Novel 2,3-dihydro-1,4-benzoxazines as potent and orally bioavailable inhibitors of tumor-driven angiogenesis
Novel 2,3-dihydro-1,4-benzoxazines as potent and orally bioavailable inhibitors of tumor-driven angiogenesis
复制标题
DOI：
10.1021/jm701129j
复制
发表时间：
2008-03-27
影响因子：
7.3
通讯作者：
Harmanget, Jean-Christophe
中科院分区：
文献类型：
--
作者：
La, Daniel S.;Belzile, Julie;Harmanget, Jean-Christophe
血管生成对于实体瘤生长至关重要，并且其预防是用于治疗疾病状态如癌症的经证实的策略。血管内皮生长因子（VEGF）途径提供了几个机会，小分子可以作为内皮细胞增殖和迁移的抑制剂。这些过程的关键是在其配体VEGF刺激下通过VEGFR-2或激酶插入结构域受体（KDR）的信号传导。在此，我们报告了2，3-二氢-1，4-苯并恶嗪作为内在KDR活性（IC 50 < 0.1 μ M）和人脐静脉内皮细胞（HUVEC）增殖（IC 50 < 0.1 μ M）的抑制剂的发现。更具体地，化合物16被鉴定为在血管生成体内模型中表现出功效的有效（KDR：<InM和HUVEC：4 nM）和选择性抑制剂。此外，该系列分子通常经口吸收良好，进一步证明了2，3-二氢-1，4-苯并恶嗪部分。作为产生基于激酶的抗血管生成治疗剂的有前景的平台。
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 mu M) and human umbilical vein endothelial cell (HUVEC) proliferation with IC50 < 0.1 mu M. 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.