title: Design and synthesis of 2-N-substituted indazolone derivatives as non-carboxylic acid glycogen synthase activators.
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.
authors.affiliation: Discovery Chemistry, Small Molecule Research, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States. yiminqian81@gmail.com
authors.forename: Yimin
authors.initials: Y
authors.lastname: Qian
authors.forename: David
authors.initials: D
authors.lastname: Bolin
authors.forename: Karin
authors.initials: K
authors.lastname: Conde-Knape
authors.forename: Paul
authors.initials: P
authors.lastname: Gillespie
authors.forename: Stuart
authors.initials: S
authors.lastname: Hayden
authors.forename: Kuo-Sen
authors.initials: KS
authors.lastname: Huang
authors.forename: Andrée R
authors.initials: AR
authors.lastname: Olivier
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sato
authors.forename: Qing
authors.initials: Q
authors.lastname: Xiang
authors.forename: Weiya
authors.initials: W
authors.lastname: Yun
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D006006:Glycogen Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007191:Indazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D006006:Glycogen Synthase