title: Design, synthesis, and binding mode prediction of 2-pyridone-based selective CB2 receptor agonists.
abstract: Selective CB2 agonists have the potential for treating pain without central CB1-mediated adverse effects. Screening efforts identified 1,2-dihydro-3-isoquinolone 1; however, this compound has the drawbacks of being difficult to synthesize with two asymmetric carbons on an isoquinolone scaffold and of having a highly lipophilic physicochemical property. To address these two major problems, we designed the 2-pyridone-based lead 15a, which showed moderate affinity for CB2. Optimization of 15a led to identification of 39f with high affinity for CB2 and selectivity over CB1. Prediction of the binding mode of 39f in complex with an active-state CB2 homology model provided structural insights into its high affinity for CB2.
authors: 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: Ken-ichi
authors: K
authors: Kusakabe
authors: Yukio
authors: Y
authors: Tada
authors: Yasuyoshi
authors: Y
authors: Iso
authors: Masahiro
authors: M
authors: Sakagami
authors: Yasuhide
authors: Y
authors: Morioka
authors: Nobuo
authors: N
authors: Chomei
authors: Satomi
authors: S
authors: Shinonome
authors: Keiko
authors: K
authors: Kawamoto
authors: Hideyuki
authors: H
authors: Takenaka
authors: Kiyoshi
authors: K
authors: Yasui
authors: Hiroshi
authors: H
authors: Hamana
authors: Kohji
authors: K
authors: Hanasaki
mesh_terms: D020134:Catalytic Domain; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D011728:Pyridones; D043885:Receptor, Cannabinoid, CB2; D011994:Recombinant Proteins; C017679:2-hydroxypyridine