1. SAR-studies of γ-secretase modulators with PPARγ-agonistic and 5-lipoxygenase-inhibitory activity for Alzheimer’s disease
- Author
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Sascha Weggen, Ramona Steri, Isabella Ogorek, Sven Popella, Oliver Werz, Gerd Dannhardt, Manfred Schubert-Zsilavecz, Julia Ness, Martina Hieke, Friederike Dehm, Daniel Flesch, and Christina Lamers
- Subjects
Clinical Biochemistry ,Pharmaceutical Science ,Peroxisome proliferator-activated receptor ,Inflammation ,Disease ,Pharmacology ,Inhibitory postsynaptic potential ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Alzheimer Disease ,Drug Discovery ,medicine ,Humans ,Lipoxygenase Inhibitors ,γ secretase ,Caproates ,Molecular Biology ,Hexanoic acid ,chemistry.chemical_classification ,Arachidonate 5-Lipoxygenase ,biology ,Organic Chemistry ,PPAR gamma ,chemistry ,Arachidonate 5-lipoxygenase ,biology.protein ,Molecular Medicine ,Amyloid Precursor Protein Secretases ,medicine.symptom ,Derivative (chemistry) - 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 0.79 μM (Aβ42), 0.3 μM (5-lipoxygenase) and an EC50 value of 4.64 μM 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.
- Published
- 2015