Structure-Activity Relationship Studies of SARS-CoV-2 Main Protease Inhibitors Containing 4-Fluorobenzothiazole-2-carbonyl Moieties

被引：17

作者：

Tsuji, Kohei ^{[1
]}

Ishii, Takahiro ^{[1
]}

Kobayakawa, Takuya ^{[1
]}

Higashi-Kuwata, Nobuyo ^{[2
]}

Shinohara, Kouki ^{[1
]}

Azuma, Chika ^{[1
]}

Miura, Yutaro ^{[1
]}

Nakano, Hiroki ^{[1
]}

Wada, Naoya ^{[1
]}

Hattori, Shin-ichiro ^{[2
]}

Bulut, Haydar ^{[3
]}

Mitsuya, Hiroaki ^{[2
,3
,4
]}

Tamamura, Hirokazu ^{[1
]}

机构：

[1] Tokyo Med & Dent Univ TMDU, Inst Biomat & Bioengn, Dept Med Chem, Chiyoda Ku, Tokyo 1010062, Japan

[2] Natl Ctr Global Hlth & Med Res Inst, Dept Refractory Viral Infect, Shinjuku Ku, Tokyo 1628655, Japan

[3] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA

[4] Kumamoto Univ Hosp, Dept Clin Sci, Chuo Ku, Kumamoto 8608556, Japan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年

关键词：

RESPIRATORY SYNDROME CORONAVIRUS; PAPAIN-LIKE PROTEASE; COVALENT INHIBITORS; DISCOVERY; SARS; MECHANISM; DESIGN; POTENT; SITE;

D O I：

10.1021/acs.jmedchem.3c00777

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The main protease (M-pro) of SARS-CoV-2 is an attractive target for the development of drugs to treat COVID-19. Here, we report the design, synthesis, and structure-activity relationship (SAR) studies of highly potent SARS-CoV-2 M-pro inhibitors including TKB245 (5)/TKB248 (6). Since we have previously developed M-pro inhibitors (3) and (4), several hybrid molecules of these previous compounds combined with nirmatrelvir (1) were designed and synthesized. Compounds such as TKB245 (5) and TKB248 (6), containing a 4-fluorobenzothiazole moiety at the P1' site, are highly effective in the blockade of SARS-CoV-2 replication in VeroE6 cells. Replacement of the P1-P2 amide with the thioamide surrogate in TKB248 (6) improved its PK profile in mice compared to that of TKB245 (5). A new diversity-oriented synthetic route to TKB245 (5) derivatives was also developed. The results of the SAR studies suggest that TKB245 (5) and TKB248 (6) are useful lead compounds for the further development of M-pro inhibitors.

引用

页码：13516 / 13529

页数：14

共 56 条

[1]

[Anonymous], Merck and Ridgeback's Investigational Oral Antiviral Molnupiravir Reduced the Risk of Hospitalization or Death by Approximately 50 Percent Compared to Placebo for Patients with Mild or Moderate COVID-19 in Positive Interim Analysis of Phase 3 Study - Merck.com

[2]

Anson BJ., 2020, RES SQ, p10.21203/rs.3.rs, DOI [DOI 10.21203/RS.3.RS-26344/V1, 10.21203/rs.3.rs-26344/v1]

[3] Peptidomimetic α-Acyloxymethylketone Warheads with Six-Membered Lactam P1 Glutamine Mimic: SARS-CoV-2 3CL Protease Inhibition, Coronavirus Antiviral Activity, and in Vitro Biological Stability [J].

Bai, Bing ;

Belovodskiy, Alexandr ;

Hena, Mostofa ;

Kandadai, Appan Srinivas ;

Joyce, Michael A. ;

Saffran, Holly A. ;

Shields, Justin A. ;

Khan, Muhammad Bashir ;

Arutyunova, Elena ;

Lu, Jimmy ;

Bajwa, Sardeev K. ;

Hockman, Darren ;

Fischer, Conrad ;

Lamer, Tess ;

Vuong, Wayne ;

van Belkum, Marco J. ;

Gu, Zhengxian ;

Lin, Fusen ;

Du, Yanhua ;

Xu, Jia ;

Rahim, Mohammad ;

Young, Howard S. ;

Vederas, John C. ;

Tyrrell, D. Lorne ;

Lemieux, M. Joanne ;

Nieman, James A. .

JOURNAL OF MEDICINAL CHEMISTRY, 2022, 65 (04) :2905-2925

[4] The papain-like protease of severe acute respiratory syndrome coronavirus has deubiquitinating activity [J].

Barretto, N ;

Jukneliene, D ;

Ratia, K ;

Chen, ZB ;

Mesecar, AD ;

Baker, SC .

