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

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• 作者：Jean-Christophe Harmange ; Matthew M. Weiss ; Julie Germain ; Anthony J. Polverino ; George Borg ; James Bready ; Danlin Chen ; Deborah Choquette ; Angela Coxon ; Tom DeMelfi ; Lucian DiPietro ; Nicholas Doerr
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：March 27, 2008
• 年：2008
• 卷：51
• 期：6
• 页码：1649 - 1667
• 全文大小：1413K
• 年卷期：v.51,no.6(March 27, 2008)
• ISSN：1520-4804

文摘

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.