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

被引:223
作者
Bold, G [1 ]
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
Wyss, D
Wood, JM
机构
[1] NOVARTIS Pharma AG, Oncol Res, CH-4002 Basel, Switzerland
[2] NOVARTIS Pharma AG, Proc Res, CH-4002 Basel, Switzerland
[3] Tumor Biol Ctr, Inst Mol Med, D-79106 Freiburg, Germany
关键词
D O I
10.1021/jm9909443
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 VE GF. 1-Anilino-(4-pyridylmethyl)-phthalazines, such as CGP 79787D (or PTK787 / ZK222584), reversibly inhibit Flt-1 and KDR with IC50 values < 0.1 mu M CGP 79787D also blocks the VEGF-induced receptor autophosphorylation in CHO cells ectopically expressing the KDR receptor (ED50 = 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.
引用
收藏
页码:2310 / 2323
页数:14
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