TOPIC

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

Journal

European Journal of Medicinal Chemistry

Author(s)

Shengbin Zhou(ab1, Yanan Duan(c1, Jiang Wang(ab1, Jin Zhang(c Haifeng Sun(a,b Haowen Jiang(c, Zhanni Gu(ab, Junhua Tong(ab, Jingya Li(a, Jia Li(a, Hong Liu(ab

Year

2017

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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