Details

Autor(en) / Beteiligte

• Churcher, Ian
• Williams, Susie
• Kerrad, Sonia
• Harrison, Timothy
• Castro, José L
• Shearman, Mark S
• Lewis, Huw D
• Clarke, Earl E
• Wrigley, Jonathan D. J
• Beher, Dirk
• Tang, Yui S
• Liu, Wensheng

Titel

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 an Asymmetric Ireland−Claisen Rearrangement

Ist Teil von

• Journal of medicinal chemistry, 2003-06, Vol.46 (12), p.2275-2278

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2003

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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[e][1,4]diazepin-3-yl)butyramide (34) demonstrated excellent in vitro potency (IC50 = 0.06nM). 34 could also be selectively methylated to give [3H]-28, which is of use in radioligand binding assays.