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
  • 1. Oncology Research, and Process Research, NOVARTIS Pharma AG, CH-4002 Basel, Switzerland. [email protected]
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.