Substituted 4-morpholine N-arylsulfonamides as γ-secretase inhibitors

Eur J Med Chem. 2016 Nov 29:124:36-48. doi: 10.1016/j.ejmech.2016.08.024. Epub 2016 Aug 13.

Abstract

The design, synthesis, SAR, and biological profile of a substituted 4-morpholine sulfonamide series of γ-secretase inhibitors (GSIs) were described. In several cases, the resulting series of GSIs reduced CYP liabilities and improved γ-secretase inhibition activity compared to our previous research series. Selected compounds demonstrated significant reduction of amyloid-β (Aβ) after acute oral dosing in a transgenic animal model of Alzheimer's disease (AD).

Keywords: Alzheimer's disease; substituted 4-morpholine sulfonamide; γ-secretase inhibitor.

MeSH terms

  • Alzheimer Disease / drug therapy
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Animals
  • Drug Design*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Male
  • Mice
  • Morpholines / chemistry*
  • Morpholines / pharmacology*
  • Morpholines / therapeutic use
  • Structure-Activity Relationship
  • Sulfonamides / chemistry*

Substances

  • Enzyme Inhibitors
  • Morpholines
  • Sulfonamides
  • Amyloid Precursor Protein Secretases