tetano
Editor, Senior Moderator
Chem Pharm Bull (Tokyo)
. 2023;71(12):879-886.
doi: 10.1248/cpb.c23-00562. Exploratory Studies of Effective Inhibitors against the SARS-CoV-2 Main Protease by Halogen Incorporation and Amide Bond Replacement
Kohei Tsuji[SUP] 1 [/SUP], Takuya Kobayakawa[SUP] 1 [/SUP], Takahiro Ishii[SUP] 1 [/SUP], Nobuyo Higashi-Kuwata[SUP] 2 [/SUP], Chika Azuma[SUP] 1 [/SUP], Kouki Shinohara[SUP] 1 [/SUP], Yutaro Miura[SUP] 1 [/SUP], Kenichi Yamamoto[SUP] 1 [/SUP], Soshi Nishimura[SUP] 1 [/SUP], Shin-Ichiro Hattori[SUP] 2 [/SUP], Haydar Bulut[SUP] 3 [/SUP], Hiroaki Mitsuya[SUP] 2 3 4 [/SUP], Hirokazu Tamamura[SUP] 1 [/SUP]
Affiliations
In the development of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs, its main protease (M[SUP]pro[/SUP]), which is an essential enzyme for viral replication, is a promising target. To date, the M[SUP]pro[/SUP] inhibitors, nirmatrelvir and ensitrelvir, have been clinically developed by Pfizer Inc. and Shionogi & Co., Ltd., respectively, as orally administrable drugs to treat coronavirus disease of 2019 (COVID-19). We have also developed several potent inhibitors of SARS-CoV-2 M[SUP]pro[/SUP] that include compounds 4, 5, TKB245 (6), and TKB248 (7), which possesses a 4-fluorobenzothiazole ketone moiety as a reactive warhead. In compounds 5 and TKB248 (7) we have also found that replacement of the P1-P2 amide of compounds 4 and TKB245 (6) with the corresponding thioamide improved their pharmacokinetics (PK) profile in mice. Here, we report the design, synthesis and evaluation of SARS-CoV-2 M[SUP]pro[/SUP] inhibitors with replacement of a digestible amide bond by surrogates (9-11, 33, and 34) and introduction of fluorine atoms in a metabolically reactive methyl group on the indole moiety (8). As the results, these compounds showed comparable or less potency compared to the corresponding parent compounds, YH-53/5h (2) and 4. These results should provide useful information for further development of M[SUP]pro[/SUP] inhibitors.
Keywords: amide bond surrogate; coronavirus disease of 2019 (COVID-19); fluorination; main protease inhibitor; severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
. 2023;71(12):879-886.
doi: 10.1248/cpb.c23-00562. Exploratory Studies of Effective Inhibitors against the SARS-CoV-2 Main Protease by Halogen Incorporation and Amide Bond Replacement
Kohei Tsuji[SUP] 1 [/SUP], Takuya Kobayakawa[SUP] 1 [/SUP], Takahiro Ishii[SUP] 1 [/SUP], Nobuyo Higashi-Kuwata[SUP] 2 [/SUP], Chika Azuma[SUP] 1 [/SUP], Kouki Shinohara[SUP] 1 [/SUP], Yutaro Miura[SUP] 1 [/SUP], Kenichi Yamamoto[SUP] 1 [/SUP], Soshi Nishimura[SUP] 1 [/SUP], Shin-Ichiro Hattori[SUP] 2 [/SUP], Haydar Bulut[SUP] 3 [/SUP], Hiroaki Mitsuya[SUP] 2 3 4 [/SUP], Hirokazu Tamamura[SUP] 1 [/SUP]
Affiliations
- PMID: 38044140
- DOI: 10.1248/cpb.c23-00562
In the development of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs, its main protease (M[SUP]pro[/SUP]), which is an essential enzyme for viral replication, is a promising target. To date, the M[SUP]pro[/SUP] inhibitors, nirmatrelvir and ensitrelvir, have been clinically developed by Pfizer Inc. and Shionogi & Co., Ltd., respectively, as orally administrable drugs to treat coronavirus disease of 2019 (COVID-19). We have also developed several potent inhibitors of SARS-CoV-2 M[SUP]pro[/SUP] that include compounds 4, 5, TKB245 (6), and TKB248 (7), which possesses a 4-fluorobenzothiazole ketone moiety as a reactive warhead. In compounds 5 and TKB248 (7) we have also found that replacement of the P1-P2 amide of compounds 4 and TKB245 (6) with the corresponding thioamide improved their pharmacokinetics (PK) profile in mice. Here, we report the design, synthesis and evaluation of SARS-CoV-2 M[SUP]pro[/SUP] inhibitors with replacement of a digestible amide bond by surrogates (9-11, 33, and 34) and introduction of fluorine atoms in a metabolically reactive methyl group on the indole moiety (8). As the results, these compounds showed comparable or less potency compared to the corresponding parent compounds, YH-53/5h (2) and 4. These results should provide useful information for further development of M[SUP]pro[/SUP] inhibitors.
Keywords: amide bond surrogate; coronavirus disease of 2019 (COVID-19); fluorination; main protease inhibitor; severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).