Design and Synthesis of Highly Potent Benzodiazepine γ-Secretase Inhibitors: Preparation of (2S,3R)-3-(3,4-Difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]-diazepin-3-yl)butyramide by Use of a

摘要

Novel benzodiazepine-containing γ-secretase inhibitors for potential use in Alzheimer's disease have been designed that incorporate a substituted hydrocinnamide C-3 side chain. A syn combination of α-alkyl or aryl and β-hydroxy or hydroxymethyl substituents was shown to give highly potent compounds. In particular, (2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-((3S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[3][1,4] diazepin-3-yl)butyramide (340 demonstrated excellent in vitro potency (IC_(50) = 0.06nM). 34 could also be selectively methylated to give [~3H]-28, which is of use in radioligand binding assays.