2. Academic Validation
  3. 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 gamma-secretase inhibitor with Abeta lowering activity in a transgenic mouse model of Alzheimer's disease

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 gamma-secretase inhibitor with Abeta lowering activity in a transgenic mouse model of Alzheimer's disease

  • Bioorg Med Chem Lett. 2007 Jul 15;17(14):4006-11. doi: 10.1016/j.bmcl.2007.04.082.
C V C Prasad 1,  Ming Zheng,  Shikha Vig,  Carl Bergstrom,  David W Smith,  Qi Gao,  Suresh Yeola,  Craig T Polson,  Jason A Corsa,  Valerie L Guss,  Alice Loo,  Jian Wang,  Bogdan G Sleczka,  Charles Dangler,  Barbara J Robertson,  Joseph P Hendrick,  Susan B Roberts,  Donna M Barten
Affiliations

Affiliation

  • 1 Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. Prasad.Chaturvedula@bms.com
PMID: 17502137 DOI: 10.1016/j.bmcl.2007.04.082
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 gamma-secretase inhibitors were synthesized. Active metabolites contributing to Abeta 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.

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