SrasV1, PascalFrancis, Corpus, bibRecord, 000426

Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors

Identifieur interne : 000426 ( PascalFrancis/Corpus ); précédent : 000425; suivant : 000427

Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors

Auteurs : HUI LI ; John Tatlock ; Angelica Linton ; Javier Gonzalez ; Allen Borchardt ; Peter Dragovich ; Tanya Jewell ; Tom Prins ; RU ZHOU ; Julie Blazel ; Hans Parge ; Robert Love ; Michael Hickey ; Chau Doan ; Stephanie Shi ; Rohit Duggal ; Cristina Lewis ; Shella Fuhrman

Source :

Bioorganic & medicinal chemistry letters : (Print) [ 0960-894X ] ; 2006.

RBID : Pascal:07-0028982

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.

Notice en format standard (ISO 2709)

Pour connaître la documentation sur le format Inist Standard.

A01	`01`	`1`		`@0 0960-894X`
A03		`1`		`@0 Bioorg. med. chem. lett. : (Print)`
A05				`@2 16`
A06				`@2 18`
A08	`01`	`1`	`ENG`	`@1 Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors`
A11	`01`	`1`		`@1 HUI LI`
A11	`02`	`1`		`@1 TATLOCK (John)`
A11	`03`	`1`		`@1 LINTON (Angelica)`
A11	`04`	`1`		`@1 GONZALEZ (Javier)`
A11	`05`	`1`		`@1 BORCHARDT (Allen)`
A11	`06`	`1`		`@1 DRAGOVICH (Peter)`
A11	`07`	`1`		`@1 JEWELL (Tanya)`
A11	`08`	`1`		`@1 PRINS (Tom)`
A11	`09`	`1`		`@1 RU ZHOU`
A11	`10`	`1`		`@1 BLAZEL (Julie)`
A11	`11`	`1`		`@1 PARGE (Hans)`
A11	`12`	`1`		`@1 LOVE (Robert)`
A11	`13`	`1`		`@1 HICKEY (Michael)`
A11	`14`	`1`		`@1 DOAN (Chau)`
A11	`15`	`1`		`@1 SHI (Stephanie)`
A11	`16`	`1`		`@1 DUGGAL (Rohit)`
A11	`17`	`1`		`@1 LEWIS (Cristina)`
A11	`18`	`1`		`@1 FUHRMAN (Shella)`
A14	`01`			`@1 Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr @2 San Diego, CA 92121 @3 USA @Z 1 aut. @Z 2 aut. @Z 3 aut. @Z 4 aut. @Z 5 aut. @Z 7 aut. @Z 9 aut. @Z 11 aut. @Z 12 aut. @Z 13 aut. @Z 14 aut. @Z 15 aut. @Z 16 aut. @Z 18 aut.`
A14	`02`			`@1 Anadys Pharmaceuticals, 3115 Merryfield Row @2 San Diego, CA 92121 @3 USA @Z 6 aut. @Z 8 aut. @Z 10 aut.`
A14	`03`			`@1 Genentecb. Inc., 1 DNA Way @2 South San Francisco, CA 94098 @3 USA @Z 17 aut.`
A20				`@1 4834-4838`
A21				`@1 2006`
A23	`01`			`@0 ENG`
A43	`01`			`@1 INIST @2 22446 @5 354000133548250280`
A44				`@0 0000 @1 © 2007 INIST-CNRS. All rights reserved.`
A47	`01`	`1`		`@0 07-0028982`
A60				`@1 P`
A61				`@0 A`
A64	`01`	`1`		`@0 Bioorganic & medicinal chemistry letters : (Print)`
A66	`01`			`@0 GBR`
A99				`@0 3/4 p. ref. et notes`
C01	`01`		`ENG`	`@0 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.`
C02	`01`	`X`		`@0 002B02S05`
C03	`01`	`X`	`FRE`	`@0 Optimisation @5 01`
C03	`01`	`X`	`ENG`	`@0 Optimization @5 01`
C03	`01`	`X`	`SPA`	`@0 Optimización @5 01`
C03	`02`	`X`	`FRE`	`@0 Virus hépatite C @2 NW @5 02`
C03	`02`	`X`	`ENG`	`@0 Hepatitis C virus @2 NW @5 02`
C03	`02`	`X`	`SPA`	`@0 Hepatitis C virus @2 NW @5 02`
C03	`03`	`X`	`FRE`	`@0 DNA-directed RNA polymerase @2 FE @5 03`
C03	`03`	`X`	`ENG`	`@0 DNA-directed RNA polymerase @2 FE @5 03`
C03	`03`	`X`	`SPA`	`@0 DNA-directed RNA polymerase @2 FE @5 03`
C03	`04`	`X`	`FRE`	`@0 Inhibiteur enzyme @5 04`
C03	`04`	`X`	`ENG`	`@0 Enzyme inhibitor @5 04`
C03	`04`	`X`	`SPA`	`@0 Inhibidor enzima @5 04`
