PT - JOURNAL ARTICLE AU - Jiang Wei Zhang AU - Wen Xiao AU - Zhen Ting Gao AU - Zheng Tian Yu AU - Ji Yue (Jeff) Zhang TI - Metabolism of c-Met Kinase Inhibitors Containing Quinoline by Aldehyde Oxidase, Electron Donating, and Steric Hindrance Effect AID - 10.1124/dmd.118.081919 DP - 2018 Dec 01 TA - Drug Metabolism and Disposition PG - 1847--1855 VI - 46 IP - 12 4099 - http://dmd.aspetjournals.org/content/46/12/1847.short 4100 - http://dmd.aspetjournals.org/content/46/12/1847.full SO - Drug Metab Dispos2018 Dec 01; 46 AB - Some quinoline-containing c-Met kinase inhibitors are aldehyde oxidase (AO) substrates. 3-Substituted quinoline triazolopyridine analogs were synthesized to understand the electron-donating and steric hindrance effects on AO-mediated metabolism. Metabolic stability studies for these quinoline analogs were carried out in liver cytosol from mice, rats, cynomolgus monkeys, and humans. Several 3-N–substituted analogs were found to be unstable in monkey liver cytosolic incubations (half-life, <10 minutes), and five of them (63, 53, 51, 11, and 71) were chosen for additional mechanistic studies. Mono-oxygenation on the quinoline ring was identified by liquid chromatography tandem mass spectrometry. 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 analogs more susceptible to AO metabolism, whereas 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 Michaelis constant) and Vmax maximum velocity toward AO in kinetic studies, whereas large substituents decreased both parameters probably as a result of 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 analogs.