Rational design and synthesis of aminopiperazinones as β-secretase (BACE) inhibitors

被引:41
作者
Tresadern, Gary [1 ]
Delgado, Francisca [2 ]
Delgado, Oscar [2 ]
Gijsen, Harrie [3 ]
Macdonald, Gregor J. [3 ]
Moechars, Dieder [4 ]
Rombouts, Frederik [3 ]
Alexander, Richard [5 ]
Spurlino, John [5 ]
Van Gool, Michiel [2 ]
Antonio Vega, Juan [2 ]
Trabanco, Andres A. [2 ]
机构
[1] Janssen Pharmaceut Res & Dev, Res Informat & Integrat Genom, Poligono Ind 45007, Toledo, Spain
[2] Janssen Pharmaceut Res & Dev, Neurosci Med Chem, Poligono Ind 45007, Toledo, Spain
[3] Janssen Pharmaceut NV, Neurosci Med Chem, B-2340 Beerse, Belgium
[4] Janssen Pharmaceut NV, Janssen Res & Dev, Neurosci Biol, B-2340 Beerse, Belgium
[5] Janssen Res & Dev, Struct Biol, Spring House, PA 19477 USA
关键词
BACE; Alzheimer's disease; Amyloid; beta-Secretase inhibitor; Neurodegeneration; Amyloid beta 42 (A beta 42); Memapsin; AMYLOID PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; POTENT INHIBITORS; CLEAVING ENZYME; SITE; THERAPEUTICS; ASPARTATES; DISCOVERY; DOCKING; LEAD;
D O I
10.1016/j.bmcl.2011.10.050
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Aminopiperazinone inhibitors of BACE were identified by rational design. Structure based design guided idea prioritization and initial racemic hit 18a showed good activity. Modification in decoration and chiral separation resulted in the 40 nM inhibitor, (-)-37, which showed in vivo reduction of amyloid beta peptides. The crystal structure of 18a showed a binding mode driven by interaction with the catalytic aspartate dyad and distribution of the biaryl amide decoration towards S1 and S3 pockets. (C) 2011 Elsevier Ltd. All rights reserved.
引用
收藏
页码:7255 / 7260
页数:6
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