Discovery of (S) -2 -( (S) -2 -(3,5 -difluorophenyl ) -2-hydroxyacetamido ) -N-( (S,Z) -3 -methyl -4 -oxo -4,5 -dihydro -3H-benzo[d|[1,2 ]diazepin -5 -yl )propanamide (BMS -433796 ) : A γ-secretase inhibitor with Aβ lowering activity in a transgenic mouse model of Alzheimer's disease

Abstract We report on the design of benzodiazepinones as peptidomimetics at the carboxy terminus of hydroxyamides. Structure–activity relationships of diazepinones were investigated and orally active γ-secretase inhibitors were synthesized. Active metabolites contributing to Aβ reduction were identified by analysis of plasma samples from Tg2576 mice. In particular, ( S )-2-(( S )-2-(3,5-difluorophenyl)-2-hydroxyacetamido)- N -(( S , Z )-3-methyl-4-oxo-4,5-dihydro-3 H -benzo[ d ][1,2]diazepin-5-yl)propanamide (BMS-433796) was identified with an acceptable pharmacodynamic and pharmacokinetic profile. Chronic dosing of BMS-433796 in Tg2576 mice suggested a narrow therapeutic window and Notch-mediated toxicity at higher doses.