TY  - JOUR
AU  - Kroth, H.
AU  - Ansaloni, A.
AU  - Varisco, Y.
AU  - Jan, A.
AU  - Sreenivasachary, N.
AU  - Rezaei-Ghaleh, N.
AU  - Giriens, V.
AU  - Lohmann, S.
AU  - Pilar López-Deber, M.
AU  - Adolfsson, O.
AU  - Pihlgren, M.
AU  - Paganetti, P.
AU  - Froestl, W.
AU  - Nagel-Steger, L.
AU  - Willbold, D
AU  - Schrader, T
AU  - Zweckstetter, M.
AU  - Pfeifer, A.
AU  - Lashuel, H.A.
AU  - Muhs, A.
TI  - Discovery and structure activity relationship of small molecule inhibitors of toxic-ß--amyloid-42 fibril formation
JO  - The journal of biological chemistry
VL  - 287
SN  - 0021-9258
CY  - Bethesda, Md.
PB  - Soc.
M1  - PreJuSER-23050
SP  - 34786 - 34800
PY  - 2012
N1  - Record converted from VDB: 12.11.2012
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:22891248
C2  - pmc:PMC3464581
UR  - <Go to ISI:>//WOS:000309654200078
DO  - DOI:10.1074/jbc.M112.357665
UR  - https://juser.fz-juelich.de/record/23050
ER  -