Novel orally active, dibenzazepinone-based gamma-secretase inhibitors

Bioorg Med Chem Lett. 2007 Nov 1;17(21):5918-23. doi: 10.1016/j.bmcl.2007.07.078. Epub 2007 Aug 22.

Abstract

Structural modifications of the gamma-secretase inhibitor, LY411575, led to a malonamide analogue (S),(S)-1 with potent inhibitory activity in vitro, but disappointing activity in a mouse model of Alzheimer's disease. Identification and replacement of a metabolically labile position provided an improved compound (R/S),(S)-13 with high in vitro activity (IC(50)=1.7 nM), and in vivo activity after oral administration (MED=3 mg/kg). Further modifications gave an equipotent carbamate analogue 14 with improved molecular properties.

MeSH terms

  • Administration, Oral
  • Alanine / analogs & derivatives*
  • Alanine / chemistry
  • Alanine / pharmacology
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Animals
  • Azepines / administration & dosage
  • Azepines / chemistry
  • Azepines / pharmacology*
  • Chromatography, High Pressure Liquid
  • Enzyme Inhibitors / pharmacology*
  • Mice
  • Mice, Transgenic
  • Tandem Mass Spectrometry

Substances

  • Azepines
  • Enzyme Inhibitors
  • N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide
  • Amyloid Precursor Protein Secretases
  • Alanine