Document Report Card

ID: ALA1133741

Journal: J Med Chem

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

Authors: Bold G, Altmann KH, Frei J, Lang M, Manley PW, 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.

Abstract: 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.

CiteXplore: 10882357

DOI: 10.1021/jm9909443