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

  • Jiang Wei ZhangEmail author
  • Hai Bing Deng
  • Chun Ye Zhang
  • Jing Quan Dai
  • Qian Li
  • Qian Gang Zheng
  • Hui Xin Wan
  • Hong Ping Yu
  • Feng He
  • Yao Chang Xu
  • Sylvia Zhao
  • Ji Yue Jeff ZhangEmail author
Original Research Article

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.

Notes

Acknowledgements

We thank Novartis c-Met project team members, especially Global Discovery Chemistry Shanghai colleagues for their contributions.

Compliance with Ethical Standards

Funding

No source of funding.

Conflict of interest

All authors were or still are Novartis employee.

Ethical approval

All animal studies were in accordance with the ethical standards of the institution or practice at which the studies were conducted. All animal study procedures were approved by animal care and use committees before the studies were initiated.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Novartis Institutes for BioMedical ResearchShanghaiChina
  2. 2.InxMedShanghaiChina
  3. 3.Abbisko TherapeuticsShanghaiChina
  4. 4.Luoxin BiotechnologyShanghaiChina
  5. 5.Tayu BiotechBeijingChina
  6. 6.Janssen (China) R&D CenterShanghaiChina
  7. 7.EternBioShanghaiChina
  8. 8.Ringene PharmaceuticalShanghaiChina
  9. 9.Hengrui PharmaceuticalShanghaiChina

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