设计、合成及生物评价 4,7,12,12a-四氢-5H-噻吩[3',2':3,4]吡啶并[1,2-b]异喹啉类化合物作为新型的腺苷 5'-单磷酸激活的蛋白激酶（AMPK）间接激活剂用于治疗 2 型糖尿病。
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.
机构信息
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, PR China.
College of Chemistry and Molecular Engineering, East China Normal University, 3663 North of Zhongshan Road, Shanghai 200062, PR China.
出版信息
Eur J Med Chem. 2017 Nov 10;140:448-464. doi: 10.1016/j.ejmech.2017.09.012. Epub 2017 Sep 9.
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 (IC > 10 μM).
一系列新型小檗碱衍生物，4,7,12,12a-四氢-5H-噻吩[3',2':3,4]吡啶并[1,2-b]异喹啉被设计、合成并进行了抗糖尿病活性的生物评价。在两种细胞类型的评估中，化合物 4aa、4bq 和 4bv 刺激葡萄糖消耗（1.8-2.3 倍），减少糖异生（60-85%），抑制线粒体呼吸链复合物 I 并间接激活 AMPK。在 db/db 小鼠模型中，化合物 4bq 和 4bv 以 120mg/kg/天的剂量降低空腹血糖。此外，与小檗碱相比，化合物 4bq 和 4bv 具有改善的药代动力学特征（生物利用度分别为 45%和 106%）。化合物 4bq 和 4bv 没有明显的 hERG 抑制作用（IC>10μM）。
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