title: Optimisation of a novel series of selective CNS penetrant CB(2) agonists.
abstract: A series of benzimidazole CB(2) receptor agonists were prepared and their properties investigated. Optimisation of the three benzimidazole substituents led to the identification of compound 23, a potent CB(2) full agonist (EC(50) 2.7nM) with excellent selectivity over the CB(1) receptor (>3000-fold). Compound 23 demonstrated good CNS penetration in rat. Further optimisation led to the identification of compound 34 with improved selectivity over hERG and excellent CNS penetration in rat.
authors.affiliation: Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom. christine.watson100@gmail.com
authors.forename: Christine
authors.initials: C
authors.lastname: Watson
authors.forename: Dafydd R
authors.initials: DR
authors.lastname: Owen
authors.forename: Denise
authors.initials: D
authors.lastname: Harding
authors.forename: Kana
authors.initials: K
authors.lastname: Kon-I
authors.forename: Mark L
authors.initials: ML
authors.lastname: Lewis
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Mason
authors.forename: Miyako
authors.initials: M
authors.lastname: Matsumizu
authors.forename: Takasuke
authors.initials: T
authors.lastname: Mukaiyama
authors.forename: Margarita
authors.initials: M
authors.lastname: Rodriguez-Lens
authors.forename: Akiko
authors.initials: A
authors.lastname: Shima
authors.forename: Mifune
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Isabelle
authors.initials: I
authors.lastname: Tran
authors.forename: Tim
authors.initials: T
authors.lastname: Young
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D002490:Central Nervous System / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D001562:Benzimidazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C031000:benzimidazole