Discovery of a novel warhead against β-secretase through fragment-based lead generation

被引：120

作者：

Geschwindner, Stefan

Olsson, Lise-Lotte

Albert, Jeffrey S.

Deinum, Johanna

Edwards, Philip D.

de Beer, Tonny

Folmer, Rutger H. A. ^{[1
]}

机构：

[1] AstraZeneca R&D, Globat Struct Chem, SE-43183 Molndal, Sweden

[2] AstraZeneca R&D, CVGI Mol Pharmacol, SE-43183 Molndal, Sweden

[3] AstraZeneca R&D, CNS Lead Generat, Delaware, OH USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2007年 / 50卷 / 24期

关键词：

D O I：

10.1021/jm070825k

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Fragment-based lead generation was applied to find novel small-molecule inhibitors beta-secretase (BACE-1), a key target for the treatment of Alzheimer's disease. Fragment hits coming from a 1D NMR screen were characterized by BIAcore, and the most promising compounds were soaked into protein crystals to help the rational design of more potent hit analogues. Problems arising due to our inability to grow BACE-1 crystals at the biologically relevant pH at which the screen was run were overcome by using endothiapepsin as a surrogate aspartyl protease. Among others, we identified 6-substituted isocytosines as a novel warhead against BACE-1, and the accompanying paper in this journal describes how these were optimized to a lead series of nanomolar inhibitors.

引用

页码：5903 / 5911

页数：9

共 48 条

[1] An integrated approach to fragment-based lead generation: Philosophy, strategy and case studies from AstraZeneca's drug discovery programmes [J].

Albert, Jeffrey S. ;

Blomberg, Niklas ;

Breeze, Alexander L. ;

Brown, Alastair J. H. ;

Burrows, Jeremy N. ;

Edwards, Philip D. ;

Folmer, Rutger H. A. ;

Geschwindner, Stefan ;

Griffen, Ed J. ;

Kenny, Peter W. ;

Nowak, Thorsten ;

Olsson, Lise-Lotte ;

Sanganee, Hitesh ;

Shapiro, Adam B. .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2007, 7 (16) :1600-1629

[2] NEW METHOD FOR PREDICTING BINDING-AFFINITY IN COMPUTER-AIDED DRUG DESIGN [J].

AQVIST, J ;

MEDINA, C ;

SAMUELSSON, JE .

PROTEIN ENGINEERING, 1994, 7 (03) :385-391

[3] THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].

BAILEY, S .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :760-763

[4] Crystallography & NMR system:: A new software suite for macromolecular structure determination [J].

Brunger, AT ;

Adams, PD ;

Clore, GM ;

DeLano, WL ;

Gros, P ;

Grosse-Kunstleve, RW ;

Jiang, JS ;

Kuszewski, J ;

Nilges, M ;

Pannu, NS ;

Read, RJ ;

Rice, LM ;

Simonson, T ;

Warren, GL .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1998, 54 :905-921

[5] NMR-based screening technologies [J].

Coles, M ;

Heller, M ;

Kessler, H .

DRUG DISCOVERY TODAY, 2003, 8 (17) :803-810

[6] Application of fragment screening by X-ray crystallography to the discovery of aminopyridines as inhibitors of β-secretase [J].

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 .

JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (06) :1124-1132

[7] Identification of compounds with binding affinity to proteins via magnetization transfer from bulk water [J].

Dalvit, C ;

Pevarello, P ;

Tatò, M ;

Veronesi, M ;

Vulpetti, A ;

Sundström, M .

JOURNAL OF BIOMOLECULAR NMR, 2000, 18 (01) :65-68

[8] WaterLOGSY as a method for primary NMR screening: Practical aspects and range of applicability [J].

Dalvit, C ;

Fogliatto, G ;

Stewart, A ;

Veronesi, M ;

Stockman, B .

JOURNAL OF BIOMOLECULAR NMR, 2001, 21 (04) :349-359

[9] A thermodynamic characterization of the binding of thrombin inhibitors to human thrombin, combining biosensor technology, stopped-flow spectrophotometry, and microcalorimetry [J].

Deinum, J ;

Gustavsson, L ;

Gyzander, E ;

Kullman-Magnusson, M ;

Edström, Å ;

Karlsson, R .

ANALYTICAL BIOCHEMISTRY, 2002, 300 (02) :152-162

[10] Application of fragment-based lead generation to the discovery of novel, cyclic amidine β-secretase inhibitors with nanomolar potency, cellular activity, and high ligand efficiency [J].

Edwards, Philip D. ;

Albert, Jeffrey S. ;

Sylvester, Mark ;

Aharony, David ;

Andisik, Donald ;

Callaghan, Owen ;

Campbell, James B. ;

Carr, Robin A. ;

Chessari, Gianni ;

Congreve, Miles ;

Frederickson, Martyn ;

Folmer, Rutger H. A. ;

Geschwindner, Stefan ;

Koether, Gerard ;

Kolmodin, Karin ;

Krumrine, Jennifer ;

Mauger, Russell C. ;

Murray, Christopher W. ;

Olsson, Lise-Lotte ;

Patel, Sahil ;

Spear, Nate ;

Tian, Gaochao .

JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (24) :5912-5925

← 1 2 3 4 5 →