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 neede...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2022-05, Vol.65 (9), p.6499-6512
Main Authors: Unoh, Yuto, Uehara, Shota, Nakahara, Kenji, Nobori, Haruaki, Yamatsu, Yukiko, Yamamoto, Shiho, Maruyama, Yuki, Taoda, Yoshiyuki, Kasamatsu, Koji, Suto, Takahiro, Kouki, Kensuke, Nakahashi, Atsufumi, Kawashima, Sho, Sanaki, Takao, Toba, Shinsuke, Uemura, Kentaro, Mizutare, Tohru, Ando, Shigeru, Sasaki, Michihito, Orba, Yasuko, Sawa, Hirofumi, Sato, Akihiko, Sato, Takafumi, Kato, Teruhisa, Tachibana, Yuki
Format: Article
Language:English
Subjects:
Animals
Antiviral Agents - pharmacology
Antiviral Agents - therapeutic use
Coronavirus 3C Proteases
COVID-19 - drug therapy
COVID-19 Vaccines
Humans
Mice
Protease Inhibitors - pharmacology
Protease Inhibitors - therapeutic use
SARS-CoV-2
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.2c00117