title: Novel Liver-targeted conjugates of Glycogen Phosphorylase Inhibitor PSN-357 for the Treatment of Diabetes: Design, Synthesis, Pharmacokinetic and Pharmacological Evaluations.
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/AUCplasmaratio was 18.74) vs that of PSN-357 (AUCliver/AUCplasmaratio 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.
authors.affiliation: Key Laboratory of Traditional Chinese Medicine Research and Development of Hebei Province, Institute of Traditional Chinese Medicine, Chengde Medical University, Chengde 067000, China.
authors.forename: Liying
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Human Anatomy, Chengde Medical University, Chengde 067000, China.
authors.forename: Chengjun
authors.initials: C
authors.lastname: Song
authors.affiliation: Key Laboratory of Traditional Chinese Medicine Research and Development of Hebei Province, Institute of Traditional Chinese Medicine, Chengde Medical University, Chengde 067000, China.
authors.forename: Guangxin
authors.initials: G
authors.lastname: Miao
authors.affiliation: Department of Human Anatomy, Chengde Medical University, Chengde 067000, China.
authors.forename: Lianzhi
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Traditional Chinese Medicine Research and Development of Hebei Province, Institute of Traditional Chinese Medicine, Chengde Medical University, Chengde 067000, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Yan
authors.affiliation: School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Traditional Chinese Medicine Research and Development of Hebei Province, Institute of Traditional Chinese Medicine, Chengde Medical University, Chengde 067000, China.
authors.forename: Youde
authors.initials: Y
authors.lastname: Wang
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D001826:Body Fluids / Q000737:chemistry; D019826:Cholic Acid / Q000737:chemistry / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D057075:Enzyme Assays; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050261:Glycogenolysis; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000627:therapeutic use*; D011817:Rabbits; D013329:Structure-Activity Relationship; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D010880:Piperidines; D024981:Glycogen Phosphorylase; D019826:Cholic Acid