Application of Fragment Screening by X-ray Crystallography to the Discovery of Aminopyridines as Inhibitors of -Secre
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- 作者：Miles Congreve ; David Aharony ; Jeffrey Albert ; Owen Callaghan ; James Campbell ; Robin A. E. Carr ; Gianni Chessari ; Suzanna Cowan ; Philip D. Edwards ; Martyn Frederickson ; Rachel McMenamin ; Christopher W
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：March 22, 2007
- 年：2007
- 卷：50
- 期：6
- 页码：1124 - 1132
- 全文大小：268K
- 年卷期：v.50,no.6(March 22, 2007)
- ISSN：1520-4804
文摘
Fragment-based lead discovery has been successfully applied to the aspartyl protease enzyme 
-secretase(BACE-1). Fragment hits that contained an aminopyridine motif binding to the two catalytic aspartic acidresidues in the active site of the enzyme were the chemical starting points. Structure-based design approacheshave led to identification of low micromolar lead compounds that retain these interactions and additionallyoccupy adjacent hydrophobic pockets of the active site. These leads form two subseries, for which compounds4 (IC50 = 25 
M) and 6c (IC50 = 24 M) are representative. In the latter series, further optimization has ledto 8a (IC50 = 690 nM).
-secretase(BACE-1). Fragment hits that contained an aminopyridine motif binding to the two catalytic aspartic acidresidues in the active site of the enzyme were the chemical starting points. Structure-based design approacheshave led to identification of low micromolar lead compounds that retain these interactions and additionallyoccupy adjacent hydrophobic pockets of the active site. These leads form two subseries, for which compounds4 (IC50 = 25 M) and 6c (IC50 = 24 M) are representative. In the latter series, further optimization has ledto 8a (IC50 = 690 nM).