Synthesis of deuterated S-217622 (Ensitrelvir) with antiviral activity against coronaviruses including SARS-CoV-2

S-217622 (Ensitrelvir) is a reversible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3-chymotrypsin-like protease (3CL^{pro}) 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 3CL^{pro} and SARS-CoV-2. X-ray crystal structural studies showed similar interactions of SARS-CoV-2 3CL^{pro} 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.