Novel orally active, dibenzazepinone-based gamma-secretase inhibitors.

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.