Design and synthesis of piperazine derivatives as a novel class of γ-secretase modulators that selectively lower Aβ₄₂ production

Bioorg Med Chem. 2015 May 1;23(9):1923-34. doi: 10.1016/j.bmc.2015.03.055. Epub 2015 Mar 28.

Abstract

Novel piperazine derivatives as γ-secretase modulators (GSMs) were prepared and tested for their ability to selectively lower Aβ₄₂ production. Lead compound 3, with selective Aβ₄₂-lowering activity, was modified by replacing its imidazolylphenyl moiety with an oxazolylphenyl moiety. Optimization of the urea group significantly improved mouse microsomal stability, while retaining both activity and selectivity. These efforts led to the successful identification of an orally available and brain-penetrant GSM, 6j, which selectively reduced brain Aβ₄₂ in mice.

Keywords: Alzheimer’s disease; Amyloid beta; γ-Secretase modulator.

MeSH terms

  • Administration, Oral
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / biosynthesis*
  • Amyloid beta-Peptides / chemistry
  • Animals
  • Biological Availability
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Peptide Fragments / biosynthesis*
  • Peptide Fragments / chemistry
  • Piperazine
  • Piperazines / administration & dosage
  • Piperazines / chemical synthesis*
  • Piperazines / pharmacology*
  • Rats
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • Piperazines
  • amyloid beta-protein (1-42)
  • Piperazine
  • Amyloid Precursor Protein Secretases