title: Imidazopyridine CB2 agonists: optimization of CB2/CB1 selectivity and implications for in vivo analgesic efficacy.
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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Boston, MA, USA. bwesley_trotter@merck.com
authors.forename: B Wesley
authors.initials: BW
authors.lastname: Trotter
authors.forename: Kausik K
authors.initials: KK
authors.lastname: Nanda
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Burgey
authors.forename: Craig M
authors.initials: CM
authors.lastname: Potteiger
authors.forename: James Z
authors.initials: JZ
authors.lastname: Deng
authors.forename: Ahren I
authors.initials: AI
authors.lastname: Green
authors.forename: John C
authors.initials: JC
authors.lastname: Hartnett
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Kett
authors.forename: Zhicai
authors.initials: Z
authors.lastname: Wu
authors.forename: Darrell A
authors.initials: DA
authors.lastname: Henze
authors.forename: Kimberly
authors.initials: K
authors.lastname: Della Penna
authors.forename: Reshma
authors.initials: R
authors.lastname: Desai
authors.forename: Michael D
authors.initials: MD
authors.lastname: Leitl
authors.forename: Wei
authors.initials: W
authors.lastname: Lemaire
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: White
authors.forename: Suzie
authors.initials: S
authors.lastname: Yeh
authors.forename: Mark O
authors.initials: MO
authors.lastname: Urban
authors.forename: Stefanie A
authors.initials: SA
authors.lastname: Kane
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bilodeau
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000494:pharmacology; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism
chemical_list: D000700:Analgesics; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D005620:Freund's Adjuvant; C023666:pyridine