Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: structure-activity relationship of the aryl region

Bioorg Med Chem Lett. 2010 Oct 15;20(20):6034-9. doi: 10.1016/j.bmcl.2010.08.070. Epub 2010 Aug 19.

Abstract

The structure-activity relationship of the prime region of hydroxyethylamine BACE inhibitors is described. Variation in the aryl linker region with 5- and 6-membered heterocycles provided compounds such as 33 with improved permeability and reduced P-gp liability compared to benzyl amine analog 1.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Alzheimer Disease / drug therapy
  • 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*
  • Crystallography, X-Ray
  • Ethylamines / chemical synthesis
  • Ethylamines / chemistry*
  • Ethylamines / pharmacology*
  • Humans
  • Models, Molecular
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology*
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Ethylamines
  • Protease Inhibitors
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human