Discovery of DS42450411 as a potent orally active hepcidin production inhibitor: Design and optimization of novel 4-aminopyrimidine derivatives
[Display omitted] •Hepcidin, a peptide hormone, is a master regulator of systemic iron mobilizations (83 characters).•Hepcidin inhibition could be a strategy for treating anemia of chronic disease (80 characters).•4-Aminopyrimidine compound was founded as a hit of Hepcidin production inhibitor (82 c...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2018-11, Vol.28 (20), p.3333-3337 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Fukuda, Takeshi Ishiyama, Takashi Katagiri, Takahiro Ueda, Kenjiro Muramatsu, Sumie Hashimoto, Masami Aki, Anri Baba, Daichi Watanabe, Kengo Tanaka, Naoki |
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•Hepcidin, a peptide hormone, is a master regulator of systemic iron mobilizations (83 characters).•Hepcidin inhibition could be a strategy for treating anemia of chronic disease (80 characters).•4-Aminopyrimidine compound was founded as a hit of Hepcidin production inhibitor (82 characters).•Optimization study led to a potent and bioavailable Hepcidin production inhibitor (83 characters).•DS42450411 showed serum Hepcidin-lowering effects in an acute inflammation model (82 characters).
Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis. The inhibition of hepcidin may be a favorable strategy for the treatment of anemia of chronic disease. Here, we have reported the design, synthesis, and structure–activity relationships (SAR) of a series of 4-aminopyrimidine compounds as inhibitors of hepcidin production. The optimization study of 1 led to the design of a potent and bioavailable inhibitor of hepcidin production, 34 (DS42450411), which showed serum hepcidin-lowering effects in a mouse model of interleukin-6-induced acute inflammation. |
| doi_str_mv | 10.1016/j.bmcl.2018.09.010 |
| format | Article |
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•Hepcidin, a peptide hormone, is a master regulator of systemic iron mobilizations (83 characters).•Hepcidin inhibition could be a strategy for treating anemia of chronic disease (80 characters).•4-Aminopyrimidine compound was founded as a hit of Hepcidin production inhibitor (82 characters).•Optimization study led to a potent and bioavailable Hepcidin production inhibitor (83 characters).•DS42450411 showed serum Hepcidin-lowering effects in an acute inflammation model (82 characters).
Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis. The inhibition of hepcidin may be a favorable strategy for the treatment of anemia of chronic disease. Here, we have reported the design, synthesis, and structure–activity relationships (SAR) of a series of 4-aminopyrimidine compounds as inhibitors of hepcidin production. The optimization study of 1 led to the design of a potent and bioavailable inhibitor of hepcidin production, 34 (DS42450411), which showed serum hepcidin-lowering effects in a mouse model of interleukin-6-induced acute inflammation.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2018.09.010</identifier><identifier>PMID: 30217414</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Administration, Oral ; Aminopyridines - administration & dosage ; Aminopyridines - chemical synthesis ; Aminopyridines - pharmacokinetics ; Aminopyridines - pharmacology ; Aminopyrimidine ; Anemia - drug therapy ; Anemia - etiology ; Anemia of chronic disease ; Animals ; Binding Sites ; Cell Line, Tumor ; Drug Design ; DYRK1a ; Hepcidin ; Hepcidins - antagonists & inhibitors ; Hepcidins - blood ; Hepcidins - chemistry ; Humans ; Inflammation - chemically induced ; Inflammation - complications ; Interleukin-6 - metabolism ; Iron - metabolism ; Male ; Mice, Inbred C57BL ; Molecular Structure ; Quinazolines - administration & dosage ; Quinazolines - chemical synthesis ; Quinazolines - pharmacokinetics ; Quinazolines - pharmacology ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2018-11, Vol.28 (20), p.3333-3337</ispartof><rights>2018 Elsevier Ltd</rights><rights>Copyright © 2018 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-9aa6ae936dec76b77ea722e89b2bb00ac051159f19049cb5685e90549e059f1c3</citedby><cites>FETCH-LOGICAL-c356t-9aa6ae936dec76b77ea722e89b2bb00ac051159f19049cb5685e90549e059f1c3</cites><orcidid>0000-0002-0078-8112</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X18307418$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30217414$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fukuda, Takeshi</creatorcontrib><creatorcontrib>Ishiyama, Takashi</creatorcontrib><creatorcontrib>Katagiri, Takahiro</creatorcontrib><creatorcontrib>Ueda, Kenjiro</creatorcontrib><creatorcontrib>Muramatsu, Sumie</creatorcontrib><creatorcontrib>Hashimoto, Masami</creatorcontrib><creatorcontrib>Aki, Anri</creatorcontrib><creatorcontrib>Baba, Daichi</creatorcontrib><creatorcontrib>Watanabe, Kengo</creatorcontrib><creatorcontrib>Tanaka, Naoki</creatorcontrib><title>Discovery of DS42450411 as a potent orally active hepcidin production inhibitor: Design and optimization of novel 4-aminopyrimidine derivatives</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
•Hepcidin, a peptide hormone, is a master regulator of systemic iron mobilizations (83 characters).•Hepcidin inhibition could be a strategy for treating anemia of chronic disease (80 characters).•4-Aminopyrimidine compound was founded as a hit of Hepcidin production inhibitor (82 characters).•Optimization study led to a potent and bioavailable Hepcidin production inhibitor (83 characters).•DS42450411 showed serum Hepcidin-lowering effects in an acute inflammation model (82 characters).
Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis. The inhibition of hepcidin may be a favorable strategy for the treatment of anemia of chronic disease. Here, we have reported the design, synthesis, and structure–activity relationships (SAR) of a series of 4-aminopyrimidine compounds as inhibitors of hepcidin production. The optimization study of 1 led to the design of a potent and bioavailable inhibitor of hepcidin production, 34 (DS42450411), which showed serum hepcidin-lowering effects in a mouse model of interleukin-6-induced acute inflammation.</description><subject>Administration, Oral</subject><subject>Aminopyridines - administration & dosage</subject><subject>Aminopyridines - chemical synthesis</subject><subject>Aminopyridines - pharmacokinetics</subject><subject>Aminopyridines - pharmacology</subject><subject>Aminopyrimidine</subject><subject>Anemia - drug therapy</subject><subject>Anemia - etiology</subject><subject>Anemia of chronic disease</subject><subject>Animals</subject><subject>Binding Sites</subject><subject>Cell Line, Tumor</subject><subject>Drug Design</subject><subject>DYRK1a</subject><subject>Hepcidin</subject><subject>Hepcidins - antagonists & inhibitors</subject><subject>Hepcidins - blood</subject><subject>Hepcidins - chemistry</subject><subject>Humans</subject><subject>Inflammation - chemically induced</subject><subject>Inflammation - complications</subject><subject>Interleukin-6 - metabolism</subject><subject>Iron - metabolism</subject><subject>Male</subject><subject>Mice, Inbred C57BL</subject><subject>Molecular Structure</subject><subject>Quinazolines - administration & dosage</subject><subject>Quinazolines - chemical synthesis</subject><subject>Quinazolines - pharmacokinetics</subject><subject>Quinazolines - pharmacology</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc9O3DAQxq2qCJY_L9AD8rGXpOPEcdaIC2IpRVqJA63EzXKc2eJVYqd2dqXlJXjlOt0tR06Wxt_8Zub7CPnCIGfAxLd13vSmywtg8xxkDgw-kRnjgmclh-ozmYEUkM0lfz4hpzGuARgHzo_JSQkFqznjM_K2sNH4LYYd9Su6eOIFr4AzRnWkmg5-RDdSH3TX7ag2o90ifcHB2NY6OgTfblLNO2rdi23s6MMVXWC0vx3VrqV-GG1vX_U_ScK7NKijPNO9dX7YhfSZOEhbDHarJ3g8J0cr3UW8OLxn5Nf3u5-3P7Ll4_3D7c0yM2UlxkxqLTTKUrRoatHUNeq6KHAum6JpALSBirFKrpgELk1TiXmFEiouEaaqKc_I1z03HfFng3FUfTICu0479JuoCgbJB1EKnqTFXmqCjzHgSg1pcx12ioGaglBrNQWhpiAUSJWCSE2XB_6m6bF9b_nvfBJc7wWYrtxaDCoai85gawOaUbXefsT_C8PzmvY</recordid><startdate>20181101</startdate><enddate>20181101</enddate><creator>Fukuda, Takeshi</creator><creator>Ishiyama, Takashi</creator><creator>Katagiri, Takahiro</creator><creator>Ueda, Kenjiro</creator><creator>Muramatsu, Sumie</creator><creator>Hashimoto, Masami</creator><creator>Aki, Anri</creator><creator>Baba, Daichi</creator><creator>Watanabe, Kengo</creator><creator>Tanaka, Naoki</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/0000-0002-0078-8112</orcidid></search><sort><creationdate>20181101</creationdate><title>Discovery of DS42450411 as a potent orally active hepcidin production inhibitor: Design and optimization of novel 4-aminopyrimidine derivatives</title><author>Fukuda, Takeshi ; Ishiyama, Takashi ; Katagiri, Takahiro ; Ueda, Kenjiro ; Muramatsu, Sumie ; Hashimoto, Masami ; Aki, Anri ; Baba, Daichi ; Watanabe, Kengo ; Tanaka, Naoki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-9aa6ae936dec76b77ea722e89b2bb00ac051159f19049cb5685e90549e059f1c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Administration, Oral</topic><topic>Aminopyridines - administration & dosage</topic><topic>Aminopyridines - chemical synthesis</topic><topic>Aminopyridines - pharmacokinetics</topic><topic>Aminopyridines - pharmacology</topic><topic>Aminopyrimidine</topic><topic>Anemia - drug therapy</topic><topic>Anemia - etiology</topic><topic>Anemia of chronic disease</topic><topic>Animals</topic><topic>Binding Sites</topic><topic>Cell Line, Tumor</topic><topic>Drug Design</topic><topic>DYRK1a</topic><topic>Hepcidin</topic><topic>Hepcidins - antagonists & inhibitors</topic><topic>Hepcidins - blood</topic><topic>Hepcidins - chemistry</topic><topic>Humans</topic><topic>Inflammation - chemically induced</topic><topic>Inflammation - complications</topic><topic>Interleukin-6 - metabolism</topic><topic>Iron - metabolism</topic><topic>Male</topic><topic>Mice, Inbred C57BL</topic><topic>Molecular Structure</topic><topic>Quinazolines - administration & dosage</topic><topic>Quinazolines - chemical synthesis</topic><topic>Quinazolines - pharmacokinetics</topic><topic>Quinazolines - pharmacology</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fukuda, Takeshi</creatorcontrib><creatorcontrib>Ishiyama, Takashi</creatorcontrib><creatorcontrib>Katagiri, Takahiro</creatorcontrib><creatorcontrib>Ueda, Kenjiro</creatorcontrib><creatorcontrib>Muramatsu, Sumie</creatorcontrib><creatorcontrib>Hashimoto, Masami</creatorcontrib><creatorcontrib>Aki, Anri</creatorcontrib><creatorcontrib>Baba, Daichi</creatorcontrib><creatorcontrib>Watanabe, Kengo</creatorcontrib><creatorcontrib>Tanaka, Naoki</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>Fukuda, Takeshi</au><au>Ishiyama, Takashi</au><au>Katagiri, Takahiro</au><au>Ueda, Kenjiro</au><au>Muramatsu, Sumie</au><au>Hashimoto, Masami</au><au>Aki, Anri</au><au>Baba, Daichi</au><au>Watanabe, Kengo</au><au>Tanaka, Naoki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of DS42450411 as a potent orally active hepcidin production inhibitor: Design and optimization of novel 4-aminopyrimidine derivatives</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2018-11-01</date><risdate>2018</risdate><volume>28</volume><issue>20</issue><spage>3333</spage><epage>3337</epage><pages>3333-3337</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
•Hepcidin, a peptide hormone, is a master regulator of systemic iron mobilizations (83 characters).•Hepcidin inhibition could be a strategy for treating anemia of chronic disease (80 characters).•4-Aminopyrimidine compound was founded as a hit of Hepcidin production inhibitor (82 characters).•Optimization study led to a potent and bioavailable Hepcidin production inhibitor (83 characters).•DS42450411 showed serum Hepcidin-lowering effects in an acute inflammation model (82 characters).
Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis. The inhibition of hepcidin may be a favorable strategy for the treatment of anemia of chronic disease. Here, we have reported the design, synthesis, and structure–activity relationships (SAR) of a series of 4-aminopyrimidine compounds as inhibitors of hepcidin production. The optimization study of 1 led to the design of a potent and bioavailable inhibitor of hepcidin production, 34 (DS42450411), which showed serum hepcidin-lowering effects in a mouse model of interleukin-6-induced acute inflammation.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>30217414</pmid><doi>10.1016/j.bmcl.2018.09.010</doi><tpages>5</tpages><orcidid>https://orcid.org/0000-0002-0078-8112</orcidid></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2018-11, Vol.28 (20), p.3333-3337 |
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| subjects | Administration, Oral Aminopyridines - administration & dosage Aminopyridines - chemical synthesis Aminopyridines - pharmacokinetics Aminopyridines - pharmacology Aminopyrimidine Anemia - drug therapy Anemia - etiology Anemia of chronic disease Animals Binding Sites Cell Line, Tumor Drug Design DYRK1a Hepcidin Hepcidins - antagonists & inhibitors Hepcidins - blood Hepcidins - chemistry Humans Inflammation - chemically induced Inflammation - complications Interleukin-6 - metabolism Iron - metabolism Male Mice, Inbred C57BL Molecular Structure Quinazolines - administration & dosage Quinazolines - chemical synthesis Quinazolines - pharmacokinetics Quinazolines - pharmacology Structure-Activity Relationship |
| title | Discovery of DS42450411 as a potent orally active hepcidin production inhibitor: Design and optimization of novel 4-aminopyrimidine derivatives |
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