2,7-Disubstituted-Pyrrolotriazine Kinase Inhibitors with an Unusually High Degree of Reactive Metabolite Formation
| العنوان: | 2,7-Disubstituted-Pyrrolotriazine Kinase Inhibitors with an Unusually High Degree of Reactive Metabolite Formation |
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| المؤلفون: | Gregory R. Ott, Linda Weinberg, Henry J. Breslin, Lisa D. Aimone, Diane E. Gingrich, Kevin J. Wells-Knecht, Mark A. Ator, Gregory J. Wells, Mehran Yazdanian, Eugen F. Mesaros, Zeqi Huang, Kelli S. Zeigler, Bruce D. Dorsey, Mangeng Cheng |
| المصدر: | Chemical Research in Toxicology. 24:1994-2003 |
| بيانات النشر: | American Chemical Society (ACS), 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Spectrometry, Mass, Electrospray Ionization, Stereochemistry, Chemistry, Pharmaceutical, Toxicology, Mice, Troglitazone, chemistry.chemical_compound, Dogs, Biotransformation, medicine, Animals, Bile, Humans, Pyrroles, Sulfhydryl Compounds, Chromans, Clozapine, Protein Kinase Inhibitors, Chromatography, High Pressure Liquid, chemistry.chemical_classification, Triazines, Kinase, Haplorhini, General Medicine, Glutathione, In vitro, Rats, Biochemistry, chemistry, Toxicity, Microsomes, Liver, Microsome, Thiol, Thiazolidinediones, Protein Kinases, Chromatography, Liquid, medicine.drug |
| الوصف: | There are numerous published studies establishing a link between reactive metabolite formation and toxicity of various drugs. Although the correlation between idiosyncratic reactions and reactive metabolite formation is not 1:1, the association between the two is such that many pharmaceutical companies now monitor for reactive metabolites as a standard part of drug candidate testing and selection. The most common method involves in vitro human microsomal incubations in the presence of a thiol trapping agent, such as glutathione (GSH), followed by LC/MS analysis. In this study, we describe several 2,7-disubstituted-pyrrolotriazine analogues that are extremely potent reactive metabolite precursors. Utilizing a UPLC/UV/MS method, unprecedented levels of GSH adducts were measured that are 5-10 times higher than previously reported for high reactive metabolite-forming compounds such as clozapine and troglitazone. |
| تدمد: | 1520-5010 0893-228X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::da02cdf9e6579ea66120a72466ba6ef7 https://doi.org/10.1021/tx200304r |
| رقم الأكسشن: | edsair.doi.dedup.....da02cdf9e6579ea66120a72466ba6ef7 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15205010 0893228X |
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