Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors

J Med Chem. 2002 Dec 19;45(26):5687-93. doi: 10.1021/jm020899q.

Abstract

Two readily synthesized anthranilamide, VEGF receptor tyrosine kinase inhibitors have been prepared and evaluated as angiogenesis inhibitors. 2-[(4-Pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide (5) and N-3-isoquinolinyl-2-[(4-pyridinylmethyl)amino]benzamide (7) potently and selectively inhibit recombinant VEGFR-2 and VEGFR-3 kinases. As a consequence of their physicochemical properties, these anthranilamides readily penetrate cells and are absorbed following once daily oral administration to mice. Both 5 and 7 potently inhibit VEGF-induced angiogenesis in an implant model, with ED(50) values of 7 mg/kg. In a mouse orthotopic model of melanoma, 5 and 7 potently inhibited both the growth of the primary tumor as well as the formation of spontaneous peripheral metastases. The anthranilamides 5 and 7 represent a new structural class of VEGFR kinase inhibitors, which possess potent antiangiogenic and antitumor properties.

MeSH terms

  • Administration, Oral
  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology
  • Angiogenesis Inhibitors / chemical synthesis
  • Angiogenesis Inhibitors / chemistry
  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • CHO Cells
  • Cricetinae
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology
  • Lymphatic Metastasis
  • Melanoma / drug therapy
  • Melanoma / pathology
  • Mice
  • Phosphorylation
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*
  • ortho-Aminobenzoates / chemical synthesis*
  • ortho-Aminobenzoates / chemistry
  • ortho-Aminobenzoates / pharmacology

Substances

  • 2-((4-pyridyl)methyl)amino-N-(3-(trifluoromethyl)phenyl)benzamide
  • Amides
  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Benzamides
  • Enzyme Inhibitors
  • Isoquinolines
  • N-3-isoquinolinyl-2-((4-pyridinylmethyl)amino)benzamide
  • ortho-Aminobenzoates
  • Receptors, Vascular Endothelial Growth Factor