title: Imine derivatives as new potent and selective CB2 cannabinoid receptor agonists with an analgesic action.
abstract: In this study, a novel series of CB(2) receptor agonist imine derivatives, 1-6, was synthesized and evaluated for activity against the CB(2) receptor. In a previous paper we reported the synthesis and SARs of thiazole derivative 1, a potent CB(2) receptor agonist, but we had not assessed chemical modifications of the 5-membered heteroring of 1. In the present study, we therefore tried chemically modifying the 5-membered heteroring of 1 in an attempt to further improve binding affinity for the CB(2) receptor. In the course of making the structural modifications, we discovered that a novel pyrazole derivative 6b (CBS0550) had high affinity for the CB(2) receptor (IC(50)=2.9 nM, EC(50)=1.8 nM, E(max)=85%), high selectivity for CB(2) (CB(1) IC(50)/CB(2) IC(50)=1400), and good physicochemical properties (solubility in water: 5.9 mg/100mL at 25 degrees C). Oral administration of 6b to rats at a dose of 10mg/kg resulted in significant plasma concentrations, and orally administered compound 6b significantly reversed mechanical hyperalgesia in the Randall-Selitto model of inflammatory pain in rats.
authors.affiliation: Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, Saitama-shi, Saitama 331-9530, Japan. hiroshi.ohta@po.rd.taisho.co.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohta
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ishizaka
authors.forename: Makoto
authors.initials: M
authors.lastname: Tatsuzuki
authors.forename: Mitsukane
authors.initials: M
authors.lastname: Yoshinaga
authors.forename: Izumi
authors.initials: I
authors.lastname: Iida
authors.forename: Tomomi
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Yasumitsu
authors.initials: Y
authors.lastname: Tomishima
authors.forename: Nobuko
authors.initials: N
authors.lastname: Futaki
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Toda
authors.forename: Shuji
authors.initials: S
authors.lastname: Saito
mesh_terms: D000818:Animals; D006801:Humans; D007097:Imines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D007097:Imines; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; C031280:pyrazole