SAR studies of acidic dual gamma-secretase/PPARgamma modulators.

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Hieke M, Ness J, Steri R, Greiner C, Werz O, Schubert-Zsilavecz M, Weggen S, Zettl H

SAR studies of acidic dual gamma-secretase/PPARgamma modulators.

Bioorg Med Chem. 2011 Sep 15;19(18):5372-82. doi: 10.1016/j.bmc.2011.08.003. Epub 2011 Aug 6.

PubMed ID
21873070 [ View in PubMed
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Abstract

A novel set of dual gamma-secretase/PPARgamma 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 gamma-secretase/PPARgamma 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) Abeta42=2.4 muM and an EC(50) PPARgamma=7.2 muM and could be a valuable tool to further evaluate the concept of dual gamma-secretase/PPARgamma modulators in animal models of Alzheimer's disease.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
CarprofenProstaglandin G/H synthase 2IC 50 (nM)102N/AN/ADetails
IbuprofenProstaglandin G/H synthase 2IC 50 (nM)80000N/AN/ADetails
IndomethacinProstaglandin G/H synthase 2IC 50 (nM)10N/AN/ADetails
PioglitazonePeroxisome proliferator-activated receptor gammaEC 50 (nM)300N/AN/ADetails
RosiglitazonePeroxisome proliferator-activated receptor gammaEC 50 (nM)43N/AN/ADetails