著者

Kohei Tsuji Takuya Kobayakawa Takahiro Ishii Nobuyo Higashi-Kuwata Chika Azuma Kouki Shinohara Yutaro Miura Kenichi Yamamoto Soshi Nishimura Shin-ichiro Hattori Haydar Bulut Hiroaki Mitsuya Hirokazu Tamamura

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.71, no.12, pp.879-886, 2023-12-01 (Released:2023-12-01)

参考文献数

53

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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.

著者

三浦 雄太郎 大阪 健吾 鳥海 不二夫 菅原 俊治 Yutaro Miura Kengo Osaka Fujio Toriumi Toshiharu Sugawara

雑誌

SIG-SAI = SIG-SAI

巻号頁・発行日

vol.28, no.4, pp.1-8, 2017-03-02

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We investigate the conditions in which cooperation is dominant in social media using the models of evolutionary games of public goods games with diminishing marginal utilities and attempt to clarify the mechanisms of prosperity of social media and effect of diminishing marginal utilities. Cooperation dominant situation corresponds to that in which social media thrives, i.e., posting articles and taking reactions by comment lead to more benefits result than do nothing as free-riders. A number of studies examined what mechanism contributes to maintain cooperation dominant situation by using evolutionary game, but their models don't include the effect of diminishing marginal utility. Thus, we developed an abstract model of social media using utility function with diminishing marginal utility and we experimentally investigated the effect of diminishing marginal utilities in the meta-rewards and SNS-norms games. The result showed that the games with diminishing marginal utility could model real SNS activities more suitably than those without it.