Synthesis of (3S,4S)-4-aminopyrrolidine-3-ol derivatives and biological evaluation for their BACE1 inhibitory activities

Bioorg Med Chem Lett. 2016 Jan 1;26(1):51-4. doi: 10.1016/j.bmcl.2015.11.033. Epub 2015 Nov 11.

Abstract

Synthesis, SAR study and BACE1 inhibitory activity of (3S,4S)-4-aminopyrrolidine-3-ol derivatives (2) were described. The compound 7c exhibited more inhibition activity than 11a (IC50: 0.05μM vs 0.12μM, respectively), but the latter was more effective in cell-based assay (IC50: 1.7μM vs 40% inhibition by 7c @ 10μM) due to the relatively higher cell permeability. Most of the compounds showed high selectivity over BACE2 and cathepsin D. This work will provide useful information for further structural modifications to develop potent BACE1 inhibitors in cell.

Keywords: Alzheimer’s disease; BACE1 inhibitors; Pyrrolidine derivatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Models, Molecular
  • Molecular Structure
  • PC12 Cells
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology*
  • Rats
  • Structure-Activity Relationship

Substances

  • 4-aminopyrrolidine-3-ol
  • Protease Inhibitors
  • Pyrrolidines
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, rat