Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors
Identifieur interne : 000466 ( PascalFrancis/Checkpoint ); précédent : 000465; suivant : 000467Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors
Auteurs : HUI LI [États-Unis] ; John Tatlock [États-Unis] ; Angelica Linton [États-Unis] ; Javier Gonzalez [États-Unis] ; Allen Borchardt [États-Unis] ; Peter Dragovich [États-Unis] ; Tanya Jewell [États-Unis] ; Tom Prins [États-Unis] ; RU ZHOU [États-Unis] ; Julie Blazel [États-Unis] ; Hans Parge [États-Unis] ; Robert Love [États-Unis] ; Michael Hickey [États-Unis] ; Chau Doan [États-Unis] ; Stephanie Shi [États-Unis] ; Rohit Duggal [États-Unis] ; Cristina Lewis [États-Unis] ; Shella Fuhrman [États-Unis]Source :
- Bioorganic & medicinal chemistry letters : (Print) [ 0960-894X ] ; 2006.
Descripteurs français
- Pascal (Inist)
- Optimisation, Virus hépatite C, DNA-directed RNA polymerase, Inhibiteur enzyme, Composé non nucléoside, Criblage, Structure cristalline, Site fixation, Changement conformation, Relation structure activité, Pyranone dérivé, Cyclopentane dérivé, Lactone, Antiviral, Composé benzénique, Halogène Composé organique, RNA-directed RNA polymerase, Pyrane dérivé, NS5B polymerase, Pyran-2-one(3-[4-amino-2-(t-butyl)-5-méthylphénylsulfanyl]-6-cyclopentyl-5,6-dihydro-4-hydroxy-6-[4-hydroxyphénéthyl]), Pyrane-2,4-dione dérivé, Protéine NS5B.
English descriptors
- KwdEn :
- Antiviral, Benzenic compound, Binding site, Conformational changes, Crystalline structure, Cyclopentane derivatives, DNA-directed RNA polymerase, Enzyme inhibitor, Halogen Organic compounds, Hepatitis C virus, Lactone, Non nucleoside compound, Optimization, Pyran derivatives, Pyranone derivatives, RNA-directed RNA polymerase, Screening, Structure activity relation.
Abstract
A novel class of non-nucleoside HCV NS5B polymerase inhibitors has been identified from screening. A co-crystal structure revealed an allosteric binding site in the protein that required a unique conformational change to accommodate inhibitor binding. Herein we report the structure-activity relationships (SARs) of this novel class of dihydropyrone-containing compounds that show potent inhibitory activities against the HCV RNA polymerase in biochemical assays.
Affiliations:
Links toward previous steps (curation, corpus...)
Links to Exploration step
Pascal:07-0028982Le document en format XML
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Jolla Laboratories, 10770 Science Center Dr</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Duggal, Rohit" sort="Duggal, Rohit" uniqKey="Duggal R" first="Rohit" last="Duggal">Rohit Duggal</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>16 aut.</sZ><sZ>18 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Inc., 1 DNA Way</s1><s2>South San Francisco, CA 94098</s2><s3>USA</s3><sZ>17 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Fuhrman, Shella" sort="Fuhrman, Shella" uniqKey="Fuhrman S" first="Shella" last="Fuhrman">Shella Fuhrman</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">07-0028982</idno><date when="2006">2006</date><idno type="stanalyst">PASCAL 07-0028982 INIST</idno><idno type="RBID">Pascal:07-0028982</idno><idno type="wicri:Area/PascalFrancis/Corpus">000426</idno><idno