Metabolism of c-Met Kinase Inhibitors Containing Quinoline by Aldehyde Oxidase, Electron Donating, and Steric Hindrance Effect
| Autor: | Wen Xiao, Jiang Wei Zhang, Ji Yue Jeff Zhang, Zhen Ting Gao, Zheng Tian Yu |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Steric effects Male C-Met Stereochemistry Pharmaceutical Science In Vitro Techniques 030226 pharmacology & pharmacy Substrate Specificity Electron Transport 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Cytosol Drug Stability Species Specificity Animals Humans Aldehyde oxidase Protein Kinase Inhibitors Pharmacology Molecular Structure Chemistry Kinase Quinoline Metabolism Proto-Oncogene Proteins c-met Rats Aldehyde Oxidase Molecular Docking Simulation Kinetics Macaca fascicularis 030104 developmental biology Liver Quinolines Triazolopyridine |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 46(12) |
| ISSN: | 1521-009X |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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