کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1372607 | 981872 | 2009 | 6 صفحه PDF | دانلود رایگان |
Previous studies have demonstrated the CYP3A4 mediated oxidation of the 5-aminooxindole motif, present in the trifluoromethylpyrimidine class of PYK-2 inhibitors, to a reactive bis-imine species, which can be trapped with glutathione (GSH) in human liver microsomal incubations. The corresponding 5-aminobenzsultam derivatives, which should possess a similar oxidative liability, do not form GSH conjugates in microsomal incubations. In the current study, we conducted a retrospective analysis on representative 5-aminooxindole and 5-aminobenzsultam PYK-2 inhibitors utilizing CYP3A4 molecular docking and quantum chemical calculations to rationalize the bioactivation differences. Our analysis revealed key differences in (a) active site binding and (b) two-electron oxidation rates, which correlate with GSH adduct formation with the two moieties. The value of linear ion/orbitrap mass spectrometry to detect GSH conjugates with greater sensitivity, compared with conventional triple quadrupole mass spectrometry approaches, was also demonstrated in the course of these studies.
CYP molecular docking, ab initio measurements and sensitive MS detection techniques were used to explain differences in enzymatic oxidation of the 5-aminooxindole and 5-aminobensultam derivatives 1 and 2, respectively, to reactive metabolites.Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 19, Issue 12, 15 June 2009, Pages 3177–3182