Evidence for the in vitro bioactivation of aminopyrazole derivatives: trapping reactive aminopyrazole intermediates using glutathione ethyl ester in human liver microsomes

Eileen Ryan, Benjamin J Morrow, Catherine F Hemley, Jo-Anne Pinson, Susan A Charman, Francis C K Chiu, Richard C Foitzik

Research output: Contribution to journalArticleResearchpeer-review

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. 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.
Original languageEnglish
Pages (from-to)1747-1752
Number of pages6
JournalChemical Research in Toxicology
Volume28
Issue number9
DOIs
Publication statusPublished - 2015

Cite this

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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. 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.",
author = "Eileen Ryan and Morrow, {Benjamin J} and Hemley, {Catherine F} and Jo-Anne Pinson and Charman, {Susan A} and Chiu, {Francis C K} and Foitzik, {Richard C}",
year = "2015",
doi = "10.1021/acs.chemrestox.5b00202",
language = "English",
volume = "28",
pages = "1747--1752",
journal = "Chemical Research in Toxicology",
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Evidence for the in vitro bioactivation of aminopyrazole derivatives: trapping reactive aminopyrazole intermediates using glutathione ethyl ester in human liver microsomes. / Ryan, Eileen; Morrow, Benjamin J; Hemley, Catherine F; Pinson, Jo-Anne; Charman, Susan A; Chiu, Francis C K; Foitzik, Richard C.

In: Chemical Research in Toxicology, Vol. 28, No. 9, 2015, p. 1747-1752.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Evidence for the in vitro bioactivation of aminopyrazole derivatives: trapping reactive aminopyrazole intermediates using glutathione ethyl ester in human liver microsomes

AU - Ryan, Eileen

AU - Morrow, Benjamin J

AU - Hemley, Catherine F

AU - Pinson, Jo-Anne

AU - Charman, Susan A

AU - Chiu, Francis C K

AU - Foitzik, Richard C

PY - 2015

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AB - 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. 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.

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