부산대학교 도서관

Drug-inducedtoxicity is a leading cause of drug withdrawal fromclinical development and clinical use and represents a major impedimentto the development of new drugs. The mechanisms underlying drug-inducedtoxicities are varied; however, metabolic bioactivation to form reactivemetabolites has been identified as a major contributor.1,2 These electrophilic species can covalently modify important biologicalmacromolecules and thereby increase the risk of adverse drug reactionsor idiosyncratic toxicity. Consequently, screening compounds for theirpropensity to form reactive metabolites has become an integral partof drug discovery programs. This screening process typically involvesidentification of structural alerts as well as the generation of reactivemetabolites in vitroin subcellular hepatic fractions,followed by trapping the reactive species with nucleophiles and characterizationvia LC-MS. This article presents evidence for the bioactivation ofa series of aminopyrazole derivatives via LC-MS detection of glutathioneethyl ester-trapped reactive intermediates formed in human liver microsomalincubations. These results indicate that the aminopyrazole motif,within specific contexts, may be considered a new structural alertfor the potential formation of reactive metabolites. [ABSTRACT FROM AUTHOR]