6-Position optimization of tricyclic 4-quinolone-based inhibitors of glycogen synthase kinase-3β: discovery of nitrile derivatives with picomolar potency

Bioorg Med Chem Lett. 2012 Jan 15;22(2):1005-8. doi: 10.1016/j.bmcl.2011.12.006. Epub 2011 Dec 8.

Abstract

We previously disclosed tricylic, 6-carboxylic acid-bearing 4-quinolones as GSK-3β inhibitors. Herein we discuss the optimization of this series to yield a series of more potent 6-nitrile analogs with insignificant anti-microbial activity. Finally, kinase profiling indicated that members of this class were highly specific GSK-3 inhibitors.

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Escherichia coli / drug effects
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 beta
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Nitriles / chemistry*
  • Quinolizines / chemical synthesis
  • Quinolizines / chemistry
  • Quinolizines / pharmacology*
  • Staphylococcus aureus / drug effects
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Nitriles
  • Quinolizines
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3