title: Discovery and optimization of a novel series of N-arylamide oxadiazoles as potent, highly selective and orally bioavailable cannabinoid receptor 2 (CB2) agonists.
abstract: The CB2 receptor is an attractive therapeutic target for analgesic and anti-inflammatory agents. Herein we describe the discovery of a novel class of oxadiazole derivatives from which potent and selective CB2 agonist leads were developed. Initial hit 7 was identified from a cannabinoid target-biased library generated by virtual screening of sample collections using a pharmacophore model in combination with a series of physicochemical filters. 7 was demonstrated to be a selective CB2 agonist (CB2 EC50 = 93 nM, Emax = 98%, CB1 EC50 > 10 microM). However, this compound exhibited poor solubility and relatively high clearance in rat, resulting in low oral bioavailability. In this paper, we report detailed SAR studies on 7 en route toward improving potency, physicochemical properties, and solubility. This effort resulted in identification of 63 that is a potent and selective agonist at CB2 (EC50 = 2 nM, Emax = 110%) with excellent pharmacokinetic properties.
authors.affiliation: Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. yuanc@amgen.com
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Brian K
authors.initials: BK
authors.lastname: Albrecht
authors.forename: James
authors.initials: J
authors.lastname: Brown
authors.forename: John L
authors.initials: JL
authors.lastname: Buchanan
authors.forename: William H
authors.initials: WH
authors.lastname: Buckner
authors.forename: Erin F
authors.initials: EF
authors.lastname: DiMauro
authors.forename: Renee
authors.initials: R
authors.lastname: Emkey
authors.forename: Robert T
authors.initials: RT
authors.lastname: Fremeau
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
authors.forename: Beth J
authors.initials: BJ
authors.lastname: Hoffman
authors.forename: Liyue
authors.initials: L
authors.lastname: Huang
authors.forename: Ming
authors.initials: M
authors.lastname: Huang
authors.forename: Josie Han
authors.initials: JH
authors.lastname: Lee
authors.forename: Fen-Fen
authors.initials: FF
authors.lastname: Lin
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Martin
authors.forename: Hung Q
authors.initials: HQ
authors.lastname: Nguyen
authors.forename: Vinod F
authors.initials: VF
authors.lastname: Patel
authors.forename: Susan A
authors.initials: SA
authors.lastname: Tomlinson
authors.forename: Ryan D
authors.initials: RD
authors.lastname: White
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Xia
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Hitchcock
mesh_terms: D000284:Administration, Oral; D000634:Aminoquinolines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008958:Models, Molecular; D010069:Oxadiazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C531231:6-chloro-N-(3-(3-(2-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5-yl)propyl)quinolin-3-amine; D000634:Aminoquinolines; D010069:Oxadiazoles; D043885:Receptor, Cannabinoid, CB2