Design, Synthesis, and Evaluation of Orally Active Benzimidazoles and Benzoxazoles as Vascular Endothelial Growth Factor-2 Receptor Tyrosine Kinase Inhibitors

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• 作者：Michele H. Potashman ; James Bready ; Angela Coxon ; Thomas M. DeMelfi ; Jr. ; Lucian DiPietro ; Nicholas Doerr ; Daniel Elbaum ; Juan Estrada ; Paul Gallant ; Julie Germain ; Yan Gu ; Jean-Christophe Harmange
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：September 6, 2007
• 年：2007
• 卷：50
• 期：18
• 页码：4351 - 4373
• 全文大小：673K
• 年卷期：v.50,no.18(September 6, 2007)
• ISSN：1520-4804

文摘

Inhibition of the VEGF signaling pathway has become a valuable approach in the treatment of cancers.Guided by X-ray crystallography and molecular modeling, a series of 2-aminobenzimidazoles and2-aminobenzoxazoles were identified as potent inhibitors of VEGFR-2 (KDR) in both enzymatic and HUVECcellular proliferation assays. In this report we describe the synthesis and structure-activity relationship ofa series of 2-aminobenzimidazoles and benzoxazoles, culminating in the identification of benzoxazole 22as a potent and selective VEGFR-2 inhibitor displaying a good pharmacokinetic profile. Compound 22demonstrated efficacy in both the murine matrigel model for vascular permeability (79% inhibition observedat 100 mg/kg) and the rat corneal angiogenesis model (ED₅₀ = 16.3 mg/kg).