JOURNAL OF VIROLOGY, 2005, 79 (24) :15189-15198

[5] Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant [J].

Bernal, Jamie Lopez ;

Andrews, Nick ;

Gower, Charlotte ;

Gallagher, Eileen ;

Simmons, Ruth ;

Thelwall, Simon ;

Stowe, Julia ;

Tessier, Elise ;

Groves, Natalie ;

Dabrera, Gavin ;

Myers, Richard ;

Campbell, Colin N. J. ;

Amirthalingam, Gayatri ;

Edmunds, Matt ;

Zambon, Maria ;

Brown, Kevin E. ;

Hopkins, Susan ;

Chand, Meera ;

Ramsay, Mary .

NEW ENGLAND JOURNAL OF MEDICINE, 2021, 385 (07) :585-594

[6] Thioamide Substitution Selectively Modulates Proteolysis and Receptor Activity of Therapeutic Peptide Hormones [J].

Chen, Xing ;

Mietlicki-Baase, Elizabeth G. ;

Barrett, Taylor M. ;

McGrath, Lauren E. ;

Koch-Laskowski, Kieran ;

Ferrie, John J. ;

Hayes, Matthew R. ;

Petersson, E. James .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2017, 139 (46) :16688-16695

[7] An Assessment of the Bivalent Vaccine as a Second Booster for COVID-19 [J].

Gupta, Sneh Lata ;

Jaiswal, Rishi K. K. .

VACCINES, 2023, 11 (01)

[8] A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication [J].

Hattori, Shin-ichiro ;

Higashi-Kuwata, Nobuyo ;

Hayashi, Hironori ;

Allu, Srinivasa Rao ;

Raghavaiah, Jakka ;

Bulut, Haydar ;

Das, Debananda ;

Anson, Brandon J. ;

Lendy, Emma K. ;

Takamatsu, Yuki ;

Takamune, Nobutoki ;

Kishimoto, Naoki ;

Murayama, Kazutaka ;

Hasegawa, Kazuya ;

Li, Mi ;

Davis, David A. ;

Kodama, Eiichi N. ;

Yarchoan, Robert ;

Wlodawer, Alexander ;

Misumi, Shogo ;

Mesecar, Andrew D. ;

Ghosh, Arun K. ;

Mitsuya, Hiroaki .

NATURE COMMUNICATIONS, 2021, 12 (01)

[9] Identification of SARS-CoV-2 Mpro inhibitors containing P1' 4-fluorobenzothiazole moiety highly active against SARS-CoV-2 [J].

Higashi-Kuwata, Nobuyo ;

Tsuji, Kohei ;

Hayashi, Hironori ;

Bulut, Haydar ;

Kiso, Maki ;

Imai, Masaki ;

Ogata-Aoki, Hiromi ;

Ishii, Takahiro ;

Kobayakawa, Takuya ;

Nakano, Kenta ;

Takamune, Nobutoki ;

Kishimoto, Naoki ;

Hattori, Shin-ichiro ;

Das, Debananda ;

Uemura, Yukari ;

Shimizu, Yosuke ;

Aoki, Manabu ;

Hasegawa, Kazuya ;

Suzuki, Satoshi ;

Nishiyama, Akie ;

Saruwatari, Junji ;

Shimizu, Yukiko ;

Sukenaga, Yoshikazu ;

Takamatsu, Yuki ;

Tsuchiya, Kiyoto ;

Maeda, Kenji ;

Yoshimura, Kazuhisa ;

Iida, Shun ;

Ozono, Seiya ;

Suzuki, Tadaki ;

Okamura, Tadashi ;

Misumi, Shogo ;

Kawaoka, Yoshihiro ;

Tamamura, Hirokazu ;

Mitsuya, Hiroaki .

NATURE COMMUNICATIONS, 2023, 14 (01)

[10] Identification of a novel long-acting 4′-modified nucleoside reverse transcriptase inhibitor against HBV [J].

Higashi-Kuwata, Nobuyo ;

Hayashi, Sanae ;

Kumamoto, Hiroki ;

Ogata-Aoki, Hiromi ;

Das, Debananda ;

Venzon, David ;

Hattori, Shin-ichiro ;

Bulut, Haydar ;

Hashimoto, Mai ;

Otagiri, Masaki ;

Takamune, Nobutoki ;

Kishimoto, Naoki ;

Davis, David A. ;

Misumi, Shogo ;

Kakuni, Masakazu ;

Tanaka, Yasuhito ;

Mitsuya, Hiroaki .

JOURNAL OF HEPATOLOGY, 2021, 74 (05) :1075-1086

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