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 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.
Prasad
C V C
CV
Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. Prasad.Chaturvedula@bms.com
Zheng
Ming
M
Vig
Shikha
S
Bergstrom
Carl
C
Smith
David W
DW
Gao
Qi
Q
Yeola
Suresh
S
Polson
Craig T
CT
Corsa
Jason A
JA
Guss
Valerie L
VL
Loo
Alice
A
Wang
Jian
J
Sleczka
Bogdan G
BG
Dangler
Charles
C
Robertson
Barbara J
BJ
Hendrick
Joseph P
JP
Roberts
Susan B
SB
Barten
Donna M
DM
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
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