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
  • 1. Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. [email protected]
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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