Structure-based design, synthesis and biological evaluation of novel β-secretase inhibitors containing a pyrazole or thiazole moiety as the P3 ligand

Bioorg Med Chem Lett. 2015 Feb 1;25(3):668-72. doi: 10.1016/j.bmcl.2014.11.087. Epub 2014 Dec 6.

Abstract

We describe structure-based design, synthesis, and biological evaluation of a series of novel inhibitors bearing a pyrazole (compounds 3a-h) or a thiazole moiety (compounds 4a-e) as the P3 ligand. We have also explored Boc-β-amino-l-alanine as a novel P2 ligand. A number of inhibitors have displayed β-secretase inhibitory potency. Inhibitor 4c has shown potent BACE1 inhibitory activity, Ki=0.25nM, cellular EC50 of 194nM, and displayed good selectivity over BACE2. A model of 4c was created based upon the X-ray structure of 2-bound β-secretase which revealed critical interactions in the active site.

Keywords: Alzheimer’s disease; BACE-1; Memapsin 2; Protease inhibitors; β-secretase.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Binding Sites
  • Catalytic Domain
  • Crystallography, X-Ray
  • Drug Design*
  • Kinetics
  • Ligands
  • Molecular Dynamics Simulation
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / metabolism
  • Protein Binding
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry*
  • Pyrazoles / metabolism
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry*
  • Thiazoles / metabolism

Substances

  • Ligands
  • Protease Inhibitors
  • Pyrazoles
  • Thiazoles
  • pyrazole
  • Amyloid Precursor Protein Secretases