β-Secretase (BACE1) inhibitors with high in vivo efficacy suitable for clinical evaluation in Alzheimer's disease

J Med Chem. 2013 May 23;56(10):3980-95. doi: 10.1021/jm400225m. Epub 2013 May 2.

Abstract

An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the pKa and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF Aβ40 and 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of Aβ40 and 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Brain Chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Fluorine / chemistry
  • Humans
  • Indicators and Reagents
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Molecular
  • Oxazines / chemical synthesis
  • Oxazines / pharmacology
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship
  • X-Ray Diffraction

Substances

  • Enzyme Inhibitors
  • Indicators and Reagents
  • Oxazines
  • Fluorine
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse

Associated data

  • PDB/3ZLQ
  • PDB/3ZMG
  • PDB/4J0P
  • PDB/4J0T
  • PDB/4J0V
  • PDB/4J0Y
  • PDB/4J0Z
  • PDB/4J17
  • PDB/4J1C
  • PDB/4J1E
  • PDB/4J1F
  • PDB/4J1H
  • PDB/4J1I
  • PDB/4J1K