title: SAR-studies of γ-secretase modulators with PPARγ-agonistic and 5-lipoxygenase-inhibitory activity for Alzheimer's disease.
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.
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Flesch
authors.affiliation: Department of Neuropathology, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Ness
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Lamers
authors.affiliation: Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Dehm
authors.affiliation: Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Popella
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Ramona
authors.initials: R
authors.lastname: Steri
authors.affiliation: Department of Neuropathology, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
authors.forename: Isabella
authors.initials: I
authors.lastname: Ogorek
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Hieke
authors.affiliation: Institute of Pharmaceutical Chemistry, Johannes-Gutenberg-University Mainz, Staudingerweg 5, D-55128 Mainz, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Dannhardt
authors.affiliation: Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Department of Neuropathology, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany. Electronic address: sweggen@hhu.de.
authors.forename: Sascha
authors.initials: S
authors.lastname: Weggen
authors.affiliation: 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.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schubert-Zsilavecz
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects*; D001094:Arachidonate 5-Lipoxygenase / Q000187:drug effects*; D002208:Caproates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D047495:PPAR gamma / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D002208:Caproates; D016859:Lipoxygenase Inhibitors; D047495:PPAR gamma; C037652:hexanoic acid; D001094:Arachidonate 5-Lipoxygenase; D053829:Amyloid Precursor Protein Secretases
keywords: 5-Lipoxygenase; Alzheimer’s disease; Peroxisome-proliferator-activated-receptor; γ-Secretase; γ-Secretase-modulator