Identification of a new chemical class of potent angiogenesis inhibitors based on conformational considerations and database searching.
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.
Furet
Pascal
P
Oncology Research, Novartis Pharma AG, CH-4002 Basel, Switzerland. pascal.furet@pharma.novartis.com
Bold
Guido
G
Hofmann
Francesco
F
Manley
Paul
P
Meyer
Thomas
T
Altmann
Karl-Heinz
KH
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D016208:Databases, Factual; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D010793:Phthalazines; D011725:Pyridines; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D010793:Phthalazines; D011725:Pyridines; D062367:ortho-Aminobenzoates; C404768:vatalanib; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; C000219:anthranilamide