Discovery of a potent, orally available furopyridine derivative as a novel selective bromodomain and extra-terminal domain (BET)-first bromodomain (BD1) inhibitor
[Display omitted] 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...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2024-09, Vol.109, p.129848, Article 129848 |
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| creator | Hagihara, Shuichi Ishizawa, Kouhei Kikuchi, Manami Kawano, Yuko Nishidate, Akiko Matsumoto, Fumi Hashimoto, Naohiro Sasaki, Chiduko Miyaguchi, Ikuko Okada, Okimasa Akashi, Tomoya Nakayama, Shinji Ogasawara, Yuko Endo, Junichi |
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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. |
| doi_str_mv | 10.1016/j.bmcl.2024.129848 |
| format | Article |
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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.</description><identifier>ISSN: 0960-894X</identifier><identifier>ISSN: 1464-3405</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2024.129848</identifier><identifier>PMID: 38876176</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Administration, Oral ; Animals ; BD1 selectivity ; BET family ; Drug Discovery ; Furopyridine ; Humans ; Inflammation ; Lipopolysaccharides - antagonists & inhibitors ; Lipopolysaccharides - pharmacology ; Mice ; Molecular Structure ; Orally available ; Protein Domains ; Pyridines - chemical synthesis ; Pyridines - chemistry ; Pyridines - pharmacology ; Rats ; Structure-Activity Relationship ; X-ray crystallography</subject><ispartof>Bioorganic & medicinal chemistry letters, 2024-09, Vol.109, p.129848, Article 129848</ispartof><rights>2024</rights><rights>Copyright © 2024. Published by Elsevier Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c237t-356c68414383c91d5c71c23b284154864c4c3e83af3d55e3b0bd16b2e9a745e03</cites><orcidid>0009-0001-0259-5306</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2024.129848$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38876176$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hagihara, Shuichi</creatorcontrib><creatorcontrib>Ishizawa, Kouhei</creatorcontrib><creatorcontrib>Kikuchi, Manami</creatorcontrib><creatorcontrib>Kawano, Yuko</creatorcontrib><creatorcontrib>Nishidate, Akiko</creatorcontrib><creatorcontrib>Matsumoto, Fumi</creatorcontrib><creatorcontrib>Hashimoto, Naohiro</creatorcontrib><creatorcontrib>Sasaki, Chiduko</creatorcontrib><creatorcontrib>Miyaguchi, Ikuko</creatorcontrib><creatorcontrib>Okada, Okimasa</creatorcontrib><creatorcontrib>Akashi, Tomoya</creatorcontrib><creatorcontrib>Nakayama, Shinji</creatorcontrib><creatorcontrib>Ogasawara, Yuko</creatorcontrib><creatorcontrib>Endo, Junichi</creatorcontrib><title>Discovery of a potent, orally available furopyridine derivative as a novel selective bromodomain and extra-terminal domain (BET)-first bromodomain (BD1) inhibitor</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
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.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>BD1 selectivity</subject><subject>BET family</subject><subject>Drug Discovery</subject><subject>Furopyridine</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Lipopolysaccharides - antagonists & inhibitors</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>Mice</subject><subject>Molecular Structure</subject><subject>Orally available</subject><subject>Protein Domains</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacology</subject><subject>Rats</subject><subject>Structure-Activity Relationship</subject><subject>X-ray crystallography</subject><issn>0960-894X</issn><issn>1464-3405</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc2KFDEUhYMoTjv6Ai4kyx6w2qSSSqXAjfPjDwy4GcFdSCW3ME0qaZN0Yb-OT2rabgU3ri7ce86Bez6EXlKyoYSKN9vNOBu_aUnLN7QdJJeP0IpywRvGSfcYrcggSCMH_vUCPct5SwjlhPOn6IJJ2QvaixX6eeuyiQukA44T1ngXC4TyGsekvT9gvWjn9egBT_sUd4fkrAuALSS36OIWwDpXV6gJHmfwYH4vxxTnaOOsXcA6WAw_StJNgTS7oD0-X9bXdw9XzeRSLv841te39Aq78M2NrsT0HD2ZtM_w4jwv0Zf3dw83H5v7zx8-3by7b0zL-tKwThghOeVMMjNQ25me1svY1l3HpeCGGwaS6YnZrgM2ktFSMbYw6J53QNglWp9ydyl-30Muaq7dgPc6QNxnxYiQfdcJKaq0PUlNijknmNQuuVmng6JEHdmorTqyUUc26sSmml6d8_fjDPav5Q-MKnh7EkD9cnGQVDYOggHrUi1W2ej-l_8LK3Ch0g</recordid><startdate>20240901</startdate><enddate>