Discovery of a novel tricyclic 4H-thiazolo[5',4':4,5]pyrano[2,3-c]pyridine-2-amino scaffold and its application in a PI3Kα inhibitor with high PI3K isoform selectivity and potent cellular activity

Bioorg Med Chem Lett. 2015 Sep 1;25(17):3582-4. doi: 10.1016/j.bmcl.2015.06.077. Epub 2015 Jun 30.

Abstract

A novel, previously undescribed 4H-thiazolo[5',4':4,5]pyrano[2,3-c]pyridine tricyclic scaffold has been discovered. The application of this novel chemotype leading to a potent and selective prototype PI3Kα inhibitor with favorable physicochemical and PK-properties is described.

Keywords: 4H-Thiazolo[5′,4′:4,5]pyrano[2,3-c]pyridine-2-amino derivative; Oncology; Phosphatidylinositol-3-kinase (PI3K); Selective PI3Kα Inhibitor.

MeSH terms

  • Amination
  • Animals
  • Class I Phosphatidylinositol 3-Kinases
  • Humans
  • Models, Molecular
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridines / chemistry*
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • Rats
  • Thiazoles / chemistry*
  • Thiazoles / pharmacokinetics
  • Thiazoles / pharmacology*

Substances

  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Pyridines
  • Thiazoles
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human