Structure-based optimization of oxadiazole-based GSK-3 inhibitors

Fabio Lo Monte, Thomas Kramer, Jiamin Gu, Martin Brodrecht, Johannes Pilakowski, Ana Fuertes, Juan Manuel Dominguez, Batya Plotkin, Hagit Eldar-Finkelman, Boris Schmidt

Research output: Contribution to journalArticlepeer-review


Inhibition of glycogen synthase kinase-3 (GSK-3) induces neuroprotective effects, e.g. decreases β-amyloid production and reduces tau hyperphosphorylation, which are both associated with Alzheimer's disease (AD). The two isoforms of GSK-3 in mammalians are GSK-3α and β, which share 98% homology in their catalytic domains. We investigated GSK-3 inhibitors based on 2 different scaffolds in order to elucidate the demands of the ATP-binding pocket [1]. Particularly, the oxadiazole scaffold provided potent and selective GSK-3 inhibitors. For example, the most potent inhibitor of the present series, the acetamide 26d, is characterized by an IC50 of 2 nM for GSK-3α and 17 nM for GSK-3β. In addition, the benzodioxane 8g showed up to 27-fold selectivity for GSK-3α over GSK-3β, with an IC 50 of 35 nM for GSK-3α. Two GSK-3 inhibitors were further profiled for efficacy and toxicity in the wild-type (wt) zebrafish embryo assay to evaluate simultaneously permeability and safety.

Original languageEnglish
Pages (from-to)26-40
Number of pages15
JournalEuropean Journal of Medicinal Chemistry
StatePublished - Mar 2013


  • Alzheimer's disease
  • Glycogen synthase Kinase-3 (GSK-3)
  • Reversible inhibition
  • Structure-activity relationship (SAR)
  • Zebrafish phenotype

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


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