Design of potent and selective GSK3beta inhibitors with acceptable safety profile and pharmacokinetics

Bioorg Med Chem Lett. 2010 Apr 1;20(7):2344-9. doi: 10.1016/j.bmcl.2010.01.132. Epub 2010 Feb 2.

Abstract

From potent and selective inhibitors of GSK3beta displaying CYP1A2 inhibition and poor PK properties, mostly linked to metabolic instability and in vivo hydrolysis of the amide bond, we were able to obtain safe and orally available inhibitors with good half lives.

MeSH terms

  • Animals
  • Cytochrome P-450 CYP1A2 / metabolism
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Mice
  • Models, Molecular
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Protein Kinase Inhibitors / pharmacology*

Substances

  • Cytochrome P-450 CYP1A2 Inhibitors
  • Protein Kinase Inhibitors
  • Cytochrome P-450 CYP1A2
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3