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

• Published in: Bioorganic & medicinal chemistry letters Vol. 25; no. 4; pp. 841 - 846
• Main Authors: Flesch, Daniel, Ness, Julia, Lamers, Christina, Dehm, Friederike, Popella, Sven, Steri, Ramona, Ogorek, Isabella, Hieke, Martina, Dannhardt, Gerd, Werz, Oliver, Weggen, Sascha, Schubert-Zsilavecz, Manfred
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.02.2015; Elsevier
• Subjects: 5-Lipoxygenase; Alzheimer Disease - drug therapy; Alzheimer’s disease; Amyloid Precursor Protein Secretases - drug effects; Arachidonate 5-Lipoxygenase - drug effects; Caproates - chemistry; Caproates - pharmacology; Caproates - therapeutic use; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Humans; Life Sciences & Biomedicine; Lipoxygenase Inhibitors - pharmacology; Lipoxygenase Inhibitors - therapeutic use; Peroxisome-proliferator-activated-receptor; Pharmacology & Pharmacy; Physical Sciences; PPAR gamma - agonists; Science & Technology; Structure-Activity Relationship; γ-Secretase; γ-Secretase-modulator; γ-Secretase-modulator; Peroxisome-proliferator-activated-receptor; Alzheimer’s disease; γ-Secretase; 5-Lipoxygenase; TARGET; PATHOLOGY; gamma-Secretase-modulator; gamma-Secretase; PROSTAGLANDIN E-2 SYNTHASE-1; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; NSAIDS; MOUSE MODEL; IN-VIVO; BIOLOGICAL EVALUATION; INHIBITORS; Alzheimer's disease; DERIVATIVES
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.12.073

[Display omitted] 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.