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Design, synthesis, and binding mode prediction of 2-pyridone-based selective CB2 receptor agonists.
Kusakabe, Ken-ichi; Tada, Yukio; Iso, Yasuyoshi; Sakagami, Masahiro; Morioka, Yasuhide; Chomei, Nobuo; Shinonome, Satomi; Kawamoto, Keiko; Takenaka, Hideyuki; Yasui, Kiyoshi; Hamana, Hiroshi; Hanasaki, Kohji.
Afiliação
  • Kusakabe K; Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 11-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan. ken-ichi.kusakabe@shionogi.co.jp
Bioorg Med Chem ; 21(7): 2045-55, 2013 Apr 01.
Article em En | MEDLINE | ID: mdl-23395112
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piridonas / Desenho de Fármacos / Receptor CB2 de Canabinoide Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Bioorg Med Chem Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2013 Tipo de documento: Article País de afiliação: Japão

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piridonas / Desenho de Fármacos / Receptor CB2 de Canabinoide Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Bioorg Med Chem Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2013 Tipo de documento: Article País de afiliação: Japão