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. Epub 2011 Aug 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Animals
  • CHO Cells
  • COS Cells
  • Caproates / chemical synthesis
  • Caproates / chemistry
  • Caproates / pharmacology*
  • Cell Survival / drug effects
  • Chlorocebus aethiops
  • Cricetinae
  • Cyclooxygenase 1 / metabolism
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase Inhibitors / chemical synthesis
  • Cyclooxygenase Inhibitors / chemistry
  • Cyclooxygenase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Conformation
  • PPAR gamma / antagonists & inhibitors*
  • Recombinant Proteins / antagonists & inhibitors
  • Sheep
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Caproates
  • Cyclooxygenase Inhibitors
  • PPAR gamma
  • Recombinant Proteins
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Amyloid Precursor Protein Secretases