type="wicri:Area/PascalFrancis/Curation">000563</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000466</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000466</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors</title><author><name sortKey="Hui Li" sort="Hui Li" uniqKey="Hui Li" last="Hui Li">HUI LI</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Tatlock, John" sort="Tatlock, John" uniqKey="Tatlock J" first="John" last="Tatlock">John Tatlock</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Linton, Angelica" sort="Linton, Angelica" uniqKey="Linton A" first="Angelica" last="Linton">Angelica Linton</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Gonzalez, Javier" sort="Gonzalez, Javier" uniqKey="Gonzalez J" first="Javier" last="Gonzalez">Javier Gonzalez</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Borchardt, Allen" sort="Borchardt, Allen" uniqKey="Borchardt A" first="Allen" last="Borchardt">Allen Borchardt</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Dragovich, Peter" sort="Dragovich, Peter" uniqKey="Dragovich P" first="Peter" last="Dragovich">Peter Dragovich</name><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Anadys Pharmaceuticals, 3115 Merryfield Row</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Jewell, Tanya" sort="Jewell, Tanya" uniqKey="Jewell T" first="Tanya" last="Jewell">Tanya Jewell</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Prins, Tom" sort="Prins, Tom" uniqKey="Prins T" first="Tom" last="Prins">Tom Prins</name><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Anadys Pharmaceuticals, 3115 Merryfield Row</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Ru Zhou" sort="Ru Zhou" uniqKey="Ru Zhou" last="Ru Zhou">RU ZHOU</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Blazel, Julie" sort="Blazel, Julie" uniqKey="Blazel J" first="Julie" last="Blazel">Julie Blazel</name><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Anadys Pharmaceuticals, 3115 Merryfield Row</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Parge, Hans" sort="Parge, Hans" uniqKey="Parge H" first="Hans" last="Parge">Hans Parge</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Love, Robert" sort="Love, Robert" uniqKey="Love R" first="Robert" last="Love">Robert Love</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Hickey, Michael" sort="Hickey, Michael" uniqKey="Hickey M" first="Michael" last="Hickey">Michael Hickey</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Doan, Chau" sort="Doan, Chau" uniqKey="Doan C" first="Chau" last="Doan">Chau Doan</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Shi, Stephanie" sort="Shi, Stephanie" uniqKey="Shi S" first="Stephanie" last="Shi">Stephanie Shi</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Duggal, Rohit" sort="Duggal, Rohit" uniqKey="Duggal R" first="Rohit" last="Duggal">Rohit Duggal</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Lewis, Cristina" sort="Lewis, Cristina" uniqKey="Lewis C" first="Cristina" last="Lewis">Cristina Lewis</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Genentecb. Inc., 1 DNA Way</s1><s2>South San Francisco, CA 94098</s2><s3>USA</s3><sZ>17 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Fuhrman, Shella" sort="Fuhrman, Shella" uniqKey="Fuhrman S" first="Shella" last="Fuhrman">Shella Fuhrman</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author></analytic><series><title