyperalgesia / drug therapy
Pyridines / chemical synthesis
Pyridines / chemistry*
Pyridines / therapeutic use
Rats
Receptor, Cannabinoid, CB1 / agonists*
Receptor, Cannabinoid, CB1 / metabolism
Receptor, Cannabinoid, CB2 / agonists*
Receptor, Cannabinoid, CB2 / metabolism

Substances

Analgesics
Pyridines
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2
Freund's Adjuvant
pyridine