Discovery of the Clinical Candidate <b>S-892216</b> : A Second-Generation of SARS-CoV-2 3CL Protease Inhibitor for Treating COVID-19
The coronavirus disease 2019 (COVID-19) pandemic crisis has been mitigated by worldwide efforts to develop vaccines and therapeutic drugs. However, there remains concern regarding public health and an unmet need for therapeutic options. Herein, we report the discovery of <b>S-892216</b>, a second-generation SARS-CoV-2 3C-like protease (3CL<sup>pro</sup>) inhibitor, to treat COVID-19. <b>S-892216</b> is a reversible covalent 3CL<sup>pro</sup> inhibitor with highly potent antiviral activity and an EC<sub>50</sub> value of 2.48 nM against SARS-CoV-2 infected cells. Structure-based design of a covalent modifier for compound <b>1</b> revealed that introducing a nitrile warhead increased 3CL<sup>pro</sup> inhibition activity by 180-fold. Subsequent optimization efforts yielded <b>S-892216</b>, which combined a favorable pharmacokinetic profile and high off-target selectivity. <b>S-892216</b> exhibited antiviral activity against diverse SARS-CoV-2 variants, including major mutations reducing antiviral activities of nirmatrelvir and ensitrelvir. In SARS-CoV-2-infected mice, <b>S-892216</b> inhibited viral replication in the lungs similar to ensitrelvir, although at a 30-fold lower dose.
Authors
- Takafumi Sato (ORCID: https://orcid.org/0000-0001-6534-2560)
- Jun Sato (ORCID: https://orcid.org/0000-0002-0225-9476)
- Miki Tanimura
- Yuto Unoh (ORCID: https://orcid.org/0000-0002-5200-7349)
- Kana Kurahashi
- Tetsuya Miyano (ORCID: https://orcid.org/0000-0003-4126-251X)
- Shiho Yamamoto (ORCID: https://orcid.org/0000-0002-1731-7931)
- Hirofumi Sawa (ORCID: https://orcid.org/0000-0003-2569-2755)
- Sho Kawashima
- Keiichiro Hirai
- Hirohiko Shibayama (ORCID: https://orcid.org/0000-0003-4014-2815)
- Haruaki Nobori (ORCID: https://orcid.org/0000-0001-5735-0843)
- Qianhui Zhang (ORCID: https://orcid.org/0000-0001-7536-5897)
- Shota Uehara (ORCID: https://orcid.org/0000-0001-5214-8531)
- Ryosuke Watari (ORCID: https://orcid.org/0009-0004-1846-0467)
- Yuki Tachibana (ORCID: https://orcid.org/0000-0001-6845-4453)
- Reiko Dodo
- Kenji Nakahara (ORCID: https://orcid.org/0000-0002-2867-0669)
- Yuki Maruyama (ORCID: https://orcid.org/0000-0002-0812-1478)
- Masayuki Takamatsu (ORCID: https://orcid.org/0009-0003-4810-065X)
- Teruhisa Kato (ORCID: https://orcid.org/0000-0001-5041-0110)
- Akihiro Hori
Institutions
- Hokkaido University (JP)
- Global Virus Network (US)
- Shionogi (Japan) (JP)
- Futaba (Japan) (JP)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-07-05
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00754
- Citations
- 8
- Primary Topic
- Computational Drug Discovery Methods
- Type
- article
- Field-Weighted Citation Impact
- 12.03
Funders
- Japan Agency for Medical Research and Development