SrasV1, PascalFrancis, Curation, bibRecord, 000608

Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives

Identifieur interne : 000608 ( PascalFrancis/Curation ); précédent : 000607; suivant : 000609

Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives

Auteurs : Christopher Mcguigan [Royaume-Uni] ; Alshaimaa Hassan-Abdallah [Royaume-Uni] ; Sheila Srinivasan [Royaume-Uni] ; YIKANG WANG [Royaume-Uni] ; Adam Siddiqui [Royaume-Uni] ; Susan M. Daluge [États-Unis] ; Kristjan S. Gudmundsson [États-Unis] ; HUIQIANG ZHOU [États-Unis] ; Ed W. Mclean [États-Unis] ; Jennifer P. Peckham [États-Unis] ; Thimysta C. Burnette [États-Unis] ; Harry Marr [États-Unis] ; Richard Hazen [États-Unis] ; Lynn D. Condreay [États-Unis] ; Lance Johnson [États-Unis] ; Jan Balzarini [Belgique]

Source :

Journal of medicinal chemistry : (Print) [ 0022-2623 ] ; 2006.

RBID : Pascal:07-0201590

Descripteurs français

Pascal (Inist)
- Phosphoramidate organique, Antiviral, Composé monocyclique, Relation structure activité, Promédicament, Purine nucléotide, α-Aminoacide, Aminoester, Virus immunodéficience humaine, Virus hépatite B, Synthèse chimique, In vitro, Résistance hydrolyse, Adénine dérivé, Cyclopentaneméthanol dérivé, Carbanucléoside.

English descriptors

KwdEn :
- Adenine derivatives, Aminoester, Antiviral, Carbanucleoside, Chemical synthesis, Hepatitis B virus, Human immunodeficiency virus, Hydrolysis resistance, In vitro, Monocyclic compound, Organic amidophosphate, Prodrug, Purine nucleotide, Structure activity relation, α-Aminoacid.

Abstract

We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinct SARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4A and the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potency improvements over the parent drug. In conclusion, the ProTide approach is highly successful when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinical candidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinal S9 fractions.

