Iminoheterocycles as gamma-secretase modulators

Bioorg Med Chem Lett. 2010 Sep 15;20(18):5380-4. doi: 10.1016/j.bmcl.2010.07.121. Epub 2010 Aug 1.

Abstract

The synthesis of a novel series of iminoheterocycles and their structure-activity relationship (SAR) as modulators of gamma-secretase activity will be detailed. Encouraging SAR generated from a monocyclic core led to a structurally unique bicyclic core. Selected compounds exhibit good potency as gamma-secretase modulators, excellent rat pharmacokinetics, and lowering of Abeta42 levels in various in vivo models.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Brain / metabolism
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
  • Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
  • Humans
  • Imines / chemistry*
  • Imines / pharmacokinetics
  • Imines / therapeutic use*
  • Mice
  • Mice, Transgenic
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / metabolism*
  • Rats
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Bridged Bicyclo Compounds, Heterocyclic
  • Imines
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • Amyloid Precursor Protein Secretases