Exploring the chemical space of γ-secretase modulators

被引：22

作者：

Zettl, Heiko ^{[1
]}

Weggen, Sascha ^{[2
]}

Schneider, Petra ^{[1
]}

Schneider, Gisbert ^{[1
]}

机构：

[1] ETH, Dept Chem & Appl Biosci, Inst Pharmaceut Sci, CH-8093 Zurich, Switzerland

[2] Univ Dusseldorf, Mol Neuropathol Grp, Dept Neuropathol, D-40225 Dusseldorf, Germany

来源：

TRENDS IN PHARMACOLOGICAL SCIENCES | 2010年 / 31卷 / 09期

关键词：

NONSTEROIDAL ANTIINFLAMMATORY DRUGS; SIGNAL PEPTIDE PEPTIDASE; SELF-ORGANIZING MAPS; ALZHEIMERS-DISEASE; A-BETA-42; PRODUCTION; SMALL MOLECULES; LIBRARY DESIGN; TARGET; RECEPTOR; INHIBITORS;

D O I：

10.1016/j.tips.2010.05.007

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

gamma-Secretase is a key enzyme in the pathophysiology of Alzheimer's disease (AD) and is responsible for the production of potentially toxic amyloid-beta (A beta) 42 peptides. gamma-Secretase modulators (GSMs) are small molecules (<600 Da) causing a product shift from A beta 42 toward shorter and less toxic A beta fragments. Classical non-steroidal anti-inflammatory drugs (NSAIDs) constituted the first class of GSMs, and therefore many of today's GSMs exhibit NSAID-like overall structure combining an acidic head group with a lipophilic backbone. Recent developments include structurally different non-acidic GSMs. Here we summarize common structural features of GSMs, pick up the controversial discussion regarding their mechanism of action, and show how computational analysis of pharmacophoric features can help reveal their pharmacological profile.

引用

页码：402 / 410

页数：9

共 59 条

[1] Nonspecificity of Binding of γ-Secretase Modulators to the Amyloid Precursor Protein [J].

Beel, Andrew J. ;

Barrett, Paul ;

Schnier, Paul D. ;

Hitchcock, Stephen A. ;

Bagal, Dhanashri ;

Sanders, Charles R. ;

Jordan, John B. .

BIOCHEMISTRY, 2009, 48 (50) :11837-11839

[2] Selected non-steroidal anti-inflammatory drugs and their derivatives target γ-secretase at a novel site -: Evidence for an allosteric mechanism [J].

Beher, D ;

Clarke, EE ;

Wrigley, JDJ ;

Martin, ACL ;

Nadin, A ;

Churcher, I ;

Shearman, MS .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (42) :43419-43426

[3] γ-secretases: from cell biology to therapeutic strategies [J].

Bergmans, Bruno A. ;

De Strooper, Bart .

LANCET NEUROLOGY, 2010, 9 (02) :215-226

[4] Biomarkers of Alzheimer's disease [J].

Craig-Schapiro, Rebecca ;

Fagan, Anne M. ;

Holtzman, David M. .

NEUROBIOLOGY OF DISEASE, 2009, 35 (02) :128-140

[5] Insensitivity to Aβ42-lowering nonsteroidal anti-inflammatory drugs and γ-secretase inhibitors is common among aggressive presenilin-1 mutations [J].

Czirr, Eva ;

Leuchtenberger, Stefanie ;

Dorner-Ciossek, Cornelia ;

Schneider, Anna ;

Jucker, Mathias ;

Koo, Edward H. ;

Pietrzik, Claus U. ;

Baumann, Karlheinz ;

Weggen, Sascha .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (34) :24504-24513

[6] NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo [J].

Eriksen, JL ;

Sagi, SA ;

Smith, TE ;

Weggen, S ;

Das, P ;

McLendon, DC ;

Ozols, VV ;

Jessing, KW ;

Zavitz, KH ;

Koo, EH ;

Golde, TE .

JOURNAL OF CLINICAL INVESTIGATION, 2003, 112 (03) :440-449

[7] The clinical use of structural MRI in Alzheimer disease [J].

Frisoni, Giovanni B. ;

Fox, Nick C. ;

Jack, Clifford R., Jr. ;

Scheltens, Philip ;

Thompson, Paul M. .

NATURE REVIEWS NEUROLOGY, 2010, 6 (02) :67-77

[8] Safety, tolerability, pharmacokinetics, and Aβ levels after short-term administration of R-flurbiprofen in healthy elderly individuals [J].

Galasko, Douglas R. ;

Graff-Radford, Neil ;

May, Susanne ;

Hendrix, Suzanne ;

Cottrell, Barbara A. ;

Sagi, Sarah A. ;

Mather, Gary ;

Laughlin, Mark ;

Zavitz, Kenton H. ;

Swabb, Edward ;

Golde, Todd E. ;

Murphy, Michael P. ;

Koo, Edward H. .

ALZHEIMER DISEASE & ASSOCIATED DISORDERS, 2007, 21 (04) :292-299

[9] Alzheimer disease therapy: Can the amyloid cascade be halted? [J].

Golde, TE .

JOURNAL OF CLINICAL INVESTIGATION, 2003, 111 (01) :11-18

[10] Effect of Tarenflurbil on Cognitive Decline and Activities of Daily Living in Patients With Mild Alzheimer Disease A Randomized Controlled Trial [J].

Green, Robert C. ;

Schneider, Lon S. ;

Amato, David A. ;

Beelen, Andrew P. ;

Wilcock, Gordon ;

Swabb, Edward A. ;

Zavitz, Kenton H. .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2009, 302 (23) :2557-2564

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