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2,7-Disubstituted-Pyrrolotriazine Kinase Inhibitors with an Unusually High Degree of Reactive Metabolite Formation
- Source :
- Chemical Research in Toxicology. 24:1994-2003
- Publication Year :
- 2011
- Publisher :
- American Chemical Society (ACS), 2011.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 15205010 and 0893228X
- Volume :
- 24
- Database :
- OpenAIRE
- Journal :
- Chemical Research in Toxicology
- Accession number :
- edsair.doi.dedup.....da02cdf9e6579ea66120a72466ba6ef7