RT Journal Article SR Electronic T1 Metabolism of c-Met Kinase Inhibitors Containing Quinoline by Aldehyde Oxidase, Electron Donating, and Steric Hindrance Effect JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1847 OP 1855 DO 10.1124/dmd.118.081919 VO 46 IS 12 A1 Jiang Wei Zhang A1 Wen Xiao A1 Zhen Ting Gao A1 Zheng Tian Yu A1 Ji Yue (Jeff) Zhang YR 2018 UL http://dmd.aspetjournals.org/content/46/12/1847.abstract 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.