Identification of a new chemical class of potent angiogenesis inhibitors based on conformational considerations and database searching

• Published in: Bioorganic & medicinal chemistry letters 2003-09, Vol.13 (18), p.2967-2971
• Main Authors: Furet, Pascal, Bold, Guido, Hofmann, Francesco, Manley, Paul, Meyer, Thomas, Altmann, Karl-Heinz
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - chemical synthesis; Angiogenesis Inhibitors - pharmacology; Databases, Factual; Humans; Inhibitory Concentration 50; Models, Molecular; Molecular Conformation; ortho-Aminobenzoates - chemical synthesis; ortho-Aminobenzoates - pharmacology; Phthalazines; Pyridines; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; Structure-Activity Relationship; Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00626-7

The vascular endothelial growth factor (VEGF) tyrosine kinase receptors KDR and Flt-1 are targets of current interest in anticancer drug research. PTK787/ZK222584 is a potent inhibitor of these enzymes in clinical evaluation as an antiangiogenic agent. The development of a hypothesis concerning the bioactive conformation of this compound has led to the discovery of a new class of potent inhibitors of KDR and Flt-1, the anthranilamides. This could be achieved with a limited experimental effort, which only involved the testing of one archive compound and the synthesis and testing of one appropriate analogue. The discovery of a new class of inhibitors of the kinase activity of the vascular endothelial growth factor tyrosine kinase receptors KDR and Flt-1 is described.