Zhang, Jiangwei, Xiao, Sean, Gao, Zhenting, Yu, Zhengtian and Zhang, Jeff (2018) Metabolism of quinoline containing C-Met kinase inhibitors by aldehyde oxidase, effect of electron donating group and steric hindrance. Drug metabolism and disposition. pp. 1-34. ISSN https://doi.org/10.1124/dmd.118.081919

Abstract

Quinoline-containing c-Met kinase inhibitors are known to be substrate of aldehyde oxidase (AO). 3-substituted quinoline analogues were synthesized to try to block the AO metabolism. Metabolic stability study for these quinoline analogues were carried out in liver cytosol fractions from mouse, rat, cyno monkey, and human. Several 3-N- substituted analogues were found to be extremely instable in monkey liver cytosol incubation (t1/2 < 10 min). Five compounds (63, 53, 51, 11, and 71) were selected for detailed study. Monooxygenated metabolite on the quinoline ring was identified by MS/MS fragments and the characteristic later retention time compared with parent compound in the LC/MS. Metabolite formation was inhibited by AO inhibitors menadione and raloxifene but not by xanthine oxidase inhibitor allopurinol. Electron donating group at 3-positon made it vulnerable to AO, larger 3- substituents were found to rescue molecule as half-life increased. Although species differences were observed, the general trend applies in all the species tested. Electron donating group at 3-positon increased both the affinity (decreased Km) and Vm towards AO in kinetic study, while steric hindrance had opposite effect. A common structure feature with high aldehyde oxidase liability was proposed. Our finding might be helpful to quinoline modification to avoid AO liability.

Item Type:	Article
Date Deposited:	27 Sep 2018 00:45
Last Modified:	27 Sep 2018 00:45
URI:	https://oak.novartis.com/id/eprint/35813