NSAID-derived γ-secretase modulators. Part III: Membrane anchoring

被引：12

作者：

Baumann, Stefanie ^{[1
]}

Hoettecke, Nicole ^{[1
]}

Schubenel, Robert ^{[2
]}

Baumann, Karlheinz ^{[2
]}

Schmidt, Boris ^{[1
]}

机构：

[1] Tech Univ Darmstadt, Clemens Schopf Inst Chem & Biochem, D-64287 Darmstadt, Germany

[2] Preclin Res CNS, Div Pharmaceut, F Hoffmann La Roche Ltd, CH-4070 Basel, Switzerland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 24期

关键词：

Alzheimer's disease; Gamma-secretase modulator; Carprofen; Membrane anchor; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; A-BETA-42; PRODUCTION; PRECURSOR PROTEIN; ENANTIOMERS; INHIBITOR; RECEPTOR;

D O I：

10.1016/j.bmcl.2009.10.035

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

Selective lowering of A beta(42) levels with small-molecule substrate targeting c-secretase modulators (sGSMs), such as some non-steroidal anti-inflammatory drugs, is a promising therapeutic approach for Alzheimer's disease. Here we present N-substituted carbazole-and O-substituted fenofibrate-derived sGSMs and their activity data. Seven out of 19 screened compounds exhibited promising activity against A beta(42) secretion at a low micromolar level. We presume that the sGSMs interact with lys624 at the membrane interface and that the lipophilic substituents anchor the compound orientation in the membrane. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：6986 / 6990

页数：5

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