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@ARTICLE{Kroth:136651,
author = {Kroth, Heiko and Ansaloni, Annalisa and Varisco, Yvan and
Jan, Asad and Sreenivasachary, Nampally and Rezaei-Ghaleh,
Nasrollah and Giriens, Valérie and Lohmann, Sophie and
López-Deber, María Pilar and Adolfsson, Oskar and
Pihlgren, Maria and Paganetti, Paolo and Froestl, Wolfgang
and Nagel-Steger, Luitgard and Willbold, Dieter and
Schrader, Thomas and Zweckstetter, Markus and Pfeifer,
Andrea and Lashuel, Hilal A and Muhs, Andreas},
title = {{D}iscovery and structure activity relationship of small
molecule inhibitors of toxic β-amyloid-42 fibril
formation.},
journal = {The journal of biological chemistry},
volume = {287},
number = {41},
issn = {0021-9258},
address = {Bethesda, Md.},
publisher = {Soc.60645},
reportid = {DZNE-2020-02973},
pages = {34786-34800},
year = {2012},
abstract = {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.},
keywords = {Amyloid beta-Peptides: antagonists $\&$ inhibitors /
Amyloid beta-Peptides: chemistry / Cell Line, Tumor /
Cytotoxins: antagonists $\&$ inhibitors / Cytotoxins:
chemistry / Humans / Hydrogen Bonding / Hydrophobic and
Hydrophilic Interactions / Peptide Fragments: antagonists
$\&$ inhibitors / Peptide Fragments: chemistry / Protein
Structure, Secondary / Pyrazoles: chemistry /
Structure-Activity Relationship / 3-aminopyrazole (NLM
Chemicals) / Amyloid beta-Peptides (NLM Chemicals) /
Cytotoxins (NLM Chemicals) / Peptide Fragments (NLM
Chemicals) / Pyrazoles (NLM Chemicals) / amyloid
beta-protein (1-42) (NLM Chemicals)},
cin = {AG Zweckstetter},
ddc = {540},
cid = {I:(DE-2719)1410001},
pnm = {342 - Disease Mechanisms and Model Systems (POF3-342)},
pid = {G:(DE-HGF)POF3-342},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:22891248},
pmc = {pmc:PMC3464581},
doi = {10.1074/jbc.M112.357665},
url = {https://pub.dzne.de/record/136651},
}