Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Bold, G. et al.

Bold, Altmann, Frei, Lang, Manley, Traxler, Wietfeld, Brüggen, Buchdunger, Cozens, Ferrari, Furet, Hofmann, Martiny-Baron, Mestan, Rösel, Sills, Stover, Acemoglu, Boss, Emmenegger, Lässer, Masso, Roth, Schlachter, Vetterli,

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 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.[1]

References

New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. Bold, G., Altmann, K.H., Frei, J., Lang, M., Manley, P.W., Traxler, P., Wietfeld, B., Brüggen, J., Buchdunger, E., Cozens, R., Ferrari, S., Furet, P., Hofmann, F., Martiny-Baron, G., Mestan, J., Rösel, J., Sills, M., Stover, D., Acemoglu, F., Boss, E., Emmenegger, R., Lässer, L., Masso, E., Roth, R., Schlachter, C., Vetterli, W. J. Med. Chem. (2000) [Pubmed]

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