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

The sprouting of new blood vessels, or angiogenesis, is necessary for any s olid tumor to grow large enough to cause life-threatening disease. Vascular endothelial growth factor (VEGF) is one of the key promoters of tumor indu ced angiogenesis. VEGF receptors, the tyrosine kinases Flt-1 and KDR, are e xpressed on vascular endothelial cells and initiate angiogenesis upon activ ation by VE GF. 1-Anilino-(4-pyridylmethyl)-phthalazines, such as CGP 79787 D (or PTK787 / ZK222584), reversibly inhibit Flt-1 and KDR with IC50 values < 0.1 mu M CGP 79787D also blocks the VEGF-induced receptor autophosphoryl ation in CHO cells ectopically expressing the KDR receptor (ED50 = 34 nM). Modification of the 1-anilino moiety afforded derivatives with higher selec tivity 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 qua lify for further profiling and as candidates for clinical evaluation.