TY - JOUR
T1 - Synthesis and evaluation of tofacitinib analogs designed to mitigate metabolic activation
AU - Tateishi, Yasuhiro
AU - Shibazaki, Chikako
AU - Takahashi, Kyoko
AU - Nakamura, Shigeo
AU - Kazuki, Yasuhiro
AU - Mashino, Tadahiko
AU - Ohe, Tomoyuki
N1 - Funding Information:
This research was supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research) from AMED under Grant Number JP21am0101089 (T.O.) and JP21am0101124 (Y.K.). This work was also supported by Keio University Doctoral Student Grant-in-Aid Program .
Publisher Copyright:
© 2021 The Japanese Society for the Study of Xenobiotics
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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.
KW - Cytochrome P450
KW - Hepatocyte toxicity
KW - Metabolic activation
KW - Tofacitinib
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U2 - 10.1016/j.dmpk.2021.100439
DO - 10.1016/j.dmpk.2021.100439
M3 - Article
C2 - 35139477
AN - SCOPUS:85124214732
SN - 1347-4367
VL - 43
JO - Drug Metabolism and Pharmacokinetics
JF - Drug Metabolism and Pharmacokinetics
M1 - 100439
ER -