Discovery of a Potent, Selective, and Orally Active Human Epidermal Growth Factor Receptor-2 Sheddase Inhibitor for the Treatment of Cancer

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• 作者：Wenqing Yao ; Jincong Zhuo ; David M. Burns ; Meizhong Xu ; Colin Zhang ; Yun-Long Li ; Ding-Quan Qian ; Chunhong He ; Lingkai Weng ; Eric Shi ; Qiyan Lin ; Costas Agrios ; Timothy C. Burn ; Eian Caulder ; Maryanne
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：February 22, 2007
• 年：2007
• 卷：50
• 期：4
• 页码：603 - 606
• 全文大小：78K
• 年卷期：v.50,no.4(February 22, 2007)
• ISSN：1520-4804

文摘

The design, synthesis, evaluation, and identification of anovel class of (6S,7S)-N-hydroxy-6-carboxamide-5-azaspiro[2.5]octane-7-carboxamides as the first potent and selective inhibitors of humanepidermal growth factor receptor-2 (HER-2) sheddase is described.Several compounds were identified that possess excellent pharmacodynamic and pharmacokinetic properties and were shown to decreasetumor size, cleaved HER-2 extracellular domain plasma levels, andpotentiate the effects of the humanized anti-HER-2 monoclonal antibody(trastuzumab) in vivo in a HER-2 overexpressing cancer murinexenograft model.