title: 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.
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.
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. Prasad.Chaturvedula@bms.com
authors.forename: C V C
authors.initials: CV
authors.lastname: Prasad
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.forename: Shikha
authors.initials: S
authors.lastname: Vig
authors.forename: Carl
authors.initials: C
authors.lastname: Bergstrom
authors.forename: David W
authors.initials: DW
authors.lastname: Smith
authors.forename: Qi
authors.initials: Q
authors.lastname: Gao
authors.forename: Suresh
authors.initials: S
authors.lastname: Yeola
authors.forename: Craig T
authors.initials: CT
authors.lastname: Polson
authors.forename: Jason A
authors.initials: JA
authors.lastname: Corsa
authors.forename: Valerie L
authors.initials: VL
authors.lastname: Guss
authors.forename: Alice
authors.initials: A
authors.lastname: Loo
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Bogdan G
authors.initials: BG
authors.lastname: Sleczka
authors.forename: Charles
authors.initials: C
authors.lastname: Dangler
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Robertson
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Hendrick
authors.forename: Susan B
authors.initials: SB
authors.lastname: Roberts
authors.forename: Donna M
authors.initials: DM
authors.lastname: Barten
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000544:Alzheimer Disease / Q000201:enzymology* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular
chemical_list: C522903:2-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-(3-methyl-4-oxo-4,5-dihydro-3H-benzo(d)(1,2)diazepin-5-yl)propanamide; D016229:Amyloid beta-Peptides; D001570:Benzodiazepinones; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine