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Research ArticleArticle

Metabolism of c-Met kinase inhibitors containing quinoline by aldehyde oxidase, electron donating and steric hindrance effect

Jiang Wei Zhang, Wen Xiao, Zhen Ting Gao, Zheng Tian Yu and Ji Yue (Jeff) Zhang
Drug Metabolism and Disposition September 12, 2018, dmd.118.081919; DOI: https://doi.org/10.1124/dmd.118.081919
Jiang Wei Zhang
China Novartis Institutes for Biomedical Research
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  • For correspondence: zjw@dicp.ac.cn jeff.zhang@novartis.com
Wen Xiao
China Novartis Institutes for Biomedical Research
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Zhen Ting Gao
China Novartis Institutes for Biomedical Research
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Zheng Tian Yu
China Novartis Institutes for Biomedical Research
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Ji Yue (Jeff) Zhang
China Novartis Institutes for Biomedical Research
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  • For correspondence: zjw@dicp.ac.cn jeff.zhang@novartis.com
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Abstract

Some quinoline containing c-Met kinase inhibitors are aldehyde oxidase (AO) substrates. 3-substituted quinoline triazolopyridine analogues were synthesized to understand the electron donating and steric hindrance effect on AO-mediated metabolism. Metabolic stability studies for these quinoline analogues were carried out in liver cytosol from mice, rats, cyno monkeys, and humans. Several 3-N-substituted analogues were found to be unstable in monkey liver cytosolic incubations (t1/2 < 10 min), and five of them (63, 53, 51, 11, and 71) were chosen for additional mechanistic studies. Monooxygenation on the quinoline ring was identified by LC/MS/MS. Metabolite formation was inhibited by the AO inhibitors menadione and raloxifene, but not by the xanthine oxidase inhibitor allopurinol. It was found that small electron donating groups at the 3-quinoline moiety made the analogues more susceptible to AO metabolism, while large 3-substituents could reverse the trend. Although species differences were observed, this trend was applicable to all species tested. Small electron donating substituents at the 3-quinoline moiety increased both affinity (decreased Km) and Vmax towards AO in kinetic studies, while large substituents decreased both parameters probably due to steric hindrance. Based on our analysis, a common structural feature with high AO liability was proposed. Our finding could provide useful information for chemists to minimize potential AO liability when designing quinoline analogues.

  • aldehyde oxidases
  • mass spectrometry/MS
  • metabolite identification
  • structure-activity relationships
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 51 (2)
Drug Metabolism and Disposition
Vol. 51, Issue 2
1 Feb 2023
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Research ArticleArticle

Metabolism of c-Met kinase inhibitors containing quinoline by aldehyde oxidase, electron donating and steric hindrance effect

Jiang Wei Zhang, Wen Xiao, Zhen Ting Gao, Zheng Tian Yu and Ji Yue (Jeff) Zhang
Drug Metabolism and Disposition September 12, 2018, dmd.118.081919; DOI: https://doi.org/10.1124/dmd.118.081919

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Research ArticleArticle

Metabolism of c-Met kinase inhibitors containing quinoline by aldehyde oxidase, electron donating and steric hindrance effect

Jiang Wei Zhang, Wen Xiao, Zhen Ting Gao, Zheng Tian Yu and Ji Yue (Jeff) Zhang
Drug Metabolism and Disposition September 12, 2018, dmd.118.081919; DOI: https://doi.org/10.1124/dmd.118.081919
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