Improving the permeability of the hydroxyethylamine BACE-1 inhibitors: structure-activity relationship of P2' substituents

Bioorg Med Chem Lett. 2010 Aug 15;20(16):4789-94. doi: 10.1016/j.bmcl.2010.06.112. Epub 2010 Jun 25.

Abstract

Herein we describe further evolution of hydroxyethylamine inhibitors of BACE-1 with enhanced permeability characteristics necessary for CNS penetration. Variation at the P2' position of the inhibitor with more polar substituents led to compounds 19 and 32, which retained the potency of more lipophilic analog 1 but with much higher observed passive permeability in MDCK cellular assay.

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / chemistry*
  • Acetamides / pharmacokinetics
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Binding Sites
  • Butanols / chemical synthesis
  • Butanols / chemistry*
  • Butanols / pharmacokinetics
  • Cell Membrane Permeability / drug effects
  • Crystallography, X-Ray
  • Cyclohexylamines / chemical synthesis
  • Cyclohexylamines / chemistry*
  • Cyclohexylamines / pharmacokinetics
  • Humans
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacokinetics
  • Structure-Activity Relationship

Substances

  • Acetamides
  • Butanols
  • Cyclohexylamines
  • Protease Inhibitors
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human