level="j" type="main">Bioorganic & medicinal chemistry letters : (Print)</title><title level="j" type="abbreviated">Bioorg. med. chem. lett. : (Print)</title><idno type="ISSN">0960-894X</idno><imprint><date when="2006">2006</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Bioorganic & medicinal chemistry letters : (Print)</title><title level="j" type="abbreviated">Bioorg. med. chem. lett. : (Print)</title><idno type="ISSN">0960-894X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral</term><term>Benzenic compound</term><term>Binding site</term><term>Conformational changes</term><term>Crystalline structure</term><term>Cyclopentane derivatives</term><term>DNA-directed RNA polymerase</term><term>Enzyme inhibitor</term><term>Halogen Organic compounds</term><term>Hepatitis C virus</term><term>Lactone</term><term>Non nucleoside compound</term><term>Optimization</term><term>Pyran derivatives</term><term>Pyranone derivatives</term><term>RNA-directed RNA polymerase</term><term>Screening</term><term>Structure activity relation</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Optimisation</term><term>Virus hépatite C</term><term>DNA-directed RNA polymerase</term><term>Inhibiteur enzyme</term><term>Composé non nucléoside</term><term>Criblage</term><term>Structure cristalline</term><term>Site fixation</term><term>Changement conformation</term><term>Relation structure activité</term><term>Pyranone dérivé</term><term>Cyclopentane dérivé</term><term>Lactone</term><term>Antiviral</term><term>Composé benzénique</term><term>Halogène Composé organique</term><term>RNA-directed RNA polymerase</term><term>Pyrane dérivé</term><term>NS5B polymerase</term><term>Pyran-2-one(3-[4-amino-2-(t-butyl)-5-méthylphénylsulfanyl]-6-cyclopentyl-5,6-dihydro-4-hydroxy-6-[4-hydroxyphénéthyl])</term><term>Pyrane-2,4-dione dérivé</term><term>Protéine NS5B</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">A novel class of non-nucleoside HCV NS5B polymerase inhibitors has been identified from screening. A co-crystal structure revealed an allosteric binding site in the protein that required a unique conformational change to accommodate inhibitor binding. Herein we report the structure-activity relationships (SARs) of this novel class of dihydropyrone-containing compounds that show potent inhibitory activities against the HCV RNA polymerase in biochemical assays.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0960-894X</s0></fA01><fA03 i2="1"><s0>Bioorg. med. chem. lett. : (Print)</s0></fA03><fA05><s2>16</s2></fA05><fA06><s2>18</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors</s1></fA08><fA11 i1="01" i2="1"><s1>HUI LI</s1></fA11><fA11 i1="02" i2="1"><s1>TATLOCK (John)</s1></fA11><fA11 i1="03" i2="1"><s1>LINTON (Angelica)</s1></fA11><fA11 i1="04" i2="1"><s1>GONZALEZ (Javier)</s1></fA11><fA11 i1="05" i2="1"><s1>BORCHARDT (Allen)</s1></fA11><fA11 i1="06" i2="1"><s1>DRAGOVICH (Peter)</s1></fA11><fA11 i1="07" i2="1"><s1>JEWELL (Tanya)</s1></fA11><fA11 i1="08" i2="1"><s1>PRINS (Tom)</s1></fA11><fA11 i1="09" i2="1"><s1>RU ZHOU</s1></fA11><fA11 i1="10" i2="1"><s1>BLAZEL (Julie)</s1></fA11><fA11 i1="11" i2="1"><s1>PARGE (Hans)</s1></fA11><fA11 i1="12" i2="1"><s1>LOVE (Robert)</s1></fA11><fA11 i1="13" i2="1"><s1>HICKEY (Michael)</s1></fA11><fA11 i1="14" i2="1"><s1>DOAN (Chau)</s1></fA11><fA11 i1="15" i2="1"><s1>SHI (Stephanie)</s1></fA11><fA11 i1="16" i2="1"><s1>DUGGAL (Rohit)</s1></fA11><fA11 i1="17" i2="1"><s1>LEWIS (Cristina)</s1></fA11><fA11 i1="18" i2="1"><s1>FUHRMAN (Shella)</s1></fA11><fA14 i1="01"><s1>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ><sZ>11 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>14 aut.