Synthesis and evaluation of tofacitinib analogs designed to mitigate metabolic activation

Yasuhiro Tateishi, Chikako Shibazaki, Kyoko Takahashi, Shigeo Nakamura, Yasuhiro Kazuki, Tadahiko Mashino, Tomoyuki Ohe

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


Tofacitinib (TFT), a JAK inhibitor used for the treatment of rheumatoid arthritis and other diseases, is associated with severe liver injury that is believed to be caused by its reactive aldehyde or epoxide metabolites. In this study, we synthesized six tofacitinib analogs designed to avoid the formation of reactive metabolites and evaluated their JAK3 inhibitory activity, metabolic stability, CYP3A time-dependent inhibition, and cytotoxicity. Our data indicated that purine analog 3, which showed little inhibition of CYP3A and cytotoxicity and inhibited JAK3 in the nanomolar range, could be a safer drug candidate than TFT. In addition, the results of the bioactivation study using TFT and its analogs suggest that the epoxide metabolite might contribute to TFT-induced CYP3A4 mechanism-based inhibition and hepatic toxicity.

Original languageEnglish
Article number100439
JournalDrug Metabolism And Pharmacokinetics
Publication statusPublished - 2022 Apr


  • Cytochrome P450
  • Hepatocyte toxicity
  • Metabolic activation
  • Tofacitinib

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)


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