Structure–activity relationship study of hydroxyethylamine isostere and P1′ site structure of peptide mimetic BACE1 inhibitors

Kobayashi, Kazuya; Otani, Takuya; Ijiri, Saki; Kawasaki, Yuki; Matsubara, Hiroki; Miyagi, Takahiro; Kitajima, Taishi; Iseki, Risa; Ishizawa, Katsuyasu; Shindo, Naoka; Okawa, Kouta; Ueda, Kouta; Ando, Syun; Kawakita, Momoka; Hattori, Yoshiyuki; Akaji, Kenichi

doi:10.1016/j.bmc.2021.116459

Cited by 3 publications

(2 citation statements)

References 31 publications

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“…In our previous study, we reported that the introduction of a 4-carboxymethylphenyl group instead of a p-tolyl group increased inhibitory activity 10-fold [3]. Based on these results, the dimethyl branched macrocyclic derivative 29 containing a 4-carboxymethylphenyl group at the P1' site was synthesized (Figure 4).…”

Section: Resultsmentioning

confidence: 93%

Synthesis and Structural Optimization of Macrocyclic BACE1 Inhibitors with a Hydrophobic Cross-Linked Structure

Kobayashi¹,

Otani²,

Hattori³

et al. 2022

Proceedings of the 36th European and the 12th International Peptide Symposium

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Section: Resultsmentioning

confidence: 93%

Synthesis and Structural Optimization of Macrocyclic BACE1 Inhibitors with a Hydrophobic Cross-Linked Structure

Kobayashi¹,

Otani²,

Hattori³

et al. 2022

Proceedings of the 36th European and the 12th International Peptide Symposium

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“…β-secretase (BACE1; β-site APP cleaving enzyme 1) for the treatment of Alzheimer's disease. 51,52) Therefore, we examined the hydroxyethylamine unit to SARS-CoV-2 inhibitors as an amide bond surrogate by synthesizing the N-methylated hydroxyethylamine-type derivatives 10 and 33 and the hydroxyethylamine-type derivatives 11 and 34. We found that these hydroxyethylamine-type derivatives showed attenuated potencies relative to the parent compounds YH-53/5h (2) and 4.…”

Section: Discussionmentioning

confidence: 99%

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

Tsuji,

Kobayakawa,

Ishii

et al. 2023

CHEMICAL & PHARMACEUTICAL BULLETIN

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In the development of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs, its main protease (M pro ), which is an essential enzyme for viral replication, is a promising target. To date, the M pro 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 pro 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 pro 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 pro inhibitors. Key words amide bond surrogate, coronavirus disease of 2019 (COVID-19), fluorination, main protease inhibitor, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2

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Macrocyclic BACE1 inhibitors with hydrophobic cross-linked structures: Optimization of ring size and ring structure

Otani

Hattori

Akaji

et al. 2021

Bioorganic & Medicinal Chemistry

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Structure–activity relationship study of hydroxyethylamine isostere and P1′ site structure of peptide mimetic BACE1 inhibitors

Cited by 3 publications

References 31 publications

Synthesis and Structural Optimization of Macrocyclic BACE1 Inhibitors with a Hydrophobic Cross-Linked Structure

Synthesis and Structural Optimization of Macrocyclic BACE1 Inhibitors with a Hydrophobic Cross-Linked Structure

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

Macrocyclic BACE1 inhibitors with hydrophobic cross-linked structures: Optimization of ring size and ring structure

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