</sZ><sZ>15 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ></fA14><fA14 i1="02"><s1>Anadys Pharmaceuticals, 3115 Merryfield Row</s1><s2>San Diego, CA 92121</s2><s3>USA</s3><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>10 aut.</sZ></fA14><fA14 i1="03"><s1>Genentecb. Inc., 1 DNA Way</s1><s2>South San Francisco, CA 94098</s2><s3>USA</s3><sZ>17 aut.</sZ></fA14><fA20><s1>4834-4838</s1></fA20><fA21><s1>2006</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>22446</s2><s5>354000133548250280</s5></fA43><fA44><s0>0000</s0><s1>© 2007 INIST-CNRS. All rights reserved.</s1></fA44><fA47 i1="01" i2="1"><s0>07-0028982</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>Bioorganic & medicinal chemistry letters : (Print)</s0></fA64><fA66 i1="01"><s0>GBR</s0></fA66><fA99><s0>3/4 p. ref. et notes</s0></fA99><fC01 i1="01" l="ENG"><s0>A novel class of non-nucleoside HCV NS5B polymerase inhibitors has been identified from screening. A co-crystal structure revealed an allosteric binding site in the protein that required a unique conformational change to accommodate inhibitor binding. Herein we report the structure-activity relationships (SARs) of this novel class of dihydropyrone-containing compounds that show potent inhibitory activities against the HCV RNA polymerase in biochemical assays.</s0></fC01><fC02 i1="01" i2="X"><s0>002B02S05</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Optimisation</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Optimization</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Optimización</s0><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Virus hépatite C</s0><s2>NW</s2><s5>02</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Hepatitis C virus</s0><s2>NW</s2><s5>02</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Hepatitis C virus</s0><s2>NW</s2><s5>02</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>DNA-directed RNA polymerase</s0><s2>FE</s2><s5>03</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>DNA-directed RNA polymerase</s0><s2>FE</s2><s5>03</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>DNA-directed RNA polymerase</s0><s2>FE</s2><s5>03</s5></fC03><fC03 i1="04" i2="X" l="FRE"><s0>Inhibiteur enzyme</s0><s5>04</s5></fC03><fC03 i1="04" i2="X" l="ENG"><s0>Enzyme inhibitor</s0><s5>04</s5></fC03><fC03 i1="04" i2="X" l="SPA"><s0>Inhibidor enzima</s0><s5>04</s5></fC03><fC03 i1="05" i2="X" l="FRE"><s0>Composé non nucléoside</s0><s5>05</s5></fC03><fC03 i1="05" i2="X" l="ENG"><s0>Non nucleoside compound</s0><s5>05</s5></fC03><fC03 i1="05" i2="X" l="SPA"><s0>Compuesto no nucleósido</s0><s5>05</s5></fC03><fC03 i1="06" i2="X" l="FRE"><s0>Criblage</s0><s5>06</s5></fC03><fC03 i1="06" i2="X" l="ENG"><s0>Screening</s0><s5>06</s5></fC03><fC03 i1="06" i2="X" l="SPA"><s0>Cernido</s0><s5>06</s5></fC03><fC03 i1="07" i2="X" l="FRE"><s0>Structure cristalline</s0><s5>07</s5></fC03><fC03 i1="07" i2="X" l="ENG"><s0>Crystalline