1. Synthesis of deuterated S-217622 (Ensitrelvir) with antiviral activity against coronaviruses including SARS-CoV-2.
- Author
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Yang, Yujian, Cao, Liu, Yan, Ming, Zhou, Jun, Yang, Sidi, Xu, Tiefeng, Huang, Siyao, Li, Kun, Zhou, Qifan, Li, Guanguan, Zhu, Yujun, Cong, Feng, Zhang, Hongmin, Guo, Deyin, Li, Yingjun, and Zhang, Xumu
- Subjects
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SARS-CoV-2 , *CORONAVIRUSES - Abstract
S-217622 (Ensitrelvir) is a reversible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3-chymotrypsin-like protease (3CLpro) inhibitor which obtained emergency regulatory approval in Japan for the treatment of SARS-CoV-2 infection on Nov 22, 2022. Herein, analogs of S-271622 with deuterium-for-hydrogen replacement were synthesized for comparison of the antiviral activities and pharmacokinetic (PK) profiles. Compared to the parent compound, C11- d2 -S-217622 compound YY-278 retained in vitro activity against 3CLpro and SARS-CoV-2. X-ray crystal structural studies showed similar interactions of SARS-CoV-2 3CLpro with YY-278 and S-271622. The PK profiling revealed the relatively favorable bioavailability and plasma exposure of YY-278. In addition, YY-278 , as well as S-217622 , displayed broadly anti-coronaviral activities against 6 other coronaviruses that infect humans and animals. These results laid the foundation for further research on the therapeutic potential of YY-278 against COVID-19 and other coronaviral diseases. • Deuterated analogs of the 3CLpro inhibitor S-217622 were synthesized. • YY-278 broadly inhibited the replication of SARS-CoV-2 and other coronaviruses. • The crystal structure of YY-278 bound to 3CLpro revealed key interactions. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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