New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis.
J Med Chem
; 43(12): 2310-23, 2000 Jun 15.
Article
en En
| MEDLINE
| ID: mdl-10882357
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.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Ftalazinas
/
Piridinas
/
Receptores de Factores de Crecimiento
/
Proteínas Tirosina Quinasas Receptoras
/
Inhibidores de la Angiogénesis
/
Inhibidores Enzimáticos
/
Compuestos de Anilina
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2000
Tipo del documento:
Article
País de afiliación:
Suiza