Quinolone derivatives containing strained spirocycle as orally active glycogen synthase kinase 3β (GSK-3β) inhibitors for type 2 diabetics

Bioorg Med Chem. 2012 Feb 1;20(3):1188-200. doi: 10.1016/j.bmc.2011.12.046. Epub 2011 Dec 30.

Abstract

The design, synthesis, and evaluation of 6-6-7 tricyclic quinolones containing the strained spirocycle moiety aiming at the GSK-3β inhibitor were described. Among the synthesized compounds, 44, having a cyclobutane ring on a spirocycle, showed excellent GSK-3β inhibitory activity in both cell-free and cell-based assays (IC(50) = 36nM, EC(50) = 3.2μM, respectively). Additionally, 44 decreased the plasma glucose concentration dose-dependently after an oral glucose tolerance test in mice.

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / enzymology
  • Drug Design
  • Glucose Tolerance Test
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Hep G2 Cells
  • Humans
  • Male
  • Mice
  • Models, Molecular
  • Quinolones / chemical synthesis
  • Quinolones / chemistry*
  • Quinolones / pharmacokinetics
  • Quinolones / pharmacology*
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacokinetics
  • Spiro Compounds / pharmacology

Substances

  • Quinolones
  • Spiro Compounds
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3