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A02	`01`			`@0 JMCMAR`
A03		`1`		`@0 J. med. chem. : (Print)`
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A06				`@2 24`
A08	`01`	`1`	`ENG`	`@1 Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives`
A11	`01`	`1`		`@1 MCGUIGAN (Christopher)`
A11	`02`	`1`		`@1 HASSAN-ABDALLAH (Alshaimaa)`
A11	`03`	`1`		`@1 SRINIVASAN (Sheila)`
A11	`04`	`1`		`@1 YIKANG WANG`
A11	`05`	`1`		`@1 SIDDIQUI (Adam)`
A11	`06`	`1`		`@1 DALUGE (Susan M.)`
A11	`07`	`1`		`@1 GUDMUNDSSON (Kristjan S.)`
A11	`08`	`1`		`@1 HUIQIANG ZHOU`
A11	`09`	`1`		`@1 MCLEAN (Ed W.)`
A11	`10`	`1`		`@1 PECKHAM (Jennifer P.)`
A11	`11`	`1`		`@1 BURNETTE (Thimysta C.)`
A11	`12`	`1`		`@1 MARR (Harry)`
A11	`13`	`1`		`@1 HAZEN (Richard)`
A11	`14`	`1`		`@1 CONDREAY (Lynn D.)`
A11	`15`	`1`		`@1 JOHNSON (Lance)`
A11	`16`	`1`		`@1 BALZARINI (Jan)`
A14	`01`			`@1 Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue @2 Cardiff CF10 3XF @3 GBR @Z 1 aut. @Z 2 aut. @Z 3 aut. @Z 4 aut. @Z 5 aut.`
A14	`02`			`@1 Division of Chemistry MV CEDD; Drug Metabolism and Pharmacokinetics and Virology Departments, GlaxoSmithKline @2 Research Triangle Park, North Carolina 27709 @3 USA @Z 6 aut. @Z 7 aut. @Z 8 aut. @Z 9 aut. @Z 10 aut. @Z 11 aut. @Z 12 aut. @Z 13 aut. @Z 14 aut. @Z 15 aut.`
A14	`03`			`@1 Rega Institute for Medical Research, Katholieke Universiteit Leuven @2 3000 Leuven @3 BEL @Z 16 aut.`
A20				`@1 7215-7226`
A21				`@1 2006`
A23	`01`			`@0 ENG`
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A44				`@0 0000 @1 © 2007 INIST-CNRS. All rights reserved.`
A45				`@0 44 ref.`
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A60				`@1 P`
A61				`@0 A`
A64	`01`	`1`		`@0 Journal of medicinal chemistry : (Print)`
A66	`01`			`@0 USA`
C01	`01`		`ENG`	@0 We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinct SARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4A and the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potency improvements over the parent drug. In conclusion, the ProTide approach is highly successful when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinical candidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinal S9 fractions.
C02	`01`	`X`		`@0 002B02S05`
C03	`01`	`X`	`FRE`	`@0 Phosphoramidate organique @5 01`
C03	`01`	`X`	`ENG`	`@0 Organic amidophosphate @5 01`
C03	`01`	`X`	`SPA`	`@0 Fosforamidato orgánico @5 01`
C03	`02`	`X`	`FRE`	`@0 Antiviral @5 02`
C03	`02`	`X`	`ENG`	`@0 Antiviral @5 02`
C03	`02`	`X`	`SPA`	`@0 Antiviral @5 02`
C03	`03`	`X`	`FRE`	`@0 Composé monocyclique @5 03`
C03	`03`	`X`	`ENG`	`@0 Monocyclic compound @5 03`
C03	`03`	`X`	`SPA`	`@0 Compuesto monocíclico @5 03`
C03	`04`	`X`	`FRE`	`@0 Relation structure activité @5 04`
C03	`04`	`X`	`ENG`	`@0 Structure activity relation @5 04`
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C03	`05`	`X`	`FRE`	`@0 Promédicament @5 05`
C03	`05`	`X`	`ENG`	`@0 Prodrug @5 05`
C03	`05`	`X`	`SPA`	`@0 Promedicamento @5 05`
C03	`06`	`X`	`FRE`	`@0 Purine nucléotide @5 06`
C03	`06`	`X`	`ENG`	`@0 Purine nucleotide @5 06`
C03	`06`	`X`	`SPA`	`@0 Purina nucleótido @5 06`
C03	`07`	`X`	`FRE`	`@0 α-Aminoacide @5 07 @6 «α»-Aminoacide`
C03	`07`	`X`	`ENG`	`@0 α-Aminoacid @5 07 @6 «α»-Aminoacid`
C03	`07`	`X`	`SPA`	`@0 α-Aminoácido @5 07 @6 «α»-Aminoácido`
C03	`08`	`X`	`FRE`	`@0 Aminoester @5 09`
C03	`08`	`X`	`ENG`	`@0 Aminoester @5 09`
C03	`08`	`X`	`SPA`	`@0 Aminoester @5 09`
C03	`09`	`X`	`FRE`	`@0 Virus immunodéficience humaine @2 NW @5 10`
C03	`09`	`X`	`ENG`	`@0 Human immunodeficiency virus @2 NW @5 10`
C03	`09`	`X`	`SPA`	`@0 Human immunodeficiency virus @2 NW @5 10`
C03	`10`	`X`	`FRE`	`@0 Virus hépatite B @2 NW @5 11`
C03	`10`	`X`	`ENG`	`@0 Hepatitis B virus @2 NW @5 11`
C03	`10`	`X`	`SPA`	`@0 Hepatitis B virus @2 NW @5 11`
C03	`11`	`X`	`FRE`	`@0 Synthèse chimique @5 12`
C03	`11`	`X`	`ENG`	`@0 Chemical synthesis @5 12`
C03	`11`	`X`	`SPA`	`@0 Síntesis química @5 12`
C03	`12`	`X`	`FRE`	`@0 In vitro @5 13`
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C03	`12`	`X`	`SPA`	`@0 In vitro @5 13`
C03	`13`	`X`	`FRE`	`@0 Résistance hydrolyse @5 14`
C03	`13`	`X`	`ENG`	`@0 Hydrolysis resistance @5 14`
C03	`13`	`X`	`SPA`	`@0 Resistencia hidrólisis @5 14`
C03	`14`	`X`	`FRE`	`@0 Adénine dérivé @5 15`
C03	`14`	`X`	`ENG`	`@0 Adenine derivatives @5 15`
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C03	`15`	`X`	`FRE`	`@0 Cyclopentaneméthanol dérivé @2 NK @4 INC @5 78`
C03	`16`	`X`	`FRE`	`@0 Carbanucléoside @4 CD @5 96`
C03	`16`	`X`	`ENG`	`@0 Carbanucleoside @4 CD @5 96`
C07	`01`	`X`	`FRE`	`@0 Phosphore Composé organique @2 NC @2 NA @5 08`
C07	`01`	`X`	`ENG`	`@0 Phosphorus Organic compounds @2 NC @2 NA @5 08`
C07	`01`	`X`	`SPA`	`@0 Fósforo Compuesto orgánico @2 NC @2 NA @5 08`
C07	`02`	`X`	`FRE`	`@0 Lentivirus @2 NW`
C07	`02`	`X`	`ENG`	`@0 Lentivirus @2 NW`
C07	`02`	`X`	`SPA`	`@0 Lentivirus @2 NW`
C07	`03`	`X`	`FRE`	`@0 Retroviridae @2 NW`
C07	`03`	`X`	`ENG`	`@0 Retroviridae @2 NW`
C07	`03`	`X`	`SPA`	`@0 Retroviridae @2 NW`
C07	`04`	`X`	`FRE`	`@0 Virus @2 NW`
C07	`04`	`X`	`ENG`	`@0 Virus @2 NW`
C07	`04`	`X`	`SPA`	`@0 Virus @2 NW`
C07	`05`	`X`	`FRE`	`@0 Orthohepadnavirus @2 NW`
C07	`05`	`X`	`ENG`	`@0 Orthohepadnavirus @2 NW`
C07	`05`	`X`	`SPA`	`@0 Orthohepadnavirus @2 NW`
C07	`06`	`X`	`FRE`	`@0 Hepadnaviridae @2 NW`
C07	`06`	`X`	`ENG`	`@0 Hepadnaviridae @2 NW`
C07	`06`	`X`	`SPA`	`@0 Hepadnaviridae @2 NW`
N21				`@1 134`

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Le document en format XML

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<author><name sortKey="Condreay, Lynn D" sort="Condreay, Lynn D" uniqKey="Condreay L" first="Lynn D." last="Condreay">Lynn D. Condreay</name>
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<author><name sortKey="Johnson, Lance" sort="Johnson, Lance" uniqKