Design and synthesis of 2-N-substituted indazolone derivatives as non-carboxylic acid glycogen synthase activators

Bioorg Med Chem Lett. 2013 May 15;23(10):2936-40. doi: 10.1016/j.bmcl.2013.03.049. Epub 2013 Mar 22.

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.

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology*
  • Glycogen Synthase / antagonists & inhibitors*
  • Glycogen Synthase / metabolism
  • Indazoles / administration & dosage
  • Indazoles / chemical synthesis
  • Indazoles / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Indazoles
  • Glycogen Synthase