Novel Liver-targeted conjugates of Glycogen Phosphorylase Inhibitor PSN-357 for the Treatment of Diabetes: Design, Synthesis, Pharmacokinetic and Pharmacological Evaluations
| Autor: | Zhiwei Yan, Lianzhi Zhao, Liying Zhang, Chengjun Song, Youde Wang, Guangxin Miao, Jing Li |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
medicine.medical_specialty
Glycogenolysis Time Factors Cholic Acid Pharmacology Hypoglycemia 01 natural sciences Article Diabetes Mellitus Experimental Glycogen phosphorylase chemistry.chemical_compound Inhibitory Concentration 50 Mice Structure-Activity Relationship Pharmacokinetics Piperidines In vivo Internal medicine medicine Distribution (pharmacology) Animals Humans Tissue Distribution Enzyme Assays Multidisciplinary 010405 organic chemistry Chemistry Glycogen Phosphorylase Cholic acid Hep G2 Cells medicine.disease 0104 chemical sciences Body Fluids 010404 medicinal & biomolecular chemistry Endocrinology Liver Microsomes Liver Administration Intravenous Rabbits Conjugate |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep42251 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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