Title of article :
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 dis
Author/Authors :
C.V.C. Prasad، نويسنده , , Ming Zheng، نويسنده , , Shikha Vig، نويسنده , , Carl Bergstrom، نويسنده , , David W. Smith، نويسنده , , Qi Gao، نويسنده , , Suresh Yeola، نويسنده , , Craig T. Polson، نويسنده , , Jason A. Corsa، نويسنده , , Valerie L. Guss، نويسنده , , Alice Loo، نويسنده , , Jian Wang، نويسنده , , Bogdan G. Sleczka، نويسنده , , Charles Dangler، نويسنده , , Barbara J. Robertson، نويسنده , , Joseph P. Hendrick، نويسنده , , Susan B. Roberts، نويسنده , , Donna M. Barten، نويسنده ,
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-3H-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.