structure</s0><s5>07</s5></fC03><fC03 i1="07" i2="X" l="SPA"><s0>Estructura cristalina</s0><s5>07</s5></fC03><fC03 i1="08" i2="X" l="FRE"><s0>Site fixation</s0><s5>08</s5></fC03><fC03 i1="08" i2="X" l="ENG"><s0>Binding site</s0><s5>08</s5></fC03><fC03 i1="08" i2="X" l="SPA"><s0>Sitio fijación</s0><s5>08</s5></fC03><fC03 i1="09" i2="3" l="FRE"><s0>Changement conformation</s0><s5>09</s5></fC03><fC03 i1="09" i2="3" l="ENG"><s0>Conformational changes</s0><s5>09</s5></fC03><fC03 i1="10" i2="X" l="FRE"><s0>Relation structure activité</s0><s5>10</s5></fC03><fC03 i1="10" i2="X" l="ENG"><s0>Structure activity relation</s0><s5>10</s5></fC03><fC03 i1="10" i2="X" l="SPA"><s0>Relación estructura actividad</s0><s5>10</s5></fC03><fC03 i1="11" i2="X" l="FRE"><s0>Pyranone dérivé</s0><s2>FR</s2><s5>11</s5></fC03><fC03 i1="11" i2="X" l="ENG"><s0>Pyranone derivatives</s0><s2>FR</s2><s5>11</s5></fC03><fC03 i1="12" i2="X" l="FRE"><s0>Cyclopentane dérivé</s0><s5>12</s5></fC03><fC03 i1="12" i2="X" l="ENG"><s0>Cyclopentane derivatives</s0><s5>12</s5></fC03><fC03 i1="12" i2="X" l="SPA"><s0>Ciclopentano derivado</s0><s5>12</s5></fC03><fC03 i1="13" i2="X" l="FRE"><s0>Lactone</s0><s5>13</s5></fC03><fC03 i1="13" i2="X" l="ENG"><s0>Lactone</s0><s5>13</s5></fC03><fC03 i1="13" i2="X" l="SPA"><s0>Lactona</s0><s5>13</s5></fC03><fC03 i1="14" i2="X" l="FRE"><s0>Antiviral</s0><s5>14</s5></fC03><fC03 i1="14" i2="X" l="ENG"><s0>Antiviral</s0><s5>14</s5></fC03><fC03 i1="14" i2="X" l="SPA"><s0>Antiviral</s0><s5>14</s5></fC03><fC03 i1="15" i2="X" l="FRE"><s0>Composé benzénique</s0><s5>15</s5></fC03><fC03 i1="15" i2="X" l="ENG"><s0>Benzenic compound</s0><s5>15</s5></fC03><fC03 i1="15" i2="X" l="SPA"><s0>Compuesto bencénico</s0><s5>15</s5></fC03><fC03 i1="16" i2="X" l="FRE"><s0>Halogène Composé organique</s0><s2>NC</s2><s2>NA</s2><s5>16</s5></fC03><fC03 i1="16" i2="X" l="ENG"><s0>Halogen Organic compounds</s0><s2>NC</s2><s2>NA</s2><s5>16</s5></fC03><fC03 i1="16" i2="X" l="SPA"><s0>Halógeno Compuesto orgánico</s0><s2>NC</s2><s2>NA</s2><s5>16</s5></fC03><fC03 i1="17" i2="X" l="FRE"><s0>RNA-directed RNA polymerase</s0><s2>FE</s2><s5>32</s5></fC03><fC03 i1="17" i2="X" l="ENG"><s0>RNA-directed RNA polymerase</s0><s2>FE</s2><s5>32</s5></fC03><fC03 i1="17" i2="X" l="SPA"><s0>RNA-directed RNA polymerase</s0><s2>FE</s2><s5>32</s5></fC03><fC03 i1="18" i2="X" l="FRE"><s0>Pyrane dérivé</s0><s5>33</s5></fC03><fC03 i1="18" i2="X" l="ENG"><s0>Pyran derivatives</s0><s5>33</s5></fC03><fC03 i1="18" i2="X" l="SPA"><s0>Pirano derivado</s0><s5>33</s5></fC03><fC03 i1="19" i2="X" l="FRE"><s0>NS5B polymerase</s0><s4>INC</s4><s5>76</s5></fC03><fC03 i1="20" i2="X" l="FRE"><s0>Pyran-2-one(3-[4-amino-2-(t-butyl)-5-méthylphénylsulfanyl]-6-cyclopentyl-5,6-dihydro-4-hydroxy-6-[4-hydroxyphénéthyl])</s0><s2>NK</s2><s4>INC</s4><s5>77</s5></fC03><fC03 i1="21" i2="X" l="FRE"><s0>Pyrane-2,4-dione dérivé</s0><s2>NK</s2><s4>INC</s4><s5>78</s5></fC03><fC03 i1="22" i2="X" l="FRE"><s0>Protéine NS5B</s0><s4>INC</s4><s5>91</s5></fC03><fC07 i1="01" i2="X" l="FRE"><s0>Hepacivirus</s0><s2>NW</s2></fC07><fC07 i1="01" i2="X" l="ENG"><s0>Hepacivirus</s0><s2>NW</s2></fC07><fC07 i1="01" i2="X" l="SPA"><s0>Hepacivirus</s0><s2>NW</s2></fC07><fC07 i1="02" i2="X" l="FRE"><s0>Flaviviridae</s0><s2>NW</s2></fC07><fC07 i1="02" i2="X" l="ENG"><s0>Flaviviridae</s0><s2>NW</s2></fC07><fC07 