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

Bioorg Med Chem Lett. 2015 Feb 15;25(4):841-6. doi: 10.1016/j.bmcl.2014.12.073. Epub 2014 Dec 30.


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.

Keywords: 5-Lipoxygenase; Alzheimer’s disease; Peroxisome-proliferator-activated-receptor; γ-Secretase; γ-Secretase-modulator.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid Precursor Protein Secretases / drug effects*
  • Arachidonate 5-Lipoxygenase / drug effects*
  • Caproates / chemistry
  • Caproates / pharmacology
  • Caproates / therapeutic use*
  • Humans
  • Lipoxygenase Inhibitors / pharmacology*
  • Lipoxygenase Inhibitors / therapeutic use
  • PPAR gamma / agonists*
  • Structure-Activity Relationship


  • Caproates
  • Lipoxygenase Inhibitors
  • PPAR gamma
  • hexanoic acid
  • Arachidonate 5-Lipoxygenase
  • Amyloid Precursor Protein Secretases