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Discovery and preclinical development of AR453588 as an anti-diabetic glucokinase activator
Affiliation:1. Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece;2. Department of Organic Chemistry, University of Debrecen, H-4002 POB 400 Debrecen, Hungary;3. Institute of Chemical Biology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 11635 Athens, Greece;1. Department of Medicine and Division of Endocrinology, Stanford University, Stanford, CA 94305, USA;2. Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA;3. Department of Chemistry, Stanford University, Stanford, CA 94305, USA;4. Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA;5. Stanford Diabetes Research Center, Stanford University, Stanford, CA 94305, USA;1. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Republic of Korea;2. Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea;3. Division of Applied RI, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea;1. School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China;2. Innovation Center for Marine Drug Screening and Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266071, China;3. Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China;4. Shenzhen Institute, Guangdong Ocean University, Shenzhen 518116, China;5. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy and Cancer, Chengdu 610041, China
Abstract:Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high levels of glucose. Flux through GK is also responsible for reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can activate GK could provide a therapeutic benefit. Herein we report the further structure activity studies of a novel series of glucokinase activators (GKA). These studies led to the identification of pyridine 72 as a potent GKA that lowered post-prandial glucose in normal C57BL/6J mice, and after 14d dosing in ob/ob mice.
Keywords:Glucokinase  Glucokinase activator  Structure-aided design  Structure-based design  Diabetes  Type II diabetes  OGTT
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