Design and synthesis of 1,4-dihydropyridine derivatives as BACE-1 inhibitors

Eur J Med Chem. 2010 Jun;45(6):2578-90. doi: 10.1016/j.ejmech.2010.02.046. Epub 2010 Feb 23.

Abstract

BACE-1 has been shown to be an attractive therapeutic target in Alzheimer's disease (AD). Using a 1,4-dihydropyridine (DHP) scaffold, we synthesized new inhibitors of BACE-1 by modifying the known BACE inhibitor 2 containing a hydroxyethylamine (HEA) motif. Using structure-based drug design based on computer-aided molecular docking, the isophthalamide ring of 2 was replaced with a 1,4-dihydropyridine ring as a brain-targeting strategy. Several of the new dihydropyridine derivatives were synthesized and their BACE-1-inhibitory activities were evaluated using a cell-based, reporter gene assay system that measures the cleavage of alkaline phosphatase (AP)-APP fusion protein by BACE-1. Most of the 1,4-DHP analogs showed BACE-1-inhibitory activities with IC50 values in the range 8-30 microM, suggesting that the 1,4-DHP skeleton may be utilized to develop brain-targeting BACE-1 inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / chemistry
  • Amyloid Precursor Protein Secretases / metabolism
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / chemistry
  • Aspartic Acid Endopeptidases / metabolism
  • Cell Line
  • Dihydropyridines / chemical synthesis*
  • Dihydropyridines / chemistry
  • Dihydropyridines / metabolism
  • Dihydropyridines / pharmacology*
  • Drug Design*
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Conformation

Substances

  • Dihydropyridines
  • 1,4-dihydropyridine
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human