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Lead generation and optimization of novel GPR119 agonists with a spirocyclic cyclohexane structure.
Harada, Kazuhito; Mizukami, Jun; Watanabe, Takashi; Mori, Genki; Ubukata, Minoru; Suwa, Katsunori; Fukuda, Sumiaki; Negoro, Tamotsu; Sato, Motohide; Inaba, Takashi.
Afiliación
  • Harada K; Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan. Electronic address: kazuhito.harada@jt.com.
  • Mizukami J; Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
  • Watanabe T; Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
  • Mori G; Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
  • Ubukata M; Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
  • Suwa K; Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
  • Fukuda S; Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
  • Negoro T; Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
  • Sato M; Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
  • Inaba T; Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Bioorg Med Chem Lett ; 29(3): 373-379, 2019 02 01.
Article en En | MEDLINE | ID: mdl-30587450
ABSTRACT
We describe here the generation of a lead compound and its optimization studies that led to the identification of a novel GPR119 agonist. Based on a spirocyclic cyclohexane structure reported in our previous work, we identified compound 8 as a lead compound, being guided by ligand-lipophilicity efficiency (LLE), which linked potency and lipophilicity. Subsequent optimization studies of 8 for improvement of solubility afforded representative 21. Compound 21 had no inhibitory activity against six CYP isoforms and showed favorable pharmacokinetic properties and hypoglycemic activity in rats.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Compuestos de Espiro / Ciclohexanos / Receptores Acoplados a Proteínas G / Inhibidores Enzimáticos del Citocromo P-450 / Hipoglucemiantes Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2019 Tipo del documento: Article
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Compuestos de Espiro / Ciclohexanos / Receptores Acoplados a Proteínas G / Inhibidores Enzimáticos del Citocromo P-450 / Hipoglucemiantes Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2019 Tipo del documento: Article