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

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 identifi...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2007-07, Vol.17 (14), p.4006
Main Authors: Prasad, C V C, Zheng, Ming, Vig, Shikha, Bergstrom, Carl, Smith, David W, Gao, Qi, Yeola, Suresh, Polson, Craig T, Corsa, Jason A, Guss, Valerie L, Loo, Alice, Wang, Jian, Sleczka, Bogdan G, Dangler, Charles, Robertson, Barbara J, Hendrick, Joseph P, Roberts, Susan B, Barten, Donna M
Format: Article
Language:English
Subjects:
Alanine - analogs & derivatives
Alanine - pharmacology
Alzheimer Disease - enzymology
Alzheimer Disease - metabolism
Amyloid beta-Peptides
Amyloid Precursor Protein Secretases - antagonists & inhibitors
Animals
Benzodiazepinones - pharmacology
Enzyme Inhibitors - pharmacology
Mice
Mice, Transgenic
Models, Molecular
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Summary: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.
ISSN:0960-894X