Development of dual targeting inhibitors against aggregations of amyloid-β and tau protein

Eur J Med Chem. 2014 Oct 6:85:228-34. doi: 10.1016/j.ejmech.2014.07.095. Epub 2014 Jul 26.

Abstract

Aggregations of both amyloid-β (Aβ) and hyper-phosphorylated tau proteins are recognized as key pathological manifestations of Alzheimer's disease (AD). Agents that inhibit both those forms of aggregation show promise as drug candidates. Seventeen oligo heteroaromatic compounds were rapidly synthesized via a one-pot, 3- or 4-component coupling procedure. Evaluations showed that compounds E16 and E18 were the most potent inhibitors of Aβ and tau aggregations (E16: IC50s = 0.38, 0.29 μM against Aβ, tau, respectively, E18: IC50s = 0.55, 0.30 μM against Aβ, tau, respectively).

Keywords: Aggregation; Alzheimer's disease; Amyloid-β; Suzuki–Miyaura coupling; Tau.

MeSH terms

  • Amyloid beta-Peptides / chemistry*
  • Drug Evaluation, Preclinical
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / chemistry*
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Peptide Fragments / chemistry*
  • Protein Multimerization / drug effects*
  • Protein Structure, Secondary
  • tau Proteins / chemistry*

Substances

  • Amyloid beta-Peptides
  • Heterocyclic Compounds
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • tau Proteins