This
paper describes the identification of 6-(pyrimidin-4-yloxy)-naphthalene-1-carboxamides
as a new class of potent and selective human vascular endothelial
growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitors. In biochemical
and cellular assays, the compounds exhibit single-digit nanomolar
potency toward VEGFR2. Compounds of this series show good exposure
in rodents when dosed orally. They potently inhibit VEGF-driven angiogenesis
in a chamber model and rodent tumor models at daily doses of less
than 3 mg/kg by targeting the tumor vasculature as demonstrated by
ELISA for TIE-2 in lysates or by immunohistochemical analysis. This
novel series of compounds shows a potential for the treatment of solid
tumors and other diseases where angiogenesis plays an important role