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Naphthamides as Novel and Potent Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors: Design, Synthesis, and Evaluation

2008; American Chemical Society; Volume: 51; Issue: 6 Linguagem: Inglês

10.1021/jm701097z

1520-4804

Jean-Christophe Harmange, Matthew M. Weiss, Julie Germain, Anthony Polverino, George Borg, James Bready, Danlin Chen, Deborah M. Choquette, Angela Coxon, Tom DeMelfi, Lucian DiPietro, Nicholas Doerr, Juan Estrada, Julie Flynn, Russell F. Graceffa, Shawn Harriman, Stephen A. Kaufman, Daniel S. La, Alexander M. Long, Matthew W. Martin, Sesha Neervannan, Vinod F. Patel, Michele Potashman, Kelly Regal, Phillip M. Roveto, Michael Schrag, Charlie Starnes, Andrew S. Tasker, Yohannes Teffera, Ling Wang, Ryan D. White, Douglas A. Whittington, Roger Zanon,

Metal complexes synthesis and properties

A series of naphthyl-based compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptors. Investigations of structure-activity relationships led to the identification of a series of naphthamides that are potent inhibitors of the VEGF receptor tyrosine kinase family. Numerous analogues demonstrated low nanomolar inhibition of VEGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation, and of these several compounds possessed favorable pharmacokinetic (PK) profiles. In particular, compound 48 demonstrated significant antitumor efficacy against established HT29 human colon adenocarcinoma xenografts implanted in athymic mice. A full account of the preparation, structure-activity relationships, pharmacokinetic properties, and pharmacology of analogues within this series is presented.