title: Selective CB2 agonists with anti-pruritic activity: discovery of potent and orally available bicyclic 2-pyridones.
abstract: The CB2 receptor has emerged as a potential target for the treatment of pruritus as well as pain without CB1-mediated side effects. We previously identified 2-pyridone derivatives 1 and 2 as potent CB2 agonists; however, this series of compounds was found to have unacceptable pharmacokinetic profiles with no significant effect in vivo. To improve these profiles, we performed further structural optimization of 1 and 2, which led to the discovery of bicyclic 2-pyridone 18e with improved CB2 affinity and selectivity over CB1. In a mouse pruritus model, 18e inhibited compound 48/80 induced scratching behavior at a dose of 100 mg/kg. In addition, the docking model of 18e with an active-state CB2 homology model indicated the structural basis of its high affinity and selectivity over CB1.
authors.affiliation: Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 11-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan. ken-ichi.kusakabe@shionogi.co.jp
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Kusakabe
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Iso
authors.forename: Yukio
authors.initials: Y
authors.lastname: Tada
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakagami
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Morioka
authors.forename: Nobuo
authors.initials: N
authors.lastname: Chomei
authors.forename: Satomi
authors.initials: S
authors.lastname: Shinonome
authors.forename: Keiko
authors.initials: K
authors.lastname: Kawamoto
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takenaka
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yasui
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hamana
authors.forename: Kohji
authors.initials: K
authors.lastname: Hanasaki
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000982:Antipruritics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D016466:CHO Cells; D003412:Cricetulus; D004195:Disease Models, Animal; D055808:Drug Discovery; D051379:Mice; D008813:Mice, Inbred ICR; D062105:Molecular Docking Simulation; D011537:Pruritus / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011728:Pyridones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000737:chemistry; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000982:Antipruritics; D001643:Bridged Bicyclo Compounds; D011728:Pyridones; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2