i1="02" i2="X" l="SPA"><s0>Flaviviridae</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="FRE"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="ENG"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="SPA"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="04" i2="X" l="FRE"><s0>Nucleotidyltransferases</s0><s2>FE</s2></fC07><fC07 i1="04" i2="X" l="ENG"><s0>Nucleotidyltransferases</s0><s2>FE</s2></fC07><fC07 i1="04" i2="X" l="SPA"><s0>Nucleotidyltransferases</s0><s2>FE</s2></fC07><fC07 i1="05" i2="X" l="FRE"><s0>Transferases</s0><s2>FE</s2></fC07><fC07 i1="05" i2="X" l="ENG"><s0>Transferases</s0><s2>FE</s2></fC07><fC07 i1="05" i2="X" l="SPA"><s0>Transferases</s0><s2>FE</s2></fC07><fC07 i1="06" i2="X" l="FRE"><s0>Enzyme</s0><s2>FE</s2></fC07><fC07 i1="06" i2="X" l="ENG"><s0>Enzyme</s0><s2>FE</s2></fC07><fC07 i1="06" i2="X" l="SPA"><s0>Enzima</s0><s2>FE</s2></fC07><fN21><s1>015</s1></fN21></pA></standard></inist><affiliations><list><country><li>États-Unis</li></country><region><li>Californie</li></region></list><tree><country name="États-Unis"><region name="Californie"><name sortKey="Hui Li" sort="Hui Li" uniqKey="Hui Li" last="Hui Li">HUI LI</name></region><name sortKey="Blazel, Julie" sort="Blazel, Julie" uniqKey="Blazel J" first="Julie" last="Blazel">Julie Blazel</name><name sortKey="Borchardt, Allen" sort="Borchardt, Allen" uniqKey="Borchardt A" first="Allen" last="Borchardt">Allen Borchardt</name><name sortKey="Doan, Chau" sort="Doan, Chau" uniqKey="Doan C" first="Chau" last="Doan">Chau Doan</name><name sortKey="Dragovich, Peter" sort="Dragovich, Peter" uniqKey="Dragovich P" first="Peter" last="Dragovich">Peter Dragovich</name><name sortKey="Duggal, Rohit" sort="Duggal, Rohit" uniqKey="Duggal R" first="Rohit" last="Duggal">Rohit Duggal</name><name sortKey="Fuhrman, Shella" sort="Fuhrman, Shella" uniqKey="Fuhrman S" first="Shella" last="Fuhrman">Shella Fuhrman</name><name sortKey="Gonzalez, Javier" sort="Gonzalez, Javier" uniqKey="Gonzalez J" first="Javier" last="Gonzalez">Javier Gonzalez</name><name sortKey="Hickey, Michael" sort="Hickey, Michael" uniqKey="Hickey M" first="Michael" last="Hickey">Michael Hickey</name><name sortKey="Jewell, Tanya" sort="Jewell, Tanya" uniqKey="Jewell T" first="Tanya" last="Jewell">Tanya Jewell</name><name sortKey="Lewis, Cristina" sort="Lewis, Cristina" uniqKey="Lewis C" first="Cristina" last="Lewis">Cristina Lewis</name><name sortKey="Linton, Angelica" sort="Linton, Angelica" uniqKey="Linton A" first="Angelica" last="Linton">Angelica Linton</name><name sortKey="Love, Robert" sort="Love, Robert" uniqKey="Love R" first="Robert" last="Love">Robert Love</name><name sortKey="Parge, Hans" sort="Parge, Hans" uniqKey="Parge H" first="Hans" last="Parge">Hans Parge</name><name sortKey="Prins, Tom" sort="Prins, Tom" uniqKey="Prins T" first="Tom" last="Prins">Tom Prins</name><name sortKey="Ru Zhou" sort="Ru Zhou" uniqKey="Ru Zhou" last="Ru Zhou">RU ZHOU</name><name sortKey="Shi, Stephanie" sort="Shi, Stephanie" uniqKey="Shi S" first="Stephanie" last="Shi">Stephanie Shi</name><name sortKey="Tatlock, John" sort="Tatlock, John" uniqKey="Tatlock J" first="John" last="Tatlock">John Tatlock</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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