Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-β hydrolysis

Eur J Med Chem. 2014 May 22:79:184-93. doi: 10.1016/j.ejmech.2014.04.009. Epub 2014 Apr 4.

Abstract

Insulin degrading enzyme (IDE) is a highly conserved zinc metalloprotease that is involved in the clearance of various physiologically peptides like amyloid-beta and insulin. This enzyme has been involved in the physiopathology of diabetes and Alzheimer's disease. We describe here a series of small molecules discovered by screening. Co-crystallization of the compounds with IDE revealed a binding both at the permanent exosite and at the discontinuous, conformational catalytic site. Preliminary structure-activity relationships are described. Selective inhibition of amyloid-beta degradation over insulin hydrolysis was possible. Neuroblastoma cells treated with the optimized compound display a dose-dependent increase in amyloid-beta levels.

Keywords: Amyloid-beta peptides; Enzymes; Inhibitors; Medicinal chemistry; Structure–activity relationships; X-ray diffraction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / chemical synthesis
  • Acetates / chemistry
  • Acetates / pharmacology*
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Dose-Response Relationship, Drug
  • Humans
  • Hydrolysis
  • Imidazoles / chemistry*
  • Insulysin / metabolism*
  • Molecular Structure
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Acetates
  • Amyloid beta-Peptides
  • Imidazoles
  • Small Molecule Libraries
  • imidazole
  • Insulysin