Allosteric Inhibitors of Hepatitis C Polymerase: Discovery of Potent and Orally Bioavailable Carbon-Linked Dihydropyrones
The discovery and optimization of a novel class of carbon-linked dihydropyrones as allosteric HCV NS5B polymerase inhibitors are presented. Replacement of the sulfur linker atom with carbon reduced compound acidity and greatly increased cell permeation. Further structure−activity relationship (SAR)...
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| Veröffentlicht in: | Journal of medicinal chemistry 2007-08, Vol.50 (17), p.3969-3972 |
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| container_end_page | 3972 |
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| container_issue | 17 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 50 |
| creator | Li, Hui Linton, Angelica Tatlock, John Gonzalez, Javier Borchardt, Allen Abreo, Mel Jewell, Tanya Patel, Leena Drowns, Matthew Ludlum, Sarah Goble, Mike Yang, Michele Blazel, Julie Rahavendran, Ravi Skor, Heather Shi, Stephanie Lewis, Cristina Fuhrman, Shella |
| description | The discovery and optimization of a novel class of carbon-linked dihydropyrones as allosteric HCV NS5B polymerase inhibitors are presented. Replacement of the sulfur linker atom with carbon reduced compound acidity and greatly increased cell permeation. Further structure−activity relationship (SAR) studies led to the identification of compounds, exemplified by 23 and 24, with significantly improved antiviral activities in the cell-based replicon assay and favorable pharmacokinetic profiles. |
| doi_str_mv | 10.1021/jm0704447 |
| format | Article |
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Replacement of the sulfur linker atom with carbon reduced compound acidity and greatly increased cell permeation. Further structure−activity relationship (SAR) studies led to the identification of compounds, exemplified by 23 and 24, with significantly improved antiviral activities in the cell-based replicon assay and favorable pharmacokinetic profiles.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm0704447</identifier><identifier>PMID: 17658778</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Administration, Oral ; Allosteric Regulation ; Animals ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Antiviral Agents - chemical synthesis ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; Biological and medical sciences ; Biological Availability ; Caco-2 Cells ; Cell Line, Tumor ; Half-Life ; Hepacivirus - enzymology ; Hepatitis C virus ; Humans ; Medical sciences ; Permeability ; Pharmacology. Drug treatments ; Pyrones - chemical synthesis ; Pyrones - chemistry ; Pyrones - pharmacology ; Rats ; Stereoisomerism ; Structure-Activity Relationship ; Viral Nonstructural Proteins - antagonists & inhibitors ; Viral Nonstructural Proteins - genetics</subject><ispartof>Journal of medicinal chemistry, 2007-08, Vol.50 (17), p.3969-3972</ispartof><rights>Copyright © 2007 American Chemical Society</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a412t-1d0a59c302668f06c2fe7cc03d9ba0f5b5e49642fee639d7f523f7786409deb53</citedby><cites>FETCH-LOGICAL-a412t-1d0a59c302668f06c2fe7cc03d9ba0f5b5e49642fee639d7f523f7786409deb53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm0704447$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm0704447$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=19018806$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17658778$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Hui</creatorcontrib><creatorcontrib>Linton, Angelica</creatorcontrib><creatorcontrib>Tatlock, John</creatorcontrib><creatorcontrib>Gonzalez, Javier</creatorcontrib><creatorcontrib>Borchardt, Allen</creatorcontrib><creatorcontrib>Abreo, Mel</creatorcontrib><creatorcontrib>Jewell, Tanya</creatorcontrib><creatorcontrib>Patel, Leena</creatorcontrib><creatorcontrib>Drowns, Matthew</creatorcontrib><creatorcontrib>Ludlum, Sarah</creatorcontrib><creatorcontrib>Goble, Mike</creatorcontrib><creatorcontrib>Yang, Michele</creatorcontrib><creatorcontrib>Blazel, Julie</creatorcontrib><creatorcontrib>Rahavendran, Ravi</creatorcontrib><creatorcontrib>Skor, Heather</creatorcontrib><creatorcontrib>Shi, Stephanie</creatorcontrib><creatorcontrib>Lewis, Cristina</creatorcontrib><creatorcontrib>Fuhrman, Shella</creatorcontrib><title>Allosteric