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).

设计，合成了一系列新颖的小ber碱衍生物4,7,12,12a-tetrahydro-5 H -thieno [3'，2'：3,4]吡啶[1,2- b ]异喹啉，并对其进行了生物学评估他们的抗糖尿病活性。在两种类型的细胞中进行评估后，化合物4aa，4bq和4bv刺激了葡萄糖消耗（1.8到2.3倍），糖异生减少（60-85％），抑制了线粒体呼吸链复合体I并间接激活了AMPK。在db / db小鼠模型中，化合物4bq和4bv以120 mg / kg /天的剂量降低了空腹血糖。此外，化合物4bq和与小ber碱相比，发现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没有表现出明显的hERG抑制作用（IC ₅₀  > 10μM）。