New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis

J Med Chem. 2000 Jun 15;43(12):2310-23. doi: 10.1021/jm9909443.

Abstract

The sprouting of new blood vessels, or angiogenesis, is necessary for any solid tumor to grow large enough to cause life-threatening disease. Vascular endothelial growth factor (VEGF) is one of the key promoters of tumor induced angiogenesis. VEGF receptors, the tyrosine kinases Flt-1 and KDR, are expressed on vascular endothelial cells and initiate angiogenesis upon activation by VEGF. 1-Anilino-(4-pyridylmethyl)-phthalazines, such as CGP 79787D (or PTK787 / ZK222584), reversibly inhibit Flt-1 and KDR with IC(50) values < 0.1 microM. CGP 79787D also blocks the VEGF-induced receptor autophosphorylation in CHO cells ectopically expressing the KDR receptor (ED(50) = 34 nM). Modification of the 1-anilino moiety afforded derivatives with higher selectivity for the VEGF receptor tyrosine kinases Flt-1 and KDR compared to the related receptor tyrosine kinases PDGF-R and c-Kit. Since these 1-anilino-(4-pyridylmethyl)phthalazines are orally well absorbed, these compounds qualify for further profiling and as candidates for clinical evaluation.

MeSH terms

  • Administration, Oral
  • Angiogenesis Inhibitors / chemical synthesis*
  • Angiogenesis Inhibitors / chemistry
  • Angiogenesis Inhibitors / pharmacokinetics
  • Angiogenesis Inhibitors / pharmacology
  • Aniline Compounds / chemical synthesis*
  • Aniline Compounds / chemistry
  • Aniline Compounds / pharmacokinetics
  • Aniline Compounds / pharmacology
  • Animals
  • Biological Availability
  • CHO Cells
  • Cell Line
  • Cricetinae
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Mice
  • Models, Molecular
  • Neoplasms / blood supply
  • Neovascularization, Pathologic
  • Phosphorylation
  • Phthalazines / chemical synthesis*
  • Phthalazines / chemistry
  • Phthalazines / pharmacokinetics
  • Phthalazines / pharmacology
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Pyridines*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptors, Growth Factor / antagonists & inhibitors*
  • Receptors, Growth Factor / genetics
  • Receptors, Vascular Endothelial Growth Factor
  • Structure-Activity Relationship
  • Transfection
  • Vascular Endothelial Growth Factor Receptor-1

Substances

  • Angiogenesis Inhibitors
  • Aniline Compounds
  • Enzyme Inhibitors
  • Phthalazines
  • Proto-Oncogene Proteins
  • Pyridines
  • Receptors, Growth Factor
  • vatalanib
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor
  • Vascular Endothelial Growth Factor Receptor-1