Discovery of S‑217622, a Noncovalent Oral SARS-CoV‑2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19

The coronavirus disease
2019 (COVID-19) pandemic, caused by severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted
in millions of deaths and threatens public health and safety. Despite
the rapid global spread of COVID-19 vaccines, effective oral antiviral
drugs are urgently needed. Here, we describe the discovery of S-217622, the first oral noncovalent, nonpeptidic SARS-CoV-2
3CL protease inhibitor clinical candidate. S-217622 was
discovered via virtual screening followed by biological screening
of an in-house compound library, and optimization of the hit compound
using a structure-based drug design strategy. S-217622 exhibited antiviral activity in vitro against current
outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic
profiles in vivo for once-daily oral dosing. Furthermore, S-217622 dose-dependently inhibited intrapulmonary replication
of SARS-CoV-2 in mice, indicating that this novel noncovalent inhibitor
could be a potential oral agent for treating COVID-19.