Macrocyclic Inhibitors of β-Secretase: Functional Activity in an Animal Model
Journal of Medicinal Chemistry2006Vol. 49(21), pp. 6147–6150
Citations Over TimeTop 10% of 2006 papers
Shawn J. Stachel, Craig A. Coburn, Sethu Sankaranarayanan, Eric A. Price, Beth Pietrak, Qian Huang, Janet Lineberger, Amy S. Espeseth, Lixia Jin, Joan D. Ellis, M. Katharine Holloway, Sanjeev Munshi, Timothy J. Allison, Daria J. Hazuda, Adam J. Simon, Samuel Graham, Joseph P. Vacca
Abstract
A macrocyclic inhibitor of beta-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.
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