Design, synthesis and biological evaluation of 6-chloro-quinolin-2-one derivatives as novel FXIa inhibitors
[Display omitted] A series of 6-chloro-quinolin-2-one derivatives were designed and synthesized as FXIa inhibitors by exploration of P1, P1 prime and P2 prime groups. Each compound was accessed for inhibitory effect on FXIa and some of them were evaluated in the clotting assay. 14c demonstrated exce...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2024-02, Vol.99, p.129610-129610, Article 129610 |
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| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 99 |
| creator | Wang, Yanshi Yuan, Jianglin Yan, Sida Liu, Peng Zheng, Zhichao Zhang, Shijun Meng, Fancui Liu, Wei Huang, Changjiang Wei, Qunchao |
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A series of 6-chloro-quinolin-2-one derivatives were designed and synthesized as FXIa inhibitors by exploration of P1, P1 prime and P2 prime groups. Each compound was accessed for inhibitory effect on FXIa and some of them were evaluated in the clotting assay. 14c demonstrated excellent in-vitro potency (FXIa IC50: 15 nM, 2 x aPTT: 6.8 μM) and good in-vivo efficacy (prolonged in-vivo aPTT by more than 1-fold but not PT). Moreover, the pharmacokinetics property of 14c were evaluated following intravenous administration in rats, which indicated that 14c probably will be a clinical candidate for intravenous administration. |
| doi_str_mv | 10.1016/j.bmcl.2024.129610 |
| format | Article |
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A series of 6-chloro-quinolin-2-one derivatives were designed and synthesized as FXIa inhibitors by exploration of P1, P1 prime and P2 prime groups. Each compound was accessed for inhibitory effect on FXIa and some of them were evaluated in the clotting assay. 14c demonstrated excellent in-vitro potency (FXIa IC50: 15 nM, 2 x aPTT: 6.8 μM) and good in-vivo efficacy (prolonged in-vivo aPTT by more than 1-fold but not PT). Moreover, the pharmacokinetics property of 14c were evaluated following intravenous administration in rats, which indicated that 14c probably will be a clinical candidate for intravenous administration.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2024.129610</identifier><identifier>PMID: 38211702</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>6-chloro-quinolin-2-one derivatives ; Animals ; Blood Coagulation ; Clotting assay ; Factor XIa ; FXIa inhibitors ; Intravenous administration ; Partial Thromboplastin Time ; Rats</subject><ispartof>Bioorganic & medicinal chemistry letters, 2024-02, Vol.99, p.129610-129610, Article 129610</ispartof><rights>2024 Elsevier Ltd</rights><rights>Copyright © 2024 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c307t-b6859073370d49e4bb8799b1633836dfe14947fd701c6cb943395e8d71d38b293</cites><orcidid>0000-0002-3641-2491 ; 0000-0002-5064-0618</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X2400012X$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38211702$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Yanshi</creatorcontrib><creatorcontrib>Yuan, Jianglin</creatorcontrib><creatorcontrib>Yan, Sida</creatorcontrib><creatorcontrib>Liu, Peng</creatorcontrib><creatorcontrib>Zheng, Zhichao</creatorcontrib><creatorcontrib>Zhang, Shijun</creatorcontrib><creatorcontrib>Meng, Fancui</creatorcontrib><creatorcontrib>Liu, Wei</creatorcontrib><creatorcontrib>Huang, Changjiang</creatorcontrib><creatorcontrib>Wei, Qunchao</creatorcontrib><title>Design, synthesis and biological evaluation of 6-chloro-quinolin-2-one derivatives as novel FXIa inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
A series of 6-chloro-quinolin-2-one derivatives were designed and synthesized as FXIa inhibitors by exploration of P1, P1 prime and P2 prime groups. Each compound was accessed for inhibitory effect on FXIa and some of them were evaluated in the clotting assay. 14c demonstrated excellent in-vitro potency (FXIa IC50: 15 nM, 2 x aPTT: 6.8 μM) and good in-vivo efficacy (prolonged in-vivo aPTT by more than 1-fold but not PT). Moreover, the pharmacokinetics property of 14c were evaluated following intravenous administration in rats, which indicated that 14c probably will be a clinical candidate for intravenous administration.