{"title":"发现一种强效、可口服的呋喃吡啶衍生物，作为新型选择性溴基端域和外端域 (BET) - 第一溴基端域 (BD1) 抑制剂。","authors":"Shuichi Hagihara, Kouhei Ishizawa, Manami Kikuchi, Yuko Kawano, Akiko Nishidate, Fumi Matsumoto, Naohiro Hashimoto, Chiduko Sasaki, Ikuko Miyaguchi, Okimasa Okada, Tomoya Akashi, Shinji Nakayama, Yuko Ogasawara, Junichi Endo","doi":"10.1016/j.bmcl.2024.129848","DOIUrl":null,"url":null,"abstract":"<div><p>We explored novel immunosuppressive agents with immune tolerance using a phenotypic drug discovery strategy, focusing on costimulatory molecules in T cells, and obtained triazolothienodiazepine derivatives. Their mechanism of action is to inhibit the bromodomain and extra-terminal domain (BET) family, as we have previously reported. Selective inhibition of the first bromodomain (BD1) of the BET family is expected to exert antitumor and immunosuppressive effects, similar to BET inhibitors.</p><p>This study identified furopyridine derivatives <strong>7</strong> and <strong>8</strong> with high BD1 inhibitory activity and high selectivity over BD2. Compound <strong>7</strong> was found to be orally bioavailable and exhibited anti-inflammatory activity in a lipopolysaccharide-induced model.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.5000,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of a potent, orally available furopyridine derivative as a novel selective bromodomain and extra-terminal domain (BET)-first bromodomain (BD1) inhibitor\",\"authors\":\"Shuichi Hagihara, Kouhei Ishizawa, Manami Kikuchi, Yuko Kawano, Akiko Nishidate, Fumi Matsumoto, Naohiro Hashimoto, Chiduko Sasaki, Ikuko Miyaguchi, Okimasa Okada, Tomoya Akashi, Shinji Nakayama, Yuko Ogasawara, Junichi Endo\",\"doi\":\"10.1016/j.bmcl.2024.129848\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>We explored novel immunosuppressive agents with immune tolerance using a phenotypic drug discovery strategy, focusing on costimulatory molecules in T cells, and obtained triazolothienodiazepine derivatives. Their mechanism of action is to inhibit the bromodomain and extra-terminal domain (BET) family, as we have previously reported. Selective inhibition of the first bromodomain (BD1) of the BET family is expected to exert antitumor and immunosuppressive effects, similar to BET inhibitors.</p><p>This study identified furopyridine derivatives <strong>7</strong> and <strong>8</strong> with high BD1 inhibitory activity and high selectivity over BD2. Compound <strong>7</strong> was found to be orally bioavailable and exhibited anti-inflammatory activity in a lipopolysaccharide-induced model.</p></div>\",\"PeriodicalId\":256,\"journal\":{\"name\":\"Bioorganic & Medicinal Chemistry Letters\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.5000,\"publicationDate\":\"2024-06-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic & Medicinal Chemistry Letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0960894X24002506\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0960894X24002506","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
摘要
我们采用表型药物发现策略，以 T 细胞中的成本刺激分子为重点，探索具有免疫耐受的新型免疫抑制剂，并获得了三唑硫氮杂卓衍生物。它们的作用机制是抑制溴结构域和末端外结构域（BET）家族，正如我们之前所报道的那样。选择性抑制 BET 家族的第一个溴结构域（BD1）有望发挥与 BET 抑制剂类似的抗肿瘤和免疫抑制作用。本研究发现呋喃吡啶衍生物 7 和 8 具有很高的 BD1 抑制活性和对 BD2 的高选择性。化合物 7 具有口服生物利用度，并在脂多糖诱导模型中表现出抗炎活性。
Discovery of a potent, orally available furopyridine derivative as a novel selective bromodomain and extra-terminal domain (BET)-first bromodomain (BD1) inhibitor
We explored novel immunosuppressive agents with immune tolerance using a phenotypic drug discovery strategy, focusing on costimulatory molecules in T cells, and obtained triazolothienodiazepine derivatives. Their mechanism of action is to inhibit the bromodomain and extra-terminal domain (BET) family, as we have previously reported. Selective inhibition of the first bromodomain (BD1) of the BET family is expected to exert antitumor and immunosuppressive effects, similar to BET inhibitors.
This study identified furopyridine derivatives 7 and 8 with high BD1 inhibitory activity and high selectivity over BD2. Compound 7 was found to be orally bioavailable and exhibited anti-inflammatory activity in a lipopolysaccharide-induced model.
期刊介绍：
Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.
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