3-Heterocyclyl quinolone inhibitors of the HCV NS5B polymerase
Graphical abstract The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2012-01, Vol.22 (1), p.300-304 |
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| creator | Kumar, Dange V. Rai, Roopa Brameld, Ken A. Riggs, Jennifer Somoza, John R. Rajagopalan, Ravi Janc, James W. Xia, Yu M. Ton, Tony L. Hu, Huiyong Lehoux, Isabelle Ho, Joseph D. Young, Wendy B. Hart, Barry Green, Michael J. |
| description | Graphical abstract
The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key analog bound to NS5B facilitated the optimization of this series of compounds to afford an increase in activity against the target enzyme and improved potency in the replicon assay.
The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key analog bound to NS5B facilitated the optimization of this series of compounds to afford increased activity against the target enzyme and in the cell-based replicon assay system. |
| doi_str_mv | 10.1016/j.bmcl.2011.11.013 |
| format | Article |
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The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key analog bound to NS5B facilitated the optimization of this series of compounds to afford an increase in activity against the target enzyme and improved potency in the replicon assay.
The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key analog bound to NS5B facilitated the optimization of this series of compounds to afford increased activity against the target enzyme and in the cell-based replicon assay system.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2011.11.013</identifier><identifier>PMID: 22119470</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>3-Heterocyclyl quinolone analogs ; Allosteric Site ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Antiviral Agents - chemical synthesis ; Antiviral Agents - pharmacology ; Binding Sites ; Biological and medical sciences ; Chemistry, Pharmaceutical - methods ; Crystallography, X-Ray - methods ; Drug Design ; HCV ; Hepacivirus - enzymology ; Hepatitis C virus ; Hydrogen Bonding ; Hydrolysis ; Inhibitory Concentration 50 ; Medical sciences ; Models, Chemical ; Molecular Conformation ; NNI-2 binders ; NS5B polymerase inhibitors ; Pharmacology. Drug treatments ; Quinolones - chemical synthesis ; Quinolones - pharmacology ; Structure-Activity Relationship ; Viral Nonstructural Proteins - antagonists & inhibitors ; Viral Nonstructural Proteins - chemistry ; X-Rays</subject><ispartof>Bioorganic & medicinal chemistry letters, 2012-01, Vol.22 (1), p.300-304</ispartof><rights>2011 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c417t-cd6dbad3387e2200e54bd4e9cfbb80b74066b937afa1f25ff90c4d4da96ab0c23</citedby><cites>FETCH-LOGICAL-c417t-cd6dbad3387e2200e54bd4e9cfbb80b74066b937afa1f25ff90c4d4da96ab0c23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2011.11.013$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3549,4023,27922,27923,27924,45994</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25413317$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22119470$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kumar, Dange V.</creatorcontrib><creatorcontrib>Rai, Roopa</creatorcontrib><creatorcontrib>Brameld, Ken A.</creatorcontrib><creatorcontrib>Riggs, Jennifer</creatorcontrib><creatorcontrib>Somoza, John R.</creatorcontrib><creatorcontrib>Rajagopalan, Ravi</creatorcontrib><creatorcontrib>Janc, James W.</creatorcontrib><creatorcontrib>Xia, Yu M.</creatorcontrib><creatorcontrib>Ton, Tony L.</creatorcontrib><creatorcontrib>Hu, Huiyong</creatorcontrib><creatorcontrib>Lehoux, Isabelle</creatorcontrib><creatorcontrib>Ho, Joseph D.</creatorcontrib><creatorcontrib>Young, Wendy B.</creatorcontrib><creatorcontrib>Hart, Barry</creatorcontrib><creatorcontrib>Green, Michael J.</creatorcontrib><title>3-Heterocyclyl quinolone inhibitors of the HCV NS5B polymerase</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Graphical abstract
The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key analog bound to NS5B facilitated the optimization of this series of compounds to afford an increase in activity against the target enzyme and improved potency in the replicon assay.
The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key analog bound to NS5B facilitated the optimization of this series of compounds to afford increased activity against the target enzyme and in the cell-based replicon assay system.</description><subject>3-Heterocyclyl quinolone analogs</subject><subject>Allosteric Site</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - chemical synthesis</subject><subject>Antiviral Agents - pharmacology</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Chemistry, Pharmaceutical - methods</subject><subject>Crystallography, X-Ray - methods</subject><subject>Drug Design</subject><subject>HCV</subject><subject>Hepacivirus - enzymology</subject><subject>Hepatitis C virus</subject><subject>Hydrogen Bonding</subject><subject>Hydrolysis</subject><subject>Inhibitory Concentration 50</subject><subject>Medical sciences</subject><subject>Models, Chemical</subject><subject>Molecular Conformation</subject><subject>NNI-2 binders</subject><subject>NS5B polymerase inhibitors</subject><subject>Pharmacology. Drug treatments</subject><subject>Quinolones - chemical synthesis</subject><subject>Quinolones - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Viral Nonstructural Proteins - antagonists & inhibitors</subject><subject>Viral Nonstructural Proteins - chemistry</subject><subject>X-Rays</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtrGzEUhUVIiJ00fyCLMJvQ1ThXM5oZC0ohNWkcCO2iD7oTelwRGc3IlsYF__vK2E12gQN3853D5SPkmsKMAm3vVjPVaz-rgNJZDtD6hEwpa1lZM2hOyRR4C-Wcsz8TcpHSCoAyYOycTKqKUs46mJLPdbnEEWPQO-13vths3RB8GLBww4tTbgwxFcEW4wsWy8Xv4tuP5kuxDn7XY5QJP5AzK33Cq-O9JL--PvxcLMvn749Pi_vnUjPajaU2rVHS1PW8w6oCwIYpw5Brq9QcVMegbRWvO2kltVVjLQfNDDOSt1KBrupL8vGwu45hs8U0it4ljd7LAcM2CU7n0LCOQyarA6ljSCmiFevoehl3goLYaxMrsdcm9tpETtaWSzfH-a3q0bxW_nvKwO0RkElLb6MctEtvXMPyCu0y9-nAYZbx12EUSTscNBoXUY_CBPfeH_8AGO6Knw</recordid><startdate>20120101</startdate><enddate>20120101</enddate><creator>Kumar, Dange V.