NSAID-derived γ-secretase modulation requires an acidic moiety on the carbazole scaffold

被引：32

作者：

Zall, Andrea ^{[1
]}

Kieser, Daniel ^{[1
]}

Hoettecke, Nicole ^{[1
]}

Naumann, Eva C. ^{[1
]}

Thomaszewski, Binia ^{[1
]}

Schneider, Katrin ^{[1
]}

Steinbacher, Dirk T. ^{[1
]}

Schubenel, Robert ^{[2
]}

Masur, Stefan ^{[2
]}

Baumann, Karlheinz ^{[2
]}

Schmidt, Boris ^{[1
]}

机构：

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

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2011年 / 19卷 / 16期

关键词：

Alzheimer's disease; gamma-Secretase modulation; Carboxylic acid isosteres; Carprofen; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; INTRAMEMBRANE PROTEOLYSIS; BETA; PRESENILIN-1; GENERATION; MUTATIONS; INHIBITORS; A-BETA-42; MEMBRANE;

D O I：

10.1016/j.bmc.2011.06.062

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Modulation of gamma-secretase activity holds potential for the treatment of Alzheimer's disease. Most NSAID-derived gamma-secretase modulators feature a carboxylic acid, which may impair blood-brain barrier permeation. The structure activity relationship of 33 carbazoles featuring diverse carboxylic acid isosteres or metabolic precursors thereof was established in a cellular amyloid secretion assay. The modulatory activity was observed for acidic moieties and metabolically labile esters only, which supports our hypothesis of an acid-lysine interaction to be relevant for this type of gamma-secretase modulators. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：4903 / 4909

页数：7

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