C03	`05`	`X`	`FRE`	`@0 Composé non nucléoside @5 05`
C03	`05`	`X`	`ENG`	`@0 Non nucleoside compound @5 05`
C03	`05`	`X`	`SPA`	`@0 Compuesto no nucleósido @5 05`
C03	`06`	`X`	`FRE`	`@0 Criblage @5 06`
C03	`06`	`X`	`ENG`	`@0 Screening @5 06`
C03	`06`	`X`	`SPA`	`@0 Cernido @5 06`
C03	`07`	`X`	`FRE`	`@0 Structure cristalline @5 07`
C03	`07`	`X`	`ENG`	`@0 Crystalline structure @5 07`
C03	`07`	`X`	`SPA`	`@0 Estructura cristalina @5 07`
C03	`08`	`X`	`FRE`	`@0 Site fixation @5 08`
C03	`08`	`X`	`ENG`	`@0 Binding site @5 08`
C03	`08`	`X`	`SPA`	`@0 Sitio fijación @5 08`
C03	`09`	`3`	`FRE`	`@0 Changement conformation @5 09`
C03	`09`	`3`	`ENG`	`@0 Conformational changes @5 09`
C03	`10`	`X`	`FRE`	`@0 Relation structure activité @5 10`
C03	`10`	`X`	`ENG`	`@0 Structure activity relation @5 10`
C03	`10`	`X`	`SPA`	`@0 Relación estructura actividad @5 10`
C03	`11`	`X`	`FRE`	`@0 Pyranone dérivé @2 FR @5 11`
C03	`11`	`X`	`ENG`	`@0 Pyranone derivatives @2 FR @5 11`
C03	`12`	`X`	`FRE`	`@0 Cyclopentane dérivé @5 12`
C03	`12`	`X`	`ENG`	`@0 Cyclopentane derivatives @5 12`
C03	`12`	`X`	`SPA`	`@0 Ciclopentano derivado @5 12`
C03	`13`	`X`	`FRE`	`@0 Lactone @5 13`
C03	`13`	`X`	`ENG`	`@0 Lactone @5 13`
C03	`13`	`X`	`SPA`	`@0 Lactona @5 13`
C03	`14`	`X`	`FRE`	`@0 Antiviral @5 14`
C03	`14`	`X`	`ENG`	`@0 Antiviral @5 14`
C03	`14`	`X`	`SPA`	`@0 Antiviral @5 14`
C03	`15`	`X`	`FRE`	`@0 Composé benzénique @5 15`
C03	`15`	`X`	`ENG`	`@0 Benzenic compound @5 15`
C03	`15`	`X`	`SPA`	`@0 Compuesto bencénico @5 15`
C03	`16`	`X`	`FRE`	`@0 Halogène Composé organique @2 NC @2 NA @5 16`
C03	`16`	`X`	`ENG`	`@0 Halogen Organic compounds @2 NC @2 NA @5 16`
C03	`16`	`X`	`SPA`	`@0 Halógeno Compuesto orgánico @2 NC @2 NA @5 16`
C03	`17`	`X`	`FRE`	`@0 RNA-directed RNA polymerase @2 FE @5 32`
C03	`17`	`X`	`ENG`	`@0 RNA-directed RNA polymerase @2 FE @5 32`
C03	`17`	`X`	`SPA`	`@0 RNA-directed RNA polymerase @2 FE @5 32`
C03	`18`	`X`	`FRE`	`@0 Pyrane dérivé @5 33`
C03	`18`	`X`	`ENG`	`@0 Pyran derivatives @5 33`
C03	`18`	`X`	`SPA`	`@0 Pirano derivado @5 33`
C03	`19`	`X`	`FRE`	`@0 NS5B polymerase @4 INC @5 76`
C03	`20`	`X`	`FRE`	`@0 Pyran-2-one(3-[4-amino-2-(t-butyl)-5-méthylphénylsulfanyl]-6-cyclopentyl-5,6-dihydro-4-hydroxy-6-[4-hydroxyphénéthyl]) @2 NK @4 INC @5 77`
C03	`21`	`X`	`FRE`	`@0 Pyrane-2,4-dione dérivé @2 NK @4 INC @5 78`
C03	`22`	`X`	`FRE`	`@0 Protéine NS5B @4 INC @5 91`
C07	`01`	`X`	`FRE`	`@0 Hepacivirus @2 NW`
C07	`01`	`X`	`ENG`	`@0 Hepacivirus @2 NW`
C07	`01`	`X`	`SPA`	`@0 Hepacivirus @2 NW`
C07	`02`	`X`	`FRE`	`@0 Flaviviridae @2 NW`
C07	`02`	`X`	`ENG`	`@0 Flaviviridae @2 NW`
C07	`02`	`X`	`SPA`	`@0 Flaviviridae @2 NW`
C07	`03`	`X`	`FRE`	`@0 Virus @2 NW`
C07	`03`	`X`	`ENG`	`@0 Virus @2 NW`
C07	`03`	`X`	`SPA`	`@0 Virus @2 NW`
C07	`04`	`X`	`FRE`	`@0 Nucleotidyltransferases @2 FE`
C07	`04`	`X`	`ENG`	`@0 Nucleotidyltransferases @2 FE`
C07	`04`	`X`	`SPA`	`@0 Nucleotidyltransferases @2 FE`
C07	`05`	`X`	`FRE`	`@0 Transferases @2 FE`
C07	`05`	`X`	`ENG`	`@0 Transferases @2 FE`
C07	`05`	`X`	`SPA`	`@0 Transferases @2 FE`
C07	`06`	`X`	`FRE`	`@0 Enzyme @2 FE`
C07	`06`	`X`	`ENG`	`@0 Enzyme @2 FE`
C07	`06`	`X`	`SPA`	`@0 Enzima @2 FE`
N21				`@1 015`

Format Inist (serveur)

NO :	PASCAL 07-0028982 INIST
ET :	Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors
AU :	HUI LI; TATLOCK (John); LINTON (Angelica); GONZALEZ (Javier); BORCHARDT (Allen); DRAGOVICH (Peter); JEWELL (Tanya); PRINS (Tom); RU ZHOU; BLAZEL (Julie); PARGE (Hans); LOVE (Robert); HICKEY (Michael); DOAN (Chau); SHI (Stephanie); DUGGAL (Rohit); LEWIS (Cristina); FUHRMAN (Shella)
AF :	Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr/San Diego, CA 92121/Etats-Unis (1 aut., 2 aut., 3 aut., 4 aut., 5 aut., 7 aut., 9 aut., 11 aut., 12 aut., 13 aut., 14 aut., 15 aut., 16 aut., 18 aut.); Anadys Pharmaceuticals, 3115 Merryfield Row/San Diego, CA 92121/Etats-Unis (6 aut., 8 aut., 10 aut.); Genentecb. Inc., 1 DNA Way/South San Francisco, CA 94098/Etats-Unis (17 aut.)
DT :	Publication en série; Niveau analytique
SO :	Bioorganic & medicinal chemistry letters : (Print); ISSN 0960-894X; Royaume-Uni; Da. 2006; Vol. 16; No. 18; Pp. 4834-4838
LA :	Anglais
EA :	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.
CC :	002B02S05
FD :	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-h ydroxyphénéthyl]); Pyrane-2,4-dione dérivé; Protéine NS5B
FG :	Hepacivirus; Flaviviridae; Virus; Nucleotidyltransferases; Transferases; Enzyme
ED :	Optimization; Hepatitis C virus; DNA-directed RNA polymerase; Enzyme inhibitor; Non nucleoside compound; Screening; Crystalline structure; Binding site; Conformational changes; Structure activity relation; Pyranone derivatives; Cyclopentane derivatives; Lactone; Antiviral; Benzenic compound; Halogen Organic compounds; RNA-directed RNA polymerase; Pyran derivatives
EG :	Hepacivirus; Flaviviridae; Virus; Nucleotidyltransferases; Transferases; Enzyme
SD :	Optimización; Hepatitis C virus; DNA-directed RNA polymerase; Inhibidor enzima; Compuesto no nucleósido; Cernido; Estructura cristalina; Sitio fijación; Relación estructura actividad; Ciclopentano derivado; Lactona; Antiviral; Compuesto bencénico; Halógeno Compuesto orgánico; RNA-directed RNA polymerase; Pirano derivado
LO :	INIST-22446.354000133548250280
ID :	07-0028982

