Novel Liver-targeted conjugates of Glycogen Phosphorylase Inhibitor PSN-357 for the Treatment of Diabetes: Design, Synthesis, Pharmacokinetic and Pharmacological Evaluations

  • Sci Rep. 2017 Feb 22:7:42251. doi: 10.1038/srep42251.
Liying Zhang  1 ,  Chengjun Song  2 ,  Guangxin Miao  1 ,  Lianzhi Zhao  2 ,  Zhiwei Yan  1 ,  Jing Li  3 ,  Youde Wang  1
Affiliations
  • 1. Key Laboratory of Traditional Chinese Medicine Research and Development of Hebei Province, Institute of Traditional Chinese Medicine, Chengde Medical University, Chengde 067000, China.
  • 2. Department of Human Anatomy, Chengde Medical University, Chengde 067000, China.
  • 3. School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China.
PMID: 28225016 DOI: 10.1038/srep42251
Abstract

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 of PSN-357 were obtained. Among these conjugates, conjugate 6 exhibited 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 conjugate 6 could redistribute from plasma to liver resulting in a considerable higher exposure of PSN-357 metabolizing from 6 in liver (AUCliver/AUCplasma ratio was 18.74) vs that of PSN-357 (AUCliver/AUCplasma ratio was 10.06). In the in vivo animal study of hypoglycemia under the same dose of 50 mg/kg, conjugate 6 exhibited a small but significant hypoglycemic effects in longer-acting manners, that the hypoglycemic effects of 6 is somewhat weaker than PSN-357 from administration up to 6 h, and then became higher than PSN-357 for 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.

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