Design and synthesis of potent hydroxyethylamine (HEA) BACE-1 inhibitors carrying prime side 4,5,6,7-tetrahydrobenzazole and 4,5,6,7-tetrahydropyridinoazole templates

Bioorg Med Chem Lett. 2012 Nov 1;22(21):6721-7. doi: 10.1016/j.bmcl.2012.08.097. Epub 2012 Sep 5.

Abstract

A set of low molecular weight compounds containing a hydroxyethylamine (HEA) core structure with different prime side alkyl substituted 4,5,6,7-tetrahydrobenzazoles and one 4,5,6,7-tetrahydropyridinoazole was synthesized. Striking differences were observed on potencies in the BACE-1 enzymatic and cellular assays depending on the nature of the heteroatoms in the bicyclic ring, from the low active compound 4 to inhibitor 6, displaying BACE-1 IC(50) values of 44 nM (enzyme assay) and 65 nM (cell-based assay).

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Azoles / chemical synthesis*
  • Azoles / chemistry
  • Azoles / pharmacology
  • Benzoxazoles / chemical synthesis*
  • Benzoxazoles / chemistry
  • Benzoxazoles / pharmacology
  • Catalytic Domain
  • Crystallography, X-Ray
  • Drug Design*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Ethylamines / chemical synthesis*
  • Ethylamines / chemistry
  • Ethylamines / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Molecular Structure
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology

Substances

  • Azoles
  • Benzoxazoles
  • Enzyme Inhibitors
  • Ethylamines
  • Pyridines
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human