Links to Exploration step

Pascal:07-0028982

Le document en format XML

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<author><name sortKey="Hickey, Michael" sort="Hickey, Michael" uniqKey="Hickey M" first="Michael" last="Hickey">Michael Hickey</name>
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<author><name sortKey="Shi, Stephanie" sort="Shi, Stephanie" uniqKey="Shi S" first="Stephanie" last="Shi">Stephanie Shi</name>
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<s2>San Diego, CA 92121</s2>
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</author>
<author><name sortKey="Duggal, Rohit" sort="Duggal, Rohit" uniqKey="Duggal R" first="Rohit" last="Duggal">Rohit Duggal</name>
<affiliation><inist:fA14 i1="01"><s1>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr</s1>
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</author>
<author><name sortKey="Lewis, Cristina" sort="Lewis, Cristina" uniqKey="Lewis C" first="Cristina" last="Lewis">Cristina Lewis</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Fuhrman, Shella" sort="Fuhrman, Shella" uniqKey="Fuhrman S" first="Shella" last="Fuhrman">Shella Fuhrman</name>
<affiliation><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>
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</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>
</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><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>
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</affiliation>
</author>
<author><name sortKey="Tatlock, John" sort="Tatlock, John" uniqKey="Tatlock J" first="John" last="Tatlock">John Tatlock</name>
<affiliation><inist:fA14 i1="01"><s1>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr</s1>
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<s3>USA</s3>
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</affiliation>
</author>
<author><name sortKey="Linton, Angelica" sort="Linton, Angelica" uniqKey="Linton A" first="Angelica" last="Linton">Angelica Linton</name>
<affiliation><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>
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</affiliation>
</author>
<author><name sortKey="Gonzalez, Javier" sort="Gonzalez, Javier" uniqKey="Gonzalez J" first="Javier" last="Gonzalez">Javier Gonzalez</name>
<affiliation><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>
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</affiliation>
</author>
<author><name sortKey="Borchardt, Allen" sort="Borchardt, Allen" uniqKey="Borchardt A" first="Allen" last="Borchardt">Allen Borchardt</name>
<affiliation><inist:fA14 i1="01"><s1>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr</s1>
<s2>San Diego, CA 92121</s2>
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<author><name sortKey="Dragovich, Peter" sort="Dragovich, Peter" uniqKey="Dragovich P" first="Peter" last="Dragovich">Peter Dragovich</name>
<affiliation><inist:fA14 i1="02"><s1>Anadys Pharmaceuticals, 3115 Merryfield Row</s1>
<s2>San Diego, CA 92121</s2>
<s3>USA</s3>
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<author><name sortKey="Jewell, Tanya" sort="Jewell, Tanya" uniqKey="Jewell T" first="Tanya" last="Jewell">Tanya Jewell</name>
<affiliation><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>
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<author><name sortKey="Prins, Tom" sort="Prins, Tom" uniqKey="Prins T" first="Tom" last="Prins">Tom Prins</name>
<affiliation><inist:fA14 i1="02"><s1>Anadys Pharmaceuticals, 3115 Merryfield Row</s1>
<s2>San Diego, CA 92121</s2>
<s3>USA</s3>
<sZ>6 aut.</sZ>
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</author>
<author><name sortKey="Ru Zhou" sort="Ru Zhou" uniqKey="Ru Zhou" last="Ru Zhou">RU ZHOU</name>
<affiliation><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>
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<author><name sortKey="Blazel, Julie" sort="Blazel, Julie" uniqKey="Blazel J" first="Julie" last="Blazel">Julie Blazel</name>
<affiliation><inist:fA14 i1="02"><s1>Anadys Pharmaceuticals, 3115 Merryfield Row</s1>
<s2>San Diego, CA 92121</s2>
<s3>USA</s3>
<sZ>6 aut.</sZ>
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</author>
<author><name sortKey="Parge, Hans" sort="Parge, Hans" uniqKey="Parge H" first="Hans" last="Parge">Hans Parge</name>
