A Novel Potent Oral Series of VEGFR2 Inhibitors Abrogate Tumor Growth by Inhibiting Angiogenesis
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- 作者：Guido Bold ; Christian Schnell ; Pascal Furet ; Paul McSheehy ; Josef Brüggen ; Jürgen Mestan ; Paul W. Manley ; Peter Drückes ; Marion Burglin ; Ursula Dürler ; Jacqueline Loretan ; Robert Reuter ; Markus Wartmann ; Andreas Theuer ; Beatrice Bauer-Probst ; Georg Martiny-Baron ; Peter Allegrini ; Arnaud Goepfert ; Jeanette Wood ; Amanda Littlewood-Evans
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：January 14, 2016
- 年：2016
- 卷：59
- 期：1
- 页码：132-146
- 全文大小：720K
- ISSN：1520-4804
文摘
This paper describes the identification of 6-(pyrimidin-4-yloxy)-naphthalene-1-carboxamides as a new class of potent and selective human vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitors. In biochemical and cellular assays, the compounds exhibit single-digit nanomolar potency toward VEGFR2. Compounds of this series show good exposure in rodents when dosed orally. They potently inhibit VEGF-driven angiogenesis in a chamber model and rodent tumor models at daily doses of less than 3 mg/kg by targeting the tumor vasculature as demonstrated by ELISA for TIE-2 in lysates or by immunohistochemical analysis. This novel series of compounds shows a potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.