</creator><creator>Rai, Roopa</creator><creator>Brameld, Ken A.</creator><creator>Riggs, Jennifer</creator><creator>Somoza, John R.</creator><creator>Rajagopalan, Ravi</creator><creator>Janc, James W.</creator><creator>Xia, Yu M.</creator><creator>Ton, Tony L.</creator><creator>Hu, Huiyong</creator><creator>Lehoux, Isabelle</creator><creator>Ho, Joseph D.</creator><creator>Young, Wendy B.</creator><creator>Hart, Barry</creator><creator>Green, Michael J.</creator><general>Elsevier Ltd</general><general>Elsevier</general><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>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20120101</creationdate><title>3-Heterocyclyl quinolone inhibitors of the HCV NS5B polymerase</title><author>Kumar, Dange V. ; Rai, Roopa ; Brameld, Ken A. ; Riggs, Jennifer ; Somoza, John R. ; Rajagopalan, Ravi ; Janc, James W. ; Xia, Yu M. ; Ton, Tony L. ; Hu, Huiyong ; Lehoux, Isabelle ; Ho, Joseph D. ; Young, Wendy B. ; Hart, Barry ; Green, Michael J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c417t-cd6dbad3387e2200e54bd4e9cfbb80b74066b937afa1f25ff90c4d4da96ab0c23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>3-Heterocyclyl quinolone analogs</topic><topic>Allosteric Site</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Antiviral Agents - chemical synthesis</topic><topic>Antiviral Agents - pharmacology</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Chemistry, Pharmaceutical - methods</topic><topic>Crystallography, X-Ray - methods</topic><topic>Drug Design</topic><topic>HCV</topic><topic>Hepacivirus - enzymology</topic><topic>Hepatitis C virus</topic><topic>Hydrogen Bonding</topic><topic>Hydrolysis</topic><topic>Inhibitory Concentration 50</topic><topic>Medical sciences</topic><topic>Models, Chemical</topic><topic>Molecular Conformation</topic><topic>NNI-2 binders</topic><topic>NS5B polymerase inhibitors</topic><topic>Pharmacology. Drug treatments</topic><topic>Quinolones - chemical synthesis</topic><topic>Quinolones - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Viral Nonstructural Proteins - antagonists & inhibitors</topic><topic>Viral Nonstructural Proteins - chemistry</topic><topic>X-Rays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kumar, Dange V.</creatorcontrib><creatorcontrib>Rai, Roopa</creatorcontrib><creatorcontrib>Brameld, Ken A.</creatorcontrib><creatorcontrib>Riggs, Jennifer</creatorcontrib><creatorcontrib>Somoza, John R.</creatorcontrib><creatorcontrib>Rajagopalan, Ravi</creatorcontrib><creatorcontrib>Janc, James W.</creatorcontrib><creatorcontrib>Xia, Yu M.</creatorcontrib><creatorcontrib>Ton, Tony L.</creatorcontrib><creatorcontrib>Hu, Huiyong</creatorcontrib><creatorcontrib>Lehoux, Isabelle</creatorcontrib><creatorcontrib>Ho, Joseph D.</creatorcontrib><creatorcontrib>Young, Wendy B.</creatorcontrib><creatorcontrib>Hart, Barry</creatorcontrib><creatorcontrib>Green, Michael J.</creatorcontrib><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>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kumar, Dange V.</au><au>Rai, Roopa</au><au>Brameld, Ken A.</au><au>Riggs, Jennifer</au><au>Somoza, John R.</au><au>Rajagopalan, Ravi</au><au>Janc, James W.</au><au>Xia, Yu M.</au><au>Ton, Tony L.</au><au>Hu, Huiyong</au><au>Lehoux, Isabelle</au><au>Ho, Joseph D.</au><au>Young, Wendy B.</au><au>Hart, Barry</au><au>Green, Michael J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>3-Heterocyclyl quinolone inhibitors of the HCV NS5B polymerase</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2012-01-01</date><risdate>2012</risdate><volume>22</volume><issue>1</issue><spage>300</spage><epage>304</epage><pages>300-304</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Graphical abstract
The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key analog bound to NS5B facilitated the optimization of this series of compounds to afford an increase in activity against the target enzyme and improved potency in the replicon assay.
The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key analog bound to NS5B facilitated the optimization of this series of compounds to afford increased activity against the target enzyme and in the cell-based replicon assay system.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>22119470</pmid><doi>10.1016/j.bmcl.2011.11.013</doi><tpages>5</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2012-01, Vol.22 (1), p.300-304 |
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| subjects | 3-Heterocyclyl quinolone analogs Allosteric Site Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - chemical synthesis Antiviral Agents - pharmacology Binding Sites Biological and medical sciences Chemistry, Pharmaceutical - methods Crystallography, X-Ray - methods Drug Design HCV Hepacivirus - enzymology Hepatitis C virus Hydrogen Bonding Hydrolysis Inhibitory Concentration 50 Medical sciences Models, Chemical Molecular Conformation NNI-2 binders NS5B polymerase inhibitors Pharmacology. Drug treatments Quinolones - chemical synthesis Quinolones - pharmacology Structure-Activity Relationship Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - chemistry X-Rays |
| title | 3-Heterocyclyl quinolone inhibitors of the HCV NS5B polymerase |
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