SAR studies of acidic dual γ-secretase/PPARγ modulators.


A novel set of dual γ-secretase/PPARγ modulators characterized by a 2-benzyl hexanoic acid scaffold is presented. Synthetic efforts were focused on the variation of the substitution pattern of the central benzene. Finally, we obtained a new class of 2,5-disubstituted 2-benzylidene hexanoic acid derivatives, which act as dual γ-secretase/PPARγ modulators in the low micromolar range. We have explored broad SAR and successfully improved the dual pharmacological activity and the selectivity profile against potential off-targets such as NOTCH and COX. Compound 17 showed an IC(50) Aβ42=2.4 μM and an EC(50) PPARγ=7.2 μM and could be a valuable tool to further evaluate the concept of dual γ-secretase/PPARγ modulators in animal models of Alzheimer's disease.

DOI: 10.1016/j.bmc.2011.08.003


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@article{Hieke2011SARSO, title={SAR studies of acidic dual γ-secretase/PPARγ modulators.}, author={Martina Hieke and Julia Ness and Ramona Steri and Christine Greiner and Oliver Werz and Manfred Schubert-Zsilavecz and Sascha Weggen and Heiko Zettl}, journal={Bioorganic & medicinal chemistry}, year={2011}, volume={19 18}, pages={5372-82} }