Molecular-modeling based design, synthesis, and activity of substituted piperidines as gamma-secretase inhibitors

Bioorg Med Chem Lett. 2005 Apr 1;15(7):1891-4. doi: 10.1016/j.bmcl.2005.02.006.

Abstract

Alzheimer's disease (AD) is a debilitating disease widely thought to be associated with the accumulation of beta amyloid (Abeta) in the brain. Inhibition of gamma-secretase, one of the enzymes responsible for Abeta production, may be a useful strategy for the treatment of AD. Described below is a series of gamma-secretase inhibitors designed from a scaffold identified by a ROCS [J. Comput. Chem.1996, 17, 1653] search of the corporate database.

MeSH terms

  • Alzheimer Disease / enzymology
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Animals
  • Brain / drug effects*
  • Brain / metabolism
  • Drug Design
  • Endopeptidases / drug effects*
  • Endopeptidases / metabolism
  • Models, Molecular
  • Piperidines / chemical synthesis*
  • Piperidines / pharmacology
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacology
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Piperidines
  • Protease Inhibitors
  • Amyloid Precursor Protein Secretases
  • Endopeptidases