20240901</enddate><creator>Hagihara, Shuichi</creator><creator>Ishizawa, Kouhei</creator><creator>Kikuchi, Manami</creator><creator>Kawano, Yuko</creator><creator>Nishidate, Akiko</creator><creator>Matsumoto, Fumi</creator><creator>Hashimoto, Naohiro</creator><creator>Sasaki, Chiduko</creator><creator>Miyaguchi, Ikuko</creator><creator>Okada, Okimasa</creator><creator>Akashi, Tomoya</creator><creator>Nakayama, Shinji</creator><creator>Ogasawara, Yuko</creator><creator>Endo, Junichi</creator><general>Elsevier Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0009-0001-0259-5306</orcidid></search><sort><creationdate>20240901</creationdate><title>Discovery of a potent, orally available furopyridine derivative as a novel selective bromodomain and extra-terminal domain (BET)-first bromodomain (BD1) inhibitor</title><author>Hagihara, Shuichi ; Ishizawa, Kouhei ; Kikuchi, Manami ; Kawano, Yuko ; Nishidate, Akiko ; Matsumoto, Fumi ; Hashimoto, Naohiro ; Sasaki, Chiduko ; Miyaguchi, Ikuko ; Okada, Okimasa ; Akashi, Tomoya ; Nakayama, Shinji ; Ogasawara, Yuko ; Endo, Junichi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c237t-356c68414383c91d5c71c23b284154864c4c3e83af3d55e3b0bd16b2e9a745e03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>BD1 selectivity</topic><topic>BET family</topic><topic>Drug Discovery</topic><topic>Furopyridine</topic><topic>Humans</topic><topic>Inflammation</topic><topic>Lipopolysaccharides - antagonists & inhibitors</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>Mice</topic><topic>Molecular Structure</topic><topic>Orally available</topic><topic>Protein Domains</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - chemistry</topic><topic>Pyridines - pharmacology</topic><topic>Rats</topic><topic>Structure-Activity Relationship</topic><topic>X-ray crystallography</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hagihara, Shuichi</creatorcontrib><creatorcontrib>Ishizawa, Kouhei</creatorcontrib><creatorcontrib>Kikuchi, Manami</creatorcontrib><creatorcontrib>Kawano, Yuko</creatorcontrib><creatorcontrib>Nishidate, Akiko</creatorcontrib><creatorcontrib>Matsumoto, Fumi</creatorcontrib><creatorcontrib>Hashimoto, Naohiro</creatorcontrib><creatorcontrib>Sasaki, Chiduko</creatorcontrib><creatorcontrib>Miyaguchi, Ikuko</creatorcontrib><creatorcontrib>Okada, Okimasa</creatorcontrib><creatorcontrib>Akashi, Tomoya</creatorcontrib><creatorcontrib>Nakayama, Shinji</creatorcontrib><creatorcontrib>Ogasawara, Yuko</creatorcontrib><creatorcontrib>Endo, Junichi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hagihara, Shuichi</au><au>Ishizawa, Kouhei</au><au>Kikuchi, Manami</au><au>Kawano, Yuko</au><au>Nishidate, Akiko</au><au>Matsumoto, Fumi</au><au>Hashimoto, Naohiro</au><au>Sasaki, Chiduko</au><au>Miyaguchi, Ikuko</au><au>Okada, Okimasa</au><au>Akashi, Tomoya</au><au>Nakayama, Shinji</au><au>Ogasawara, Yuko</au><au>Endo, Junichi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of a potent, orally available furopyridine derivative as a novel selective bromodomain and extra-terminal domain (BET)-first bromodomain (BD1) inhibitor</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2024-09-01</date><risdate>2024</risdate><volume>109</volume><spage>129848</spage><pages>129848-</pages><artnum>129848</artnum><issn>0960-894X</issn><issn>1464-3405</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
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.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>38876176</pmid><doi>10.1016/j.bmcl.2024.129848</doi><orcidid>https://orcid.org/0009-0001-0259-5306</orcidid></addata></record> |
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| subjects | Administration, Oral Animals BD1 selectivity BET family Drug Discovery Furopyridine Humans Inflammation Lipopolysaccharides - antagonists & inhibitors Lipopolysaccharides - pharmacology Mice Molecular Structure Orally available Protein Domains Pyridines - chemical synthesis Pyridines - chemistry Pyridines - pharmacology Rats Structure-Activity Relationship X-ray crystallography |
| title | Discovery of a potent, orally available furopyridine derivative as a novel selective bromodomain and extra-terminal domain (BET)-first bromodomain (BD1) inhibitor |
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