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Design, synthesis and biological evaluation of 4,7,12,12a-tetrahydro-5H-thieno[3',2':3,4]pyrido[1,2-b]isoquinolines as novel adenosine 5'-monophosphate-activated protein kinase (AMPK) indirect activators for the treatment of type 2 diabetes.
Zhou, Shengbin; Duan, Yanan; Wang, Jiang; Zhang, Jin; Sun, Haifeng; Jiang, Haowen; Gu, Zhanni; Tong, Junhua; Li, Jingya; Li, Jia; Liu, Hong.
Afiliación
  • Zhou S; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203
  • Duan Y; College of Chemistry and Molecular Engineering, East China Normal University, 3663 North of Zhongshan Road, Shanghai 200062, PR China.
  • Wang J; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203
  • Zhang J; College of Chemistry and Molecular Engineering, East China Normal University, 3663 North of Zhongshan Road, Shanghai 200062, PR China.
  • Sun H; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203
  • Jiang H; College of Chemistry and Molecular Engineering, East China Normal University, 3663 North of Zhongshan Road, Shanghai 200062, PR China.
  • Gu Z; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203
  • Tong J; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203
  • Li J; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
  • Li J; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China. Electronic address: jli@simm.ac.cn.
  • Liu H; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203
Eur J Med Chem ; 140: 448-464, 2017 Nov 10.
Article en En | MEDLINE | ID: mdl-28987606
A series of novel berberine derivatives, 4,7,12,12a-tetrahydro-5H-thieno[3',2':3,4]pyrido[1,2-b]isoquinolines was designed, synthesized, and biologically evaluated for their anti-diabetic activity. Following the evaluation in two types of cells, compounds 4aa, 4bq, and 4bv stimulated glucose consumption (1.8- to 2.3-fold), reduced gluconeogenesis (60-85%), inhibited mitochondria respiratory chain complex I and activated AMPK indirectly. In a db/db mice model, compounds 4bq and 4bv lowered fasting blood glucose at a dose of 120 mg/kg/day. In addition, compounds 4bq and 4bv were found to possess improved pharmacokinetic profiles (bioavailability 45 and 106%, respectively) compared to berberine. Compounds 4bq and 4bv exhibited no obvious hERG inhibition (IC50 > 10 µM).
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diseño de Fármacos / Activadores de Enzimas / Diabetes Mellitus Tipo 2 / Proteínas Quinasas Activadas por AMP / Hipoglucemiantes / Isoquinolinas Límite: Animals Idioma: En Revista: Eur J Med Chem Año: 2017 Tipo del documento: Article Pais de publicación: Francia
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diseño de Fármacos / Activadores de Enzimas / Diabetes Mellitus Tipo 2 / Proteínas Quinasas Activadas por AMP / Hipoglucemiantes / Isoquinolinas Límite: Animals Idioma: En Revista: Eur J Med Chem Año: 2017 Tipo del documento: Article Pais de publicación: Francia