%0 Journal Article
%A Kroth, H.
%A Ansaloni, A.
%A Varisco, Y.
%A Jan, A.
%A Sreenivasachary, N.
%A Rezaei-Ghaleh, N.
%A Giriens, V.
%A Lohmann, S.
%A Pilar López-Deber, M.
%A Adolfsson, O.
%A Pihlgren, M.
%A Paganetti, P.
%A Froestl, W.
%A Nagel-Steger, L.
%A Willbold, D
%A Schrader, T
%A Zweckstetter, M.
%A Pfeifer, A.
%A Lashuel, H.A.
%A Muhs, A.
%T Discovery and structure activity relationship of small molecule inhibitors of toxic-ß--amyloid-42 fibril formation
%J The journal of biological chemistry
%V 287
%@ 0021-9258
%C Bethesda, Md.
%I Soc.
%M PreJuSER-23050
%P 34786 - 34800
%D 2012
%Z Record converted from VDB: 12.11.2012
%X Increasing evidence implicates Aβ peptides self-assembly and fibril formation as crucial events in the pathogenesis of Alzheimer disease. Thus, inhibiting Aβ aggregation, among others, has emerged as a potential therapeutic intervention for this disorder. Herein, we employed 3-aminopyrazole as a key fragment in our design of non-dye compounds capable of interacting with Aβ42 via a donor-acceptor-donor hydrogen bond pattern complementary to that of the β-sheet conformation of Aβ42. The initial design of the compounds was based on connecting two 3-aminopyrazole moieties via a linker to identify suitable scaffold molecules. Additional aryl substitutions on the two 3-aminopyrazole moieties were also explored to enhance π-π stacking/hydrophobic interactions with amino acids of Aβ42. The efficacy of these compounds on inhibiting Aβ fibril formation and toxicity in vitro was assessed using a combination of biophysical techniques and viability assays. Using structure activity relationship data from the in vitro assays, we identified compounds capable of preventing pathological self-assembly of Aβ42 leading to decreased cell toxicity.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:22891248
%2 pmc:PMC3464581
%U <Go to ISI:>//WOS:000309654200078
%R 10.1074/jbc.M112.357665
%U https://juser.fz-juelich.de/record/23050