Discovery of novel pyridazine derivatives as glucose transporter type 4 (GLUT4) translocation activators |
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| Affiliation: | 1. Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;2. Cardiovascular Metabolic Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;3. Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;1. Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Nakacho, Koganei, Tokyo 184-8588, Japan;2. Department of Biotechnology and Life Science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Nakacho, Koganei, Tokyo 184-8588, Japan;3. Department of Chemistry, Faculty of Science, Hokkaido University, Kita-ku Kita 10 Jo Nishi 8 Chome, Sapporo 060-0810, Japan;1. Discovery Chemistry, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;2. In Vivo Pharmacology, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;3. Process Chemistry, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;4. In Vitro Pharmacology, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;5. Drug Metabolism and Pharmacokinetics, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;6. SALAR Discovery, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;1. Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drug Research, Jinan University, Guangzhou 510632, China;2. Kanion Pharmaceutical Co. Ltd., State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Lianyungang 222001, China;3. Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China;1. The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, 1 Discovery Drive, Rensselaer, NY, USA;2. Faculty of Medicine, Mansoura University, Mansoura, Egypt;3. Department of Medicine, Albany Medical College, Albany, NY, USA |
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| Abstract: | We report herein the synthesis and structure-activity relationships (SAR) of a series of pyridazine derivatives with the activation of glucose transporter type 4 (GLUT4) translocation. Through a cell-based phenotype screening in L6-GLUT4-myc myoblasts and functional glucose uptake assays, lead compound 1a was identified as a functional small molecule. After further derivatization, the thienopyridazine scaffold as the central ring (B-part) was revealed to have potent GLUT4 translocation activities. Consequently, we obtained promising compound 26b, which showed a significant blood glucose lowering effect in the severe diabetic mice model (10-week aged db/db mice) after oral dosing even at 10 mg/kg, implying that our pyridazine derivatives have potential to become novel therapeutic agents for diabetes mellitus. |
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| Keywords: | Glucose transporter type 4 GLUT4 Insulin Diabetes Pyridazine |
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