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
Journal of Medicinal Chemistry2003Vol. 46(12), pp. 2275–2278
Citations Over TimeTop 16% of 2003 papers
Ian Churcher, Susie Williams, Sonia Kerrad, Timothy Harrison, José L. Castro, Mark S. Shearman, Huw D. Lewis, Earl E. Clarke, Jonathan D.J. Wrigley, Dirk Beher, Yui S. Tang, Wensheng Liu
Abstract
Novel benzodiazepine-containing gamma-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 alpha-alkyl or aryl and beta-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 (IC(50) = 0.06 nM). 34 could also be selectively methylated to give [(3)H]-28, which is of use in radioligand binding assays.
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