Format

Send to

Choose Destination
Eur J Drug Metab Pharmacokinet. 2019 Apr 27. doi: 10.1007/s13318-019-00557-9. [Epub ahead of print]

In Vitro Metabolism by Aldehyde Oxidase Leads to Poor Pharmacokinetic Profile in Rats for c-Met Inhibitor MET401.

Zhang JW1,2, Deng HB3,4, Zhang CY3,5, Dai JQ3,6, Li Q3,7, Zheng QG3,8, Wan HX3,9, Yu HP3,4, He F3,10, Xu YC3,4, Zhao S3, Zhang JYJ11.

Author information

1
Novartis Institutes for BioMedical Research, B4F2 Novartis Campus, No. 4218 Jinke Road, Shanghai, 201203, China. zjw@dicp.ac.cn.
2
InxMed, Shanghai, China. zjw@dicp.ac.cn.
3
Novartis Institutes for BioMedical Research, B4F2 Novartis Campus, No. 4218 Jinke Road, Shanghai, 201203, China.
4
Abbisko Therapeutics, Shanghai, China.
5
Luoxin Biotechnology, Shanghai, China.
6
Tayu Biotech, Beijing, China.
7
Janssen (China) R&D Center, Shanghai, China.
8
EternBio, Shanghai, China.
9
Ringene Pharmaceutical, Shanghai, China.
10
Hengrui Pharmaceutical, Shanghai, China.
11
Novartis Institutes for BioMedical Research, B4F2 Novartis Campus, No. 4218 Jinke Road, Shanghai, 201203, China. jeff.zhang@novartis.com.

Abstract

BACKGROUND AND OBJECTIVES:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

PMID:
31030415
DOI:
10.1007/s13318-019-00557-9

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center