Diamide amino-imidazoles: a novel series of γ-secretase inhibitors for the treatment of Alzheimer's disease

Bioorg Med Chem Lett. 2011 May 1;21(9):2631-6. doi: 10.1016/j.bmcl.2010.12.117. Epub 2010 Dec 30.

Abstract

The synthesis and structure-activity relationship (SAR) of a novel series of di-substituted imidazoles, derived from modification of DAPT, are described. Subsequent optimization led to identification of a highly potent series of inhibitors that contain a β-amine in the imidazole side-chain resulting in a robust in vivo reduction of plasma and brain Aβ in guinea pigs. The therapeutic index between Aβ reductions and changes in B-cell populations were studied for compound 10 h.

MeSH terms

  • Alzheimer Disease*
  • Amination / drug effects
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid beta-Peptides / blood
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Biological Assay
  • Diamide / chemical synthesis
  • Diamide / chemistry
  • Diamide / pharmacology
  • Enzyme Activation / drug effects*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Guinea Pigs
  • HeLa Cells
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Inhibitory Concentration 50
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Enzyme Inhibitors
  • Imidazoles
  • Diamide
  • imidazole
  • Amyloid Precursor Protein Secretases