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

研究成果: Article査読

3 被引用数 (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.

ジャーナルDrug Metabolism And Pharmacokinetics
出版ステータスPublished - 2022 4月

ASJC Scopus subject areas

  • 薬理学
  • 薬科学
  • 薬理学(医学)


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