1. In Vitro Metabolism by Aldehyde Oxidase Leads to Poor Pharmacokinetic Profile in Rats for c-Met Inhibitor MET401
- Author
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Qian Li, Chun Ye Zhang, Yao Chang Xu, Jing Quan Dai, Sylvia Zhao, Jiang Wei Zhang, Feng He, Ji Yue Jeff Zhang, Hui Xin Wan, Hai Bing Deng, Hong Ping Yu, and Qian Gang Zheng
- Subjects
Male ,medicine.drug_class ,Metabolite ,Guinea Pigs ,Allopurinol ,030226 pharmacology & pharmacy ,Rats, Sprague-Dawley ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Cytosol ,Dogs ,0302 clinical medicine ,Cytochrome P-450 Enzyme System ,Menadione ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Protein Kinase Inhibitors ,Aldehyde oxidase ,Xanthine oxidase inhibitor ,Pharmacology ,chemistry.chemical_classification ,biology ,Cytochrome P450 ,Metabolism ,Proto-Oncogene Proteins c-met ,Rats ,Aldehyde Oxidase ,Macaca fascicularis ,Enzyme ,Liver ,Biochemistry ,chemistry ,030220 oncology & carcinogenesis ,Hepatocytes ,Microsomes, Liver ,biology.protein ,Female ,Oxidation-Reduction ,Metabolic Networks and Pathways ,medicine.drug - Abstract
MET401 is a potent and selective c-Met inhibitor with a novel triazolopyrimidine scaffold. The aim of this study was to determine the pharmacokinetic profile of MET401 in preclinical species, and to identify the metabolic soft spot and enzyme involved, in order to help medicinal chemists to modify the compound to improve the pharmacokinetic profile. A metabolite identification study was performed in different liver fractions from various species. Chemical inhibition with selective cytochrome P450 (CYP) and molybdenum hydroxylase inhibitors was carried out to identify the enzyme involved. The deuterium substitution strategy was adopted to reduce metabolism. Pharmacokinetic studies were performed in rats to confirm the effect. Although M-2 is a minor metabolite in liver microsomal incubations, it became the predominant metabolite in incubations with liver S9, cytosol, hepatocytes and rat pharmacokinetic study. M-2 was synthesized enzymatically and the structure was identified as a mono-oxidation on the triazolopyrimidine moiety. The M-2 formation was ascribed to aldehyde oxidase (AO)-mediated metabolism based on the following evidence—M-2 production was NADPH independent, pan-CYP inhibitor 1-aminobenzotriazole and xanthine oxidase inhibitor allopurinol did not inhibit M-2 formation, and AO inhibitors menadione and raloxifene inhibited M-2 formation. The deuterated analog MET763 demonstrated an improved pharmacokinetic profile with lower clearance, longer terminal half-life and double oral exposure compared with MET401 in rats. These results indicate that the main metabolic pathway of MET401 is AO-mediated metabolism, which leads to poor in vivo pharmacokinetic profiles in rodents. The deuterium substitution strategy could be used to reduce AO-mediated metabolism liability.
- Published
- 2019