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

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. 2000 Jun 15;43(12):2310-23. doi: 10.1021/jm9909443.
G Bold 1,  K H Altmann,  J Frei,  M Lang,  P W Manley,  P Traxler,  B Wietfeld,  J Brüggen,  E Buchdunger,  R Cozens,  S Ferrari,  P Furet,  F Hofmann,  G Martiny-Baron,  J Mestan,  J Rösel,  M Sills,  D Stover,  F Acemoglu,  E Boss,  R Emmenegger,  L Lässer,  E Masso,  R Roth,  C Schlachter,  W Vetterli
Affiliations

Affiliation

  • 1 Oncology Research, and Process Research, NOVARTIS Pharma AG, CH-4002 Basel, Switzerland. guido.bold@pharma.novartis.com
PMID: 10882357 DOI: 10.1021/jm9909443
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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