Design and synthesis of highly potent benzodiazepine gamma-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

Autor:	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
Rok vydání:	2003
Předmět:	Benzodiazepines Benzodiazepinones Structure-Activity Relationship Amyloid beta-Peptides Drug Design Isotope Labeling Endopeptidases Tumor Cells Cultured Aspartic Acid Endopeptidases Humans Protease Inhibitors Amyloid Precursor Protein Secretases Ligands
Zdroj:	Journal of medicinal chemistry. 46(12)
ISSN:	0022-2623
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=pmid________::12eccae3bbbbf4c66a91024b90e2c14e https://pubmed.ncbi.nlm.nih.gov/12773031 Zobrazit plný text záznamu