Synthesis,in vitro ADME profiling and in vivo pharmacological evaluation of novel glycogen phosphorylase inhibitors |
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| Institution: | 1. Division of Crop Foundation, National Institute of Crop Science (NICS), Rural Development Administration (RDA), Wanju 55365, Republic of Korea;2. Department of Crop Science and Biotechnology, Dankook University, Cheonan 31116, Republic of Korea;3. Department of Biological Sciences, Chonbuk National University, Jeonju 54896, Republic of Korea;4. Forest Biomaterials Research Center, National Institute of Forest Science (NIFS), Jinju 52817, Republic of Korea;1. Department of Biological Sciences and Bioinformatics, Myongji University, Yongin-si, Gyunggi-do 17058, Republic of Korea;2. Department of Oriental Medicine Resources and Institute for Traditional Korean Medicine Industry, Mokpo National University, Muan-gun, Jeollanam-do 58554, Republic of Korea;1. Acerta Pharma B.V., Kloosterstraat 9, 5349 AB Oss, the Netherlands;2. Acerta Pharma LLC, 1549 Industrial Road, San Carlos, CA 94070, United States;1. Department of Nuclear Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266000, PR China;2. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, PR China;3. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing 100142, PR China |
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| Abstract: | A small set of indole-2-carboxamide derivatives identified from a high-throughput screening campaign has been described as a novel, potent, and glucose-sensitive inhibitors of glycogen phosphorylase a (GPa). Among this series of compounds, compound 2 exhibited moderate GP inhibitory activity (IC50 = 0.29 μM), good cellular efficacy (IC50 = 3.24 μM for HepG2 cells and IC50 = 7.15 μM for isolated rat hepatocytes), together with good absorption, distribution, metabolism, and elimination (ADME) profiles. The in vivo animal study revealed that compound 2 significantly inhibited an increase of fasting blood glucose level in adrenaline-induced diabetic mice. |
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| Keywords: | Diabetes Glycogen phosphorylase inhibitors Biological activity ADME Blood glucose |
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