Back to Search
Start Over
In Vitro Metabolism by Aldehyde Oxidase Leads to Poor Pharmacokinetic Profile in Rats for c-Met Inhibitor MET401
- Source :
- European Journal of Drug Metabolism and Pharmacokinetics. 44:669-680
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
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.
- 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
Subjects
Details
- ISSN :
- 21070180 and 03787966
- Volume :
- 44
- Database :
- OpenAIRE
- Journal :
- European Journal of Drug Metabolism and Pharmacokinetics
- Accession number :
- edsair.doi.dedup.....a6419719abab5c179958c0e4c47f08e4