耐性株にも有効な新型コロナウイルス阻害剤「TKB272」を開発～高活性・良好な体内動態を示す新規メインプロテアーゼ阻害剤～

2025-08-28 東京科学大学

図1. SARS-CoV-2の複製サイクルとメインプロテアーゼ阻害剤TKB272 (8)

<関連情報>

• https://www.isct.ac.jp/ja/news/wn6dmws4i9t4
• https://www.isct.ac.jp/plugins/cms/component_download_file.php?type=2&pageId=&contentsId=1&contentsDataId=2095&prevId=&key=248ced2f0a5ab53f8b124d76a33533ec.pdf
• https://pubs.acs.org/doi/10.1021/acsomega.5c05168

SARS-CoV-2主プロテアーゼ阻害剤:P1′部位に5-置換ベンゾチアゾール-2-カルボニル基を有する化合物及びその誘導体 SARS-CoV-2 Main Protease Inhibitors Containing 5-Substituted Benzothiazole-2-carbonyl Moieties at the P1′ Site and Their Derivatives

Kohei Tsuji,Takuya Kobayakawa,Nobuyo Higashi-Kuwata,Takahiro Ishii,Kouki Shinohara,Ryusei Yamamoto,Yutaro Miura,Naoya Wada,Hiroaki Mitsuya,and Hirokazu Tamamura
ACS Omega  Published: August 27, 2025
DOI:https://doi.org/10.1021/acsomega.5c05168

Abstract

Development of anti-SARS-CoV-2 agents is still required because of the appearance of drug-resistant strains, and targeting the main protease (M^pro) of SARS-CoV-2 is a powerful way to develop therapeutics against COVID-19. To date, we have developed several M^pro inhibitors including compounds 3, 4, TKB245 (6), and TKB248 (7), which have a 4-fluorobezothiazole ketone moiety as a warhead structure. Further studies led to the development of a more potent M^pro inhibitor, TKB272 (8), which has a 5-fluorobenzothiazole ketone moiety. The slight difference in the introduction position of a fluorine atom enhanced its antiviral activity approximately 3-fold for VeroE6 cells and 15-fold for HeLa^{hACE2-TMPRSS2} cells when TKB272 (8) was compared to TKB245 (6). Herein, we report the synthesis and structure–activity relationship (SAR) studies of TKB272 (8). TKB272 (8) is a promising drug candidate for COVID-19 therapy, and the present data of the SAR studies are useful for the further development of M^pro inhibitors.