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.
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