Novel Liver-targeted conjugates of Glycogen Phosphorylase Inhibitor PSN-357 for the Treatment of Diabetes: Design, Synthesis, Pharmacokinetic and Pharmacological Evaluations.
Novel Liver-targeted conjugates of Glycogen Phosphorylase Inhibitor PSN-357 for the Treatment of Diabetes: Design, Synthesis, Pharmacokinetic and Pharmacological Evaluations.
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用于治疗糖尿病的新型肝靶向结合物糖原磷酸化酶抑制剂 PSN-357：设计、合成、药代动力学和药理学评价
DOI：
10.1038/srep42251
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发表时间：
2017-02-22
影响因子：
4.6
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Zhang L;Song C;Miao G;Zhao L;Yan Z;Li J;Wang Y
PSN-357是一种有效的糖原磷酸化酶（GP）抑制剂，用于治疗2型糖尿病，其临床应用受到肝脏和骨骼肌中GP同种型之间选择性差的阻碍。本研究通过胆酸的引入，获得了9种新型的PSN-357肝靶向偶联物。在这些偶联物中，偶联物6表现出轻微的GP抑制活性（IC_（50）= 31.17 μM），良好的细胞功效（IC_（50）= 13.39 μM）和在各种条件下合适的稳定性。分布和药代动力学研究表明，结合物6可以从血浆重新分布到肝脏，导致PSN-357在肝脏中从6代谢的暴露量（AUC_（liver）/AUC_（plasmaratio）为18.74）显著高于PSN-357（AUC_（liver）/AUC_（plasmaratio）为10.06）。在相同剂量50 mg/kg的低血糖动物体内实验中，偶联物6表现出较小但显著的长效降血糖作用，即从给药至6 h，6的降血糖作用略弱于PSN-357，然后在试验的其余时间变得高于PSN-357。这些结果表明，肝靶向糖原磷酸化酶抑制剂可用于治疗2型糖尿病。
PSN-357, an effective glycogen phosphorylase (GP) inhibitor for the treatment for type 2 diabetics, is hampered in its clinical use by the poor selectivity between the GP isoforms in liver and in skeletal muscle. In this study, by the introduction of cholic acid, 9 novel potent and liver-targeted conjugates ofPSN-357were obtained. Among these conjugates, conjugate6exhibited slight GP inhibitory activity (IC50= 31.17 μM), good cellular efficacy (IC50= 13.39 μM) and suitable stability under various conditions. The distribution and pharmacokinetic studies revealed that conjugate6could redistribute from plasma to liver resulting in a considerable higher exposure ofPSN-357metabolizing from6in liver (AUCliver/AUCplasmaratio was 18.74)vsthat ofPSN-357(AUCliver/AUCplasmaratio was 10.06). In thein vivoanimal study of hypoglycemia under the same dose of 50 mg/kg, conjugate6exhibited a small but significant hypoglycemic effects in longer-acting manners, that the hypoglycemic effects of6is somewhat weaker thanPSN-357from administration up to 6 h, and then became higher thanPSN-357for the rest time of the test. Those results indicate that the liver-targeted glycogen phosphorylase inhibitor may hold utility in the treatment of type 2 diabetes.