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
收藏
页码：4903 / 4909
页数：7
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