beta-Secretase inhibitors: modification at the P4 position and improvement of inhibitory activity in cultured cells

Bioorg Med Chem Lett. 2006 Aug 15;16(16):4354-9. doi: 10.1016/j.bmcl.2006.05.046. Epub 2006 Jun 6.

Abstract

Recently, we reported potent and small-sized beta-secretase (BACE1) inhibitors KMI-570 and KMI-684 in which we replaced carboxylic acid groups at the P(1)(') position of KMI-420 and KMI-429, respectively, with tetrazole derivatives as carboxylic acid bioisosteres. These modifications improved significantly BACE1 inhibitory activity and chemical stability. In this study, the acidic tetrazole ring of the P(4) position of KMI-420 and KMI-570, respectively, was replaced with various hydrogen bond acceptor groups. We found BACE1 inhibitor KMI-574 that exhibited potent inhibitory activity in cultured cells as well as in vitro enzymatic assay.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Carboxylic Acids / chemistry
  • Cells, Cultured
  • Chemistry, Pharmaceutical
  • Drug Design
  • Endopeptidases / chemistry*
  • Esters / chemistry
  • Humans
  • Models, Chemical
  • Models, Molecular
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Tetrazoles / chemistry

Substances

  • Carboxylic Acids
  • Esters
  • Protease Inhibitors
  • Tetrazoles
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human