<affiliation><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>
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</author>
<author><name sortKey="Love, Robert" sort="Love, Robert" uniqKey="Love R" first="Robert" last="Love">Robert Love</name>
<affiliation><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>
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</author>
<author><name sortKey="Hickey, Michael" sort="Hickey, Michael" uniqKey="Hickey M" first="Michael" last="Hickey">Michael Hickey</name>
<affiliation><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>
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</author>
<author><name sortKey="Doan, Chau" sort="Doan, Chau" uniqKey="Doan C" first="Chau" last="Doan">Chau Doan</name>
<affiliation><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>
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</author>
<author><name sortKey="Shi, Stephanie" sort="Shi, Stephanie" uniqKey="Shi S" first="Stephanie" last="Shi">Stephanie Shi</name>
<affiliation><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>
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</affiliation>
</author>
<author><name sortKey="Duggal, Rohit" sort="Duggal, Rohit" uniqKey="Duggal R" first="Rohit" last="Duggal">Rohit Duggal</name>
<affiliation><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>
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</affiliation>
</author>
<author><name sortKey="Lewis, Cristina" sort="Lewis, Cristina" uniqKey="Lewis C" first="Cristina" last="Lewis">Cristina Lewis</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Fuhrman, Shella" sort="Fuhrman, Shella" uniqKey="Fuhrman S" first="Shella" last="Fuhrman">Shella Fuhrman</name>
<affiliation><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>
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</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>
<server><NO>PASCAL 07-0028982 INIST</NO>
<ET>Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors</ET>
<AU>HUI LI; TATLOCK (John); LINTON (Angelica); GONZALEZ (Javier); BORCHARDT (Allen); DRAGOVICH (Peter); JEWELL (Tanya); PRINS (Tom); RU ZHOU; BLAZEL (Julie); PARGE (Hans); LOVE (Robert); HICKEY (Michael); DOAN (Chau); SHI (Stephanie); DUGGAL (Rohit); LEWIS (Cristina); FUHRMAN (Shella)</AU>
<AF>Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr/San Diego, CA 92121/Etats-Unis (1 aut., 2 aut., 3 aut., 4 aut., 5 aut., 7 aut., 9 aut., 11 aut., 12 aut., 13 aut., 14 aut., 15 aut., 16 aut., 18 aut.); Anadys Pharmaceuticals, 3115 Merryfield Row/San Diego, CA 92121/Etats-Unis (6 aut., 8 aut., 10 aut.); Genentecb. Inc., 1 DNA Way/South San Francisco, CA 94098/Etats-Unis (17 aut.)</AF>
<DT>Publication en série; Niveau analytique</DT>
<SO>Bioorganic & medicinal chemistry letters : (Print); ISSN 0960-894X; Royaume-Uni; Da. 2006; Vol. 16; No. 18; Pp. 4834-4838</SO>
<LA>Anglais</LA>
<EA>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.</EA>
<CC>002B02S05</CC>
<FD>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-h ydroxyphénéthyl]); Pyrane-2,4-dione dérivé; Protéine NS5B</FD>
<FG>Hepacivirus; Flaviviridae; Virus; Nucleotidyltransferases; Transferases; Enzyme</FG>
<ED>Optimization; Hepatitis C virus; DNA-directed RNA polymerase; Enzyme inhibitor; Non nucleoside compound; Screening; Crystalline structure; Binding site; Conformational changes; Structure activity relation; Pyranone derivatives; Cyclopentane derivatives; Lactone; Antiviral; Benzenic compound; Halogen Organic compounds; RNA-directed RNA polymerase; Pyran derivatives</ED>
<EG>Hepacivirus; Flaviviridae; Virus; Nucleotidyltransferases; Transferases; Enzyme</EG>
<SD>Optimización; Hepatitis C virus; DNA-directed RNA polymerase; Inhibidor enzima; Compuesto no nucleósido; Cernido; Estructura cristalina; Sitio fijación; Relación estructura actividad; Ciclopentano derivado; Lactona; Antiviral; Compuesto bencénico; Halógeno Compuesto orgánico; RNA-directed RNA polymerase; Pirano derivado</SD>
<LO>INIST-22446.354000133548250280</LO>
<ID>07-0028982</ID>
</server>
</inist>
</record>

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Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors

Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors

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