Macrocyclic inhibitors of β-secretase: functional activity in an animal model

…, J Lineberger, AS Espeseth, L Jin, J Ellis…

文献索引：Stachel, Shawn J.; Coburn, Craig A.; Sankaranarayanan, Sethu; Price, Eric A.; Pietrak, Beth L.; Huang, Qian; Lineberger, Janet; Espeseth, Amy S.; Jin, Lixia; Ellis, Joan; Holloway, M. Katharine; Munshi, Sanjeev; Allison, Timothy; Hazuda, Daria; Simon, Adam J.; Graham, Samuel L.; Vacca, Joseph P. Journal of Medicinal Chemistry, 2006 , vol. 49, # 21 p. 6147 - 6150

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被引用次数: 86

摘要

A macrocyclic inhibitor of β-secretase was designed by covalently cross-linking the P1 and P3 side chains of an isophthalamide-based inhibitor. Macrocyclization resulted in significantly improved potency and physical properties when compared to the initial lead structures. More importantly, these macrocyclic inhibitors also displayed in vivo amyloid lowering when dosed in a murine model.