Application of fragment screening by X-ray crystallography to the discovery of aminopyridines as inhibitors of β-secretase

被引:125
作者
Congreve, Miles
Aharony, David
Albert, Jeffrey
Callaghan, Owen
Campbell, James
Carr, Robin A. E.
Chessari, Gianni
Cowan, Suzanna
Edwards, Philip D.
Frederickson, Martyn
McMenamin, Rachel
Murray, Christopher W.
Patel, Sahil
Wallis, Nicola
机构
[1] Astex Therapeut Ltd, Cambridge CB4 0QA, England
[2] AstraZeneca Res & Dev, Dept Chem, Wilmington, DE 19707 USA
[3] AstraZeneca Res & Dev, Dept Neurosci, Wilmington, DE 19707 USA
关键词
D O I
10.1021/jm061197u
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Fragment-based lead discovery has been successfully applied to the aspartyl protease enzyme beta-secretase (BACE-1). Fragment hits that contained an aminopyridine motif binding to the two catalytic aspartic acid residues in the active site of the enzyme were the chemical starting points. Structure-based design approaches have led to identification of low micromolar lead compounds that retain these interactions and additionally occupy adjacent hydrophobic pockets of the active site. These leads form two subseries, for which compounds 4 (IC50 = 25 mu M) and 6c (IC50 = 24 mu M) are representative. In the latter series, further optimization has led to 8a (IC50 = 690 nM).
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页码:1124 / 1132
页数:9
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