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