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Evaluation of a Series of Naphthamides as Potent, Orally Active Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitors

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

10.1021/jm701098w

1520-4804

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

Bioactive Compounds and Antitumor Agents

We have previously shown N-arylnaphthamides can be potent inhibitors of vascular endothelial growth factor receptors (VEGFRs). N-Alkyl and N-unsubstituted naphthamides were prepared and found to yield nanomolar inhibitors of VEGFR-2 (KDR) with an improved selectivity profile against a panel of tyrosine and serine/threonine kinases. The inhibitory activity of this series was retained at the cellular level. Naphthamides 3, 20, and 22 exhibited good pharmacokinetics following oral dosing and showed potent inhibition of VEGF-induced angiogenesis in the rat corneal model. Once-daily oral administration of 22 for 14 days led to 85% inhibition of established HT29 colon cancer and Calu-6 lung cancer xenografts at doses of 10 and 20 mg/kg, respectively.