Discovery of novel tricyclic pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine derivatives as VEGFR-2 inhibitors

Bioorg Chem. 2015 Jun:60:1-12. doi: 10.1016/j.bioorg.2015.03.004. Epub 2015 Apr 4.

Abstract

In an effort to develop ATP-competitive VEGFR-2 selective inhibitors, a novel series of tricyclic pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine derivatives were designed and synthesized. These compounds were characterized by IR, (1)H NMR, (13)C NMR, elemental and mass spectral analyses. Docking studies have given a partial insight into the molecular determinants of the activity of this novel series in VEGFR-2 kinase active site. Moreover, these compounds were assessed at 10μM for their selective inhibitory activities over a panel of 6 human kinases, namely VEGFR-1/Flt-1, VEGFR-2/KDR, EGFR, CDK5/p25, GSK3α and GSK3β. Compound N-(4,6-dimethylthieno[2,3-b]pyridine)-7,9-dimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine (9d) exhibited the most potent and selective inhibitory activity against VEGFR-2/KDR over the six human kinases, with an IC50 value 2.6μM. The identification of this hit candidate could aid the design of new tricyclic-based VEGFR-2 kinase modulators.

Keywords: Docking studies; Inhibitors; Kinase; Pyridothienopyrimidine; VEGFR-2.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Amination
  • Humans
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Protein Kinase Inhibitors
  • Pyrimidines
  • thieno(2,3-d)pyrimidine
  • Adenosine Triphosphate
  • Vascular Endothelial Growth Factor Receptor-2