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

Journal of medicinal chemistry (2006-10-13)
Shawn J Stachel, Craig A Coburn, Sethu Sankaranarayanan, Eric A Price, Guoxin Wu, Michelle Crouthamel, Beth L Pietrak, Qian Huang, Janet Lineberger, Amy S Espeseth, Lixia Jin, Joan Ellis, M Katharine Holloway, Sanjeev Munshi, Timothy Allison, Daria Hazuda, Adam J Simon, Samuel L Graham, Joseph P Vacca
RESUMEN

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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Catalizador Grubbs® M204, Umicore