Synthesis and structure-activity relationships of imidazo[1,2-a]pyrimidin-5(1H)-ones as a novel series of beta isoform selective phosphatidylinositol 3-kinase inhibitors

Bioorg Med Chem Lett. 2012 Mar 15;22(6):2230-4. doi: 10.1016/j.bmcl.2012.01.092. Epub 2012 Feb 4.

Abstract

A series of PI3K-beta selective inhibitors, imidazo[1,2-a]-pyrimidin-5(1H)-ones, has been rationally designed based on the docking model of the more potent R enantiomer of TGX-221, identified by a chiral separation, in a PI3K-beta homology model. Synthesis and SAR of this novel chemotype are described. Several compounds in the series demonstrated potent growth inhibition in a PTEN-deficient breast cancer cell line MDA-MB-468 under anchorage independent conditions.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Breast Neoplasms
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Female
  • Gene Deletion
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / pharmacology
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Kinetics
  • Models, Molecular
  • PTEN Phosphohydrolase / deficiency
  • PTEN Phosphohydrolase / genetics
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidinones / chemical synthesis*
  • Pyrimidinones / pharmacology
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Imidazoles
  • Isoenzymes
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Pyrimidinones
  • Phosphatidylinositol 3-Kinase
  • PTEN Phosphohydrolase
  • PTEN protein, human