Second Generation of BACE-1 Inhibitors Part 2: Optimisation of the Non-Prime Side Substituent

Bioorg Med Chem Lett. 2009 Jul 1;19(13):3669-73. doi: 10.1016/j.bmcl.2009.03.150. Epub 2009 Apr 5.

Abstract

Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer's disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors.

MeSH terms

  • Administration, Oral
  • Alzheimer Disease / drug therapy
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Binding Sites
  • Computer Simulation
  • Crystallography, X-Ray
  • Ethylamines / chemical synthesis
  • Ethylamines / chemistry*
  • Ethylamines / pharmacology
  • Humans
  • Mice
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology
  • Rats
  • Structure-Activity Relationship
  • Thiazines / chemistry
  • Thiazines / pharmacology

Substances

  • Amyloid beta-Peptides
  • Ethylamines
  • GSK188909
  • Protease Inhibitors
  • Thiazines
  • Aspartic Acid Endopeptidases