title: Evidence for the in vitro bioactivation of aminopyrazole derivatives: trapping reactive aminopyrazole intermediates using glutathione ethyl ester in human liver microsomes.
abstract: Drug-induced toxicity is a leading cause of drug withdrawal from clinical development and clinical use and represents a major impediment to the development of new drugs. The mechanisms underlying drug-induced toxicities are varied; however, metabolic bioactivation to form reactive metabolites has been identified as a major contributor.1,2 These electrophilic species can covalently modify important biological macromolecules and thereby increase the risk of adverse drug reactions or idiosyncratic toxicity. Consequently, screening compounds for their propensity to form reactive metabolites has become an integral part of drug discovery programs. This screening process typically involves identification of structural alerts as well as the generation of reactive metabolites in vitro in subcellular hepatic fractions, followed by trapping the reactive species with nucleophiles and characterization via LC-MS. This article presents evidence for the bioactivation of a series of aminopyrazole derivatives via LC-MS detection of glutathione ethyl ester-trapped reactive intermediates formed in human liver microsomal incubations. These results indicate that the aminopyrazole motif, within specific contexts, may be considered a new structural alert for the potential formation of reactive metabolites.
authors: Eileen
authors: E
authors: Ryan
authors: Cancer Therapeutics CRC , 343 Royal Parade, Parkville, Victoria 3052 Australia.
authors: Benjamin J
authors: BJ
authors: Morrow
authors: Cancer Therapeutics CRC , 343 Royal Parade, Parkville, Victoria 3052 Australia.
authors: Catherine F
authors: CF
authors: Hemley
authors: Cancer Therapeutics CRC , 343 Royal Parade, Parkville, Victoria 3052 Australia.
authors: Jo-Anne
authors: JA
authors: Pinson
authors: Susan A
authors: SA
authors: Charman
authors: Francis C K
authors: FC
authors: Chiu
authors: Cancer Therapeutics CRC , 343 Royal Parade, Parkville, Victoria 3052 Australia.
authors: Richard C
authors: RC
authors: Foitzik
mesh_terms: D065767:Activation, Metabolic; D004952:Esters / Q000737:chemistry; D005978:Glutathione / Q000737:chemistry*; D006801:Humans; D011720:Pyrazoles / Q000737:chemistry*
chemical_list: D004952:Esters; D011720:Pyrazoles; D005978:Glutathione