{"doi":"10.1248/cpb.c23-00562","title":"Exploratory Studies of Effective Inhibitors against the SARS-CoV-2 Main Protease by Halogen Incorporation and Amide Bond Replacement","abstract":"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.","journal":"Chemical and Pharmaceutical Bulletin","year":2023,"id":363199,"datarank":0.32958368660043297,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.0,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9598,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":950458,"name":"Takuya Kobayakawa","orcid":"0000-0001-9786-2608","position":1,"is_corresponding":false},{"id":1033071,"name":"Takahiro Ishii","orcid":"0000-0003-1664-6191","position":2,"is_corresponding":false},{"id":495658,"name":"Nobuyo Higashi‐Kuwata","orcid":"0000-0002-9404-3532","position":3,"is_corresponding":false},{"id":1117681,"name":"Chika Azuma","orcid":null,"position":4,"is_corresponding":false},{"id":1117682,"name":"Kouki Shinohara","orcid":null,"position":5,"is_corresponding":false},{"id":1117683,"name":"Yutaro Miura","orcid":null,"position":6,"is_corresponding":false},{"id":31493,"name":"Kenichi Yamamoto","orcid":"0000-0001-9594-7050","position":7,"is_corresponding":false},{"id":1117684,"name":"Soshi Nishimura","orcid":null,"position":8,"is_corresponding":false},{"id":296974,"name":"Shin‐ichiro Hattori","orcid":null,"position":9,"is_corresponding":false},{"id":295827,"name":"Haydar Bulut","orcid":"0000-0003-0262-6296","position":10,"is_corresponding":false},{"id":295833,"name":"Hiroaki Mitsuya","orcid":"0000-0001-9274-3853","position":11,"is_corresponding":false},{"id":588041,"name":"Hirokazu Tamamura","orcid":"0000-0003-2788-2579","position":12,"is_corresponding":false},{"id":367621,"name":"Kohei Tsuji","orcid":"0000-0003-4773-8793","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:14:28.054440Z","pmid":"38044140","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}