Novel 2,3-Dihydro-1,4-Benzoxazines as Potent and Orally Bioavailable Inhibitors of Tumor-Driven Angiogenesis

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• 作者：Daniel S. La ; Julie Belzile ; James V. Bready ; Angela Coxon ; Thomas DeMelfi ; Nicholas Doerr ; Juan Estrada ; Julie C. Flynn ; Shaun R. Flynn ; Russell F. Graceffa ; Shawn P. Harriman ; Jay F. Larrow ; Alexand
• 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：1695 - 1705
• 全文大小：1211K
• 年卷期：v.51,no.6(March 27, 2008)
• ISSN：1520-4804

文摘

Angiogenesis is vital for solid tumor growth, and its prevention is a proven strategy for the treatment of disease states such as cancer. The vascular endothelial growth factor (VEGF) pathway provides several opportunities by which small molecules can act as inhibitors of endothelial proliferation and migration. Critical to these processes is signaling through VEGFR-2 or the kinase insert domain receptor (KDR) upon stimulation by its ligand VEGF. Herein, we report the discovery of 2,3-dihydro-1,4-benzoxazines as inhibitors of intrinsic KDR activity (IC₅₀ < 0.1 µM) and human umbilical vein endothelial cell (HUVEC) proliferation with IC₅₀ < 0.1 µM. More specifically, compound 16 was identified as a potent (KDR: < 1 nM and HUVEC: 4 nM) and selective inhibitor that exhibited efficacy in angiogenic in vivo models. In addition, this series of molecules is typically well-absorbed orally, further demonstrating the 2,3-dihydro-1,4-benzoxazine moiety as a promising platform for generating kinase-based antiangiogenic therapeutic agents.