Macrocyclic Inhibitors of -Secretase: Functional Activity in an Animal Model
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- 作者：Shawn J. Stachel ; Craig A. Coburn ; Sethu Sankaranarayanan ; Eric A. Price ; Beth L. Pietrak ; Qian Huang ; Janet Lineberger ; Amy S. Espeseth ; Lixia Jin ; Joan Ellis ; M. Katharine Holloway ; Sanjeev Munshi
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：October 19, 2006
- 年：2006
- 卷：49
- 期：21
- 页码：6147 - 6150
- 全文大小：85K
- 年卷期：v.49,no.21(October 19, 2006)
- ISSN：1520-4804
文摘
A macrocyclic inhibitor of 
-secretase was designed bycovalently cross-linking the P1 and P3 side chains of an isophthalamide-based inhibitor. Macrocyclization resulted in significantly improvedpotency and physical properties when compared to the initial leadstructures. More importantly, these macrocyclic inhibitors also displayedin vivo amyloid lowering when dosed in a murine model.
-secretase was designed bycovalently cross-linking the P1 and P3 side chains of an isophthalamide-based inhibitor. Macrocyclization resulted in significantly improvedpotency and physical properties when compared to the initial leadstructures. More importantly, these macrocyclic inhibitors also displayedin vivo amyloid lowering when dosed in a murine model.