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Bioorg Med Chem Lett. 2015 Feb 15;25(4):841-6. doi: 10.1016/j.bmcl.2014.12.073. Epub 2014 Dec 30.

SAR-studies of γ-secretase modulators with PPARγ-agonistic and 5-lipoxygenase-inhibitory activity for Alzheimer's disease.

Author information

1
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
2
Department of Neuropathology, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
3
Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, D-07743 Jena, Germany.
4
Institute of Pharmaceutical Chemistry, Johannes-Gutenberg-University Mainz, Staudingerweg 5, D-55128 Mainz, Germany.
5
Department of Neuropathology, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany. Electronic address: sweggen@hhu.de.
6
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany. Electronic address: schubert-zsilavecz@pharmchem.uni-frankfurt.de.

Abstract

We present the design, synthesis and biological evaluation of compounds containing a 2-(benzylidene)hexanoic acid scaffold as multi-target directed γ-secretase-modulators. Broad structural variations were undertaken to elucidate the structure-activity-relationships at the 5-position of the aromatic core. Compound 13 showed the most potent activity profile with IC50 values of 0.79μM (Aβ42), 0.3μM (5-lipoxygenase) and an EC50 value of 4.64μM for PPARγ-activation. This derivative is the first compound exhibiting low micromolar to nanomolar activities for these three targets. Combining γ-secretase-modulation, PPARγ-agonism and inhibition of 5-lipoxygenase in one compound could be a novel disease-modifying multi-target-strategy for Alzheimer's disease to concurrently address the causative amyloid pathology and secondary pathologies like chronic brain inflammation.

KEYWORDS:

5-Lipoxygenase; Alzheimer’s disease; Peroxisome-proliferator-activated-receptor; γ-Secretase; γ-Secretase-modulator

PMID:
25575659
DOI:
10.1016/j.bmcl.2014.12.073
[Indexed for MEDLINE]

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