</description><subject>6-chloro-quinolin-2-one derivatives</subject><subject>Animals</subject><subject>Blood Coagulation</subject><subject>Clotting assay</subject><subject>Factor XIa</subject><subject>FXIa inhibitors</subject><subject>Intravenous administration</subject><subject>Partial Thromboplastin Time</subject><subject>Rats</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kD1vFDEQQC0EIpfAH6BALinw4a-11xINCiREikQDUjprbc_mfPjsxN5dKf-ePV2gpJop3jxpHkLvGN0yytSn_dYdfNpyyuWWcaMYfYE2TCpJhKTdS7ShRlHSG3l3hs5b21PKJJXyNToTPWdMU75Bv79Ci_f5I25Pedqte8NDDtjFksp99EPCsAxpHqZYMi4jVsTvUqmFPM4xlxQz4aRkwAFqXFZqgVXQcC4LJHx1dzPgmHfRxanU9ga9GofU4O3zvEC_rr79vPxObn9c31x-uSVeUD0Rp_rOUC2EpkEakM712hjHlBC9UGEEJo3UY9CUeeWdkUKYDvqgWRC940ZcoA8n70MtjzO0yR5i85DSkKHMzXLDuk5zrvmK8hPqa2mtwmgfajwM9ckyao-R7d4eI9tjZHuKvB69f_bP7gDh38nfqivw-QTA-uUSodrmI2QPIVbwkw0l_s__ByczjRU</recordid><startdate>20240201</startdate><enddate>20240201</enddate><creator>Wang, Yanshi</creator><creator>Yuan, Jianglin</creator><creator>Yan, Sida</creator><creator>Liu, Peng</creator><creator>Zheng, Zhichao</creator><creator>Zhang, Shijun</creator><creator>Meng, Fancui</creator><creator>Liu, Wei</creator><creator>Huang, Changjiang</creator><creator>Wei, Qunchao</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/0000-0002-3641-2491</orcidid><orcidid>https://orcid.org/0000-0002-5064-0618</orcidid></search><sort><creationdate>20240201</creationdate><title>Design, synthesis and biological evaluation of 6-chloro-quinolin-2-one derivatives as novel FXIa inhibitors</title><author>Wang, Yanshi ; Yuan, Jianglin ; Yan, Sida ; Liu, Peng ; Zheng, Zhichao ; Zhang, Shijun ; Meng, Fancui ; Liu, Wei ; Huang, Changjiang ; Wei, Qunchao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c307t-b6859073370d49e4bb8799b1633836dfe14947fd701c6cb943395e8d71d38b293</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>6-chloro-quinolin-2-one derivatives</topic><topic>Animals</topic><topic>Blood Coagulation</topic><topic>Clotting assay</topic><topic>Factor XIa</topic><topic>FXIa inhibitors</topic><topic>Intravenous administration</topic><topic>Partial Thromboplastin Time</topic><topic>Rats</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Yanshi</creatorcontrib><creatorcontrib>Yuan, Jianglin</creatorcontrib><creatorcontrib>Yan, Sida</creatorcontrib><creatorcontrib>Liu, Peng</creatorcontrib><creatorcontrib>Zheng, Zhichao</creatorcontrib><creatorcontrib>Zhang, Shijun</creatorcontrib><creatorcontrib>Meng, Fancui</creatorcontrib><creatorcontrib>Liu, Wei</creatorcontrib><creatorcontrib>Huang, Changjiang</creatorcontrib><creatorcontrib>Wei, Qunchao</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>Wang, Yanshi</au><au>Yuan, Jianglin</au><au>Yan, Sida</au><au>Liu, Peng</au><au>Zheng, Zhichao</au><au>Zhang, Shijun</au><au>Meng, Fancui</au><au>Liu, Wei</au><au>Huang, Changjiang</au><au>Wei, Qunchao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, synthesis and biological evaluation of 6-chloro-quinolin-2-one derivatives as novel FXIa inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2024-02-01</date><risdate>2024</risdate><volume>99</volume><spage>129610</spage><epage>129610</epage><pages>129610-129610</pages><artnum>129610</artnum><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
A series of 6-chloro-quinolin-2-one derivatives were designed and synthesized as FXIa inhibitors by exploration of P1, P1 prime and P2 prime groups. Each compound was accessed for inhibitory effect on FXIa and some of them were evaluated in the clotting assay. 14c demonstrated excellent in-vitro potency (FXIa IC50: 15 nM, 2 x aPTT: 6.8 μM) and good in-vivo efficacy (prolonged in-vivo aPTT by more than 1-fold but not PT). Moreover, the pharmacokinetics property of 14c were evaluated following intravenous administration in rats, which indicated that 14c probably will be a clinical candidate for intravenous administration.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>38211702</pmid><doi>10.1016/j.bmcl.2024.129610</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-3641-2491</orcidid><orcidid>https://orcid.org/0000-0002-5064-0618</orcidid></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2024-02, Vol.99, p.129610-129610, Article 129610 |
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| subjects | 6-chloro-quinolin-2-one derivatives Animals Blood Coagulation Clotting assay Factor XIa FXIa inhibitors Intravenous administration Partial Thromboplastin Time Rats |
| title | Design, synthesis and biological evaluation of 6-chloro-quinolin-2-one derivatives as novel FXIa inhibitors |
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