Novel orally active, dibenzazepinone-based γ-secretase inhibitors

Structural modifications of the γ-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 (IC50 = 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.

Malonamide analogues of LY411575 were found to be potent inhibitors of γ-secretase in vitro. The introduction of a pentafluoropropyl side chain improved the metabolic stability, and led to malonamide and carbamate analogues with in-vivo activity in models of Alzheimer’s disease.Figure optionsDownload as PowerPoint slide