6533b825fe1ef96bd128292f
RESEARCH PRODUCT
SAR-studies of γ-secretase modulators with PPARγ-agonistic and 5-lipoxygenase-inhibitory activity for Alzheimer’s disease
Sascha WeggenRamona SteriIsabella OgorekSven PopellaOliver WerzGerd DannhardtManfred Schubert-zsilaveczJulia NessMartina HiekeFriederike DehmDaniel FleschChristina Lamerssubject
Clinical BiochemistryPharmaceutical SciencePeroxisome proliferator-activated receptorInflammationDiseasePharmacologyInhibitory postsynaptic potentialBiochemistryStructure-Activity Relationshipchemistry.chemical_compoundAlzheimer DiseaseDrug DiscoverymedicineHumansLipoxygenase Inhibitorsγ secretaseCaproatesMolecular BiologyHexanoic acidchemistry.chemical_classificationArachidonate 5-LipoxygenasebiologyOrganic ChemistryPPAR gammachemistryBiochemistryArachidonate 5-lipoxygenasebiology.proteinMolecular MedicineAmyloid Precursor Protein Secretasesmedicine.symptomDerivative (chemistry)description
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2014-11-07 | Bioorganic & Medicinal Chemistry Letters |