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Inhibition of VEGF-mediated angiogenesis has proven to be an effective therapeutic approach to treating human tumors in clinical trial. Endothelial cell proliferation and migration, two critical steps in angiogenesis, are mediated through a specific VEGF receptor, the Kinase insert Domain containing Receptor (KDR). Inhibition of KDR kinase activity by small molecules has been shown to be a very promising way to control the VEGF pathway in human cancers. Based on available structures of KDR small molecule complexes, we identified a new series of inhibitors: Naphthoylamides. Synthesis and structure activity relationships leading to the discovery of the N-(4-chlorophenyl)-6-(6,7-dimethoxyquinolin-4-yloxy)-1-naphthamide 1 will be discussed. The pharmacokinetic properties and associated pharmacology of this compound will be also presented.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]