Inhibitors of Hepatitis C Polymerase: Discovery of Potent and Orally Bioavailable Carbon-Linked Dihydropyrones</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The discovery and optimization of a novel class of carbon-linked dihydropyrones as allosteric HCV NS5B polymerase inhibitors are presented. Replacement of the sulfur linker atom with carbon reduced compound acidity and greatly increased cell permeation. Further structure−activity relationship (SAR) studies led to the identification of compounds, exemplified by 23 and 24, with significantly improved antiviral activities in the cell-based replicon assay and favorable pharmacokinetic profiles.</description><subject>Administration, Oral</subject><subject>Allosteric Regulation</subject><subject>Animals</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - chemical synthesis</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Biological Availability</subject><subject>Caco-2 Cells</subject><subject>Cell Line, Tumor</subject><subject>Half-Life</subject><subject>Hepacivirus - enzymology</subject><subject>Hepatitis C virus</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Permeability</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyrones - chemical synthesis</subject><subject>Pyrones - chemistry</subject><subject>Pyrones - pharmacology</subject><subject>Rats</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Viral Nonstructural Proteins - antagonists & inhibitors</subject><subject>Viral Nonstructural Proteins - genetics</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkcFu1DAQhi0EosvCgRdAvoDEITB2HDvh1i6FVqzUlVgQN8txHNVbx97a2aqROHDlNXkSXO2q5cBppJlvfs3_D0IvCbwjQMn7zQACGGPiEZqRikLBamCP0QyA0oJyWh6hZyltAKAktHyKjojgVS1EPUM_j50LaTTRanzuL21rxxATDj0-M1s12tEmvMCr4KbBRJXMhz-_fuOPNulwY-J0x63CaPyIle_wRVTOTfjEBnWjrFOtM3ihYht8sbT-ynR583LqYthOMXiTnqMnvXLJvDjUOfr26XS9OCuWF5_PF8fLQjFCx4J0oKpGl0A5r3vgmvZGaA1l17QK-qqtDGs4y13Dy6YTfUXLPrvjDJrOtFU5R2_2utsYrncmjXLIDoxzypuwS5I0gguRt-bo7R7UMaQUTS-30Q4qTpKAvIta3ked2VcH0V07mO6BPGSbgdcHQCWtXB-V1zY9cA2QugaeuWLP2fyH2_u5ileSi1JUcr36Ktc_Tr5_qQST_-gqneQm7KLP2f3nwL-2wqL9</recordid><startdate>20070823</startdate><enddate>20070823</enddate><creator>Li, Hui</creator><creator>Linton, Angelica</creator><creator>Tatlock, John</creator><creator>Gonzalez, Javier</creator><creator>Borchardt, Allen</creator><creator>Abreo, Mel</creator><creator>Jewell, Tanya</creator><creator>Patel, Leena</creator><creator>Drowns, Matthew</creator><creator>Ludlum, Sarah</creator><creator>Goble, Mike</creator><creator>Yang, Michele</creator><creator>Blazel, Julie</creator><creator>Rahavendran, Ravi</creator><creator>Skor, Heather</creator><creator>Shi, Stephanie</creator><creator>Lewis, Cristina</creator><creator>Fuhrman, Shella</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><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>7QO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope></search><sort><creationdate>20070823</creationdate><title>Allosteric Inhibitors of Hepatitis C Polymerase: Discovery of Potent and Orally Bioavailable Carbon-Linked Dihydropyrones</title><author>Li, Hui ; Linton, Angelica ; Tatlock, John ; Gonzalez, Javier ; Borchardt, Allen ; Abreo, Mel ; Jewell, Tanya ; Patel, Leena ; Drowns, Matthew ; Ludlum, Sarah ; Goble, Mike ; Yang, Michele ; Blazel, Julie ; Rahavendran, Ravi ; Skor, Heather ; Shi, Stephanie ; Lewis, Cristina ; Fuhrman, Shella</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a412t-1d0a59c302668f06c2fe7cc03d9ba0f5b5e49642fee639d7f523f7786409deb53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Administration, Oral</topic><topic>Allosteric Regulation</topic><topic>Animals</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Antiviral Agents - chemical synthesis</topic><topic>Antiviral Agents - chemistry</topic><topic>Antiviral Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Biological Availability</topic><topic>Caco-2 Cells</topic><topic>Cell Line, Tumor</topic><topic>Half-Life</topic><topic>Hepacivirus - enzymology</topic><topic>Hepatitis C virus</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Permeability</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyrones - chemical synthesis</topic><topic>Pyrones - chemistry</topic><topic>Pyrones - pharmacology</topic><topic>Rats</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Viral Nonstructural Proteins - antagonists & inhibitors</topic><topic>Viral Nonstructural Proteins - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Hui</creatorcontrib><creatorcontrib>Linton, Angelica</creatorcontrib><creatorcontrib>Tatlock, John</creatorcontrib><creatorcontrib>Gonzalez, Javier</creatorcontrib><creatorcontrib>Borchardt, Allen</creatorcontrib><creatorcontrib>Abreo, Mel</creatorcontrib><creatorcontrib>Jewell, Tanya</creatorcontrib><creatorcontrib>Patel, Leena</creatorcontrib><creatorcontrib>Drowns, Matthew</creatorcontrib><creatorcontrib>Ludlum, Sarah</creatorcontrib><creatorcontrib>Goble, Mike</creatorcontrib><creatorcontrib>Yang, Michele</creatorcontrib><creatorcontrib>Blazel, Julie</creatorcontrib><creatorcontrib>Rahavendran, Ravi</creatorcontrib><creatorcontrib>Skor, Heather</creatorcontrib><creatorcontrib>Shi, Stephanie</creatorcontrib><creatorcontrib>Lewis, Cristina</creatorcontrib><creatorcontrib>Fuhrman, Shella</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Hui</au><au>Linton, Angelica</au><au>Tatlock, John</au><au>Gonzalez, Javier</au><au>Borchardt, Allen</au><au>Abreo, Mel</au><au>Jewell, Tanya</au><au>Patel, Leena</au><au>Drowns, Matthew</au><au>Ludlum, Sarah</au><au>Goble, Mike</au><au>Yang, Michele</au><au>Blazel, Julie</au><au>Rahavendran, Ravi</au><au>Skor, Heather</au><au>Shi, Stephanie</au><au>Lewis, Cristina</au><au>Fuhrman, Shella</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Allosteric Inhibitors of Hepatitis C Polymerase: Discovery of Potent and Orally Bioavailable Carbon-Linked Dihydropyrones</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2007-08-23</date><risdate>2007</risdate><volume>50</volume><issue>17</issue><spage>3969</spage><epage>3972</epage><pages>3969-3972</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>The discovery and optimization of a novel class of carbon-linked dihydropyrones as allosteric HCV NS5B polymerase inhibitors are presented. Replacement of the sulfur linker atom with carbon reduced compound acidity and greatly increased cell permeation. Further structure−activity relationship (SAR) studies led to the identification of compounds, exemplified by 23 and 24, with significantly improved antiviral activities in the cell-based replicon assay and favorable pharmacokinetic profiles.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>17658778</pmid><doi>10.1021/jm0704447</doi><tpages>4</tpages></addata></record> |
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| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2007-08, Vol.50 (17), p.3969-3972 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Administration, Oral Allosteric Regulation Animals Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - chemical synthesis Antiviral Agents - chemistry Antiviral Agents - pharmacology Biological and medical sciences Biological Availability Caco-2 Cells Cell Line, Tumor Half-Life Hepacivirus - enzymology Hepatitis C virus Humans Medical sciences Permeability Pharmacology. Drug treatments Pyrones - chemical synthesis Pyrones - chemistry Pyrones - pharmacology Rats Stereoisomerism Structure-Activity Relationship Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - genetics |
| title | Allosteric Inhibitors of Hepatitis C Polymerase: Discovery of Potent and Orally Bioavailable Carbon-Linked Dihydropyrones |
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