Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: prime side chromane-containing inhibitors

Bioorg Med Chem Lett. 2013 Aug 15;23(16):4674-9. doi: 10.1016/j.bmcl.2013.06.006. Epub 2013 Jun 11.

Abstract

The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P1' region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2' substituent of chromane-HEA(s) with polar substituents provided improvements in the compound's in vitro permeability. Significant potency gains were observed with small aliphatic substituents such as methyl, n-propyl, and cyclopropyl when placed at the C-2 position of the chromane.

Keywords: Alzheimer’s disease; BACE-1; Beta-secratase inhibitor; Cat-D; Chromane; Hydroxyethylamine.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Binding Sites
  • Cells, Cultured
  • Chromans / chemistry*
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis*
  • Ethylamines / chemical synthesis
  • Ethylamines / chemistry
  • Ethylamines / pharmacology
  • Inhibitory Concentration 50
  • Models, Molecular
  • Structure-Activity Relationship

Substances

  • Chromans
  • Enzyme Inhibitors
  • Ethylamines
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human