Novel orally active, dibenzazepinone-based gamma-secretase inhibitors.
Bioorg Med Chem Lett
; 17(21): 5918-23, 2007 Nov 01.
Article
in En
| MEDLINE
| ID: mdl-17869099
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Azepines
/
Alanine
/
Enzyme Inhibitors
/
Amyloid Precursor Protein Secretases
Limits:
Animals
Language:
En
Journal:
Bioorg Med Chem Lett
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2007
Document type:
Article
Affiliation country:
Switzerland