Chemical reactivity of methoxy 4-o-aryl quinolines: identification of glutathione displacement products in vitro and in vivo.
作者： Yohannes Teffera , Adria E. Colletti , Jean Christophe Harmange , L. Steven Hollis , Brian K. Albrecht
DOI: 10.1021/TX800307N
关键词: Microsome 、 Thioether 、 Adduct 、 Cysteine 、 Thiol 、 Quinoline 、 Chemistry 、 Stereochemistry 、 In vivo 、 Glutathione
摘要: AMG 458 {1-(2-hydroxy-2-methylpropyl)-N-[5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl]-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide} is a potent, selective inhibitor of c-Met, receptor tyrosine kinase that often deregulated in cancer. was observed to bind covalently liver microsomal proteins from rats and humans the absence NADPH. When [14C]AMG incubated with microsomes presence glutathione N-acetyl cysteine, thioether adducts were detected by radiochromatography LC/MS/MS analysis. These also formed upon incubation cysteine buffers at pH 7.4. In vivo, bile urine duct-cannulated dosed 458. The two isolated, their structures determined MS/MS NMR identified resulted thiol displacement reaction yield quinoline structure corresponding h...
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