Exploring the chemical space of γ-secretase modulators

被引：21
|
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
收藏
页码：402 / 410
页数：9
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