Yuto Unoh, Keiichiro Hirai, Shota Uehara, Sho Kawashima, Haruaki Nobori, Jun Satom, Hiromitsu Shibayama, Akihiro Hori, Kenji Nakahara, Kana Kurahashi, Masayuki Takamatsu, Shiho Yamamoto, Qianhui Zhang, Miki Tanimura, Reiko Dodo, Yuki Maruyama, Hirofumi Sawa, Ryosuke Watari, Tetsuya Miyano, Teruhisa Kato, Takafumi Sato,Yuki Tachibana
J. Med. Chem. 2025
https://doi.org/10.1021/acs.jmedchem.5c00754
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 S-892216, a second-generation SARS-CoV-2 3C-like protease (3CLpro) inhibitor, to treat COVID-19. S-892216 is a reversible covalent 3CLpro inhibitor with highly potent antiviral activity and an EC50 value of 2.48 nM against SARS-CoV-2 infected cells. Structure-based design of a covalent modifier for compound 1 revealed that introducing a nitrile warhead increased 3CLpro inhibition activity by 180-fold. Subsequent optimization efforts yielded S-892216, which combined a favorable pharmacokinetic profile and high off-target selectivity. S-892216 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, S-892216 inhibited viral replication in the lungs similar to ensitrelvir, although at a 30-fold lower dose.
