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

Flesch, Daniel and Ness, Julia and Lamers, Christina and Dehm, Friederike and Popella, Sven and Steri, Ramona and Ogorek, Isabella and Hieke, Martina and Dannhardt, Gerd and Werz, Oliver and Weggen, Sascha and Schubert-Zsilavecz, Manfred. (2015) SAR-studies of γ-secretase modulators with PPARγ-agonistic and 5-lipoxygenase-inhibitory activity for Alzheimer's disease. Bioorganic and Medicinal Chemistry Letters, 25 (4). pp. 841-846.

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Official URL: https://edoc.unibas.ch/70324/

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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.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ricklin)
UniBasel Contributors:Lamers, Christina
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Elsevier
e-ISSN:1464-3405
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:23 May 2020 16:35
Deposited On:23 May 2020 16:35

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