Exploratory Studies of Effective Inhibitors against the SARS-CoV-2 Main Protease by Halogen Incorporation and Amide Bond Replacement

• Published in: Chemical & pharmaceutical bulletin Vol. 71; no. 12; pp. 879 - 886
• Main Authors: Tsuji, Kohei, Kobayakawa, Takuya, Ishii, Takahiro, Higashi-Kuwata, Nobuyo, Azuma, Chika, Shinohara, Kouki, Miura, Yutaro, Yamamoto, Kenichi, Nishimura, Soshi, Hattori, Shin-ichiro, Bulut, Haydar, Mitsuya, Hiroaki, Tamamura, Hirokazu
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 01.12.2023; Pharmaceutical Soc Japan; Japan Science and Technology Agency
• Subjects: amide bond surrogate; Amides - pharmacology; Animals; Antiviral Agents - chemistry; Benzothiazoles - chemistry; Benzothiazoles - pharmacology; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; coronavirus disease of 2019 (COVID-19); Coronaviruses; COVID-19; Drug development; Drugs; fluorination; Fluorine; Halogens; Inhibitors; Ketones; Life Sciences & Biomedicine; main protease inhibitor; Mice; Pharmacokinetics; Pharmacology & Pharmacy; Physical Sciences; Protease; Protease Inhibitors - chemistry; Pyrrolidines - chemistry; Pyrrolidines - pharmacology; SARS-CoV-2; Science & Technology; Severe acute respiratory syndrome coronavirus 2; severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); Viral diseases; Viral Nonstructural Proteins; coronavirus disease of 2019 (COVID-19); POTENT; DESIGN; ORALLY BIOAVAILABLE INHIBITOR; COVALENT INHIBITORS; main protease in-hibitor; amide bond surrogate; severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); fluorination; HIV-1 PROTEASE; DISCOVERY; 3CL PROTEASE; main protease inhibitor
• ISSN: 0009-2363; 1347-5223; 1347-5223
• DOI: 10.1248/cpb.c23-00562

In the development of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs, its main protease (Mpro), which is an essential enzyme for viral replication, is a promising target. To date, the Mpro 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 Mpro 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 Mpro 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 Mpro inhibitors.