2. Academic Validation
  3. SAR studies of acidic dual γ-secretase/PPARγ modulators

SAR studies of acidic dual γ-secretase/PPARγ modulators

  • Bioorg Med Chem. 2011 Sep 15;19(18):5372-82. doi: 10.1016/j.bmc.2011.08.003.
Martina Hieke 1,  Julia Ness,  Ramona Steri,  Christine Greiner,  Oliver Werz,  Manfred Schubert-Zsilavecz,  Sascha Weggen,  Heiko Zettl
Affiliations

Affiliation

  • 1 Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
PMID: 21873070 DOI: 10.1016/j.bmc.2011.08.003
Abstract

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.

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