Amino-caprolactam γ-secretase inhibitors showing potential for the treatment of Alzheimer's disease

Bioorg Med Chem Lett. 2011 Jun 15;21(12):3715-20. doi: 10.1016/j.bmcl.2011.04.079. Epub 2011 May 1.

Abstract

Herein we describe the structure-activity relationship (SAR) of amino-caprolactam analogs derived from amino-caprolactam benzene sulfonamide 1, highlighting affects on the potency of γ-secretase inhibition, selectivity for the inhibition of APP versus Notch processing by γ-secretase and selected pharmakokinetic properties. Amino-caprolactams that are efficacious in reducing the cortical Aβ(x-40) levels in FVB mice via a single 100 mpk IP dose are highlighted.

MeSH terms

  • Alzheimer Disease / drug therapy
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Caprolactam / analogs & derivatives*
  • Caprolactam / chemical synthesis
  • Caprolactam / chemistry
  • Caprolactam / pharmacology
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology*
  • Infusions, Parenteral
  • Inhibitory Concentration 50
  • Mice
  • Molecular Structure
  • Peptide Fragments / metabolism

Substances

  • Amyloid beta-Peptides
  • Enzyme Inhibitors
  • Peptide Fragments
  • amyloid beta-protein (1-40)
  • Caprolactam
  • Amyloid Precursor Protein Secretases