Structure-based design, synthesis, and biological evaluation of dihydroquinazoline-derived potent β-secretase inhibitors

Bioorg Med Chem Lett. 2012 Sep 1;22(17):5460-5. doi: 10.1016/j.bmcl.2012.07.043. Epub 2012 Jul 20.

Abstract

Structure-based design, synthesis, and biological evaluation of a series of dihydroquinazoline-derived β-secretase inhibitors incorporating thiazole and pyrazole-derived P2-ligands are described. We have identified inhibitor 4f which has shown potent enzyme inhibitory (K(i)=13 nM) and cellular (IC(50)=21 nM in neuroblastoma cells) assays. A model of 4f was created based upon the X-ray structure of 3a-bound β-secretase. The model suggested possible interactions in the active site.

Publication types

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

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / enzymology
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / chemistry
  • Amyloid Precursor Protein Secretases / metabolism
  • Catalytic Domain
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry*
  • Quinazolines / pharmacology*
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry
  • Thiazoles / pharmacology

Substances

  • Enzyme Inhibitors
  • Pyrazoles
  • Quinazolines
  • Thiazoles
  • pyrazole
  • Amyloid Precursor Protein Secretases