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Design and synthesis of 2-N-substituted indazolone derivatives as non-carboxylic acid glycogen synthase activators |
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| Authors: | Yimin Qian David Bolin Karin Conde-Knape Paul Gillespie Stuart Hayden Kuo-Sen Huang Andrée R Olivier Tsutomu Sato Qing Xiang Weiya Yun Xiaolei Zhang |
| Institution: | 1. Discovery Chemistry, Small Molecule Research, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States;2. Metabolic and Vascular Diseases, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States;3. Discovery Technologies, Small Molecule Research, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States |
| Abstract: | Glycogen synthase (GS) catalyzes the transfer of glucose residues from UDP-glucose to a glycogen polymer chain, a critical step for glucose storage. Patients with type 2 diabetes normally exhibit low glycogen levels and decreased muscle glucose uptake is the major defect in whole body glucose disposal. Therefore, activating GS may provide a potential approach for the treatment of type 2 diabetes. In order to identify non-carboxylic acids GS activators, we designed and synthesized a series of 2-N-alkyl- and 2-N-aryl-indazolone derivatives and studied their activity in activating human GS. |
| Keywords: | Glycogen synthase Enzyme activation Type 2 diabetes (T2D) Metabolic stability Indazolone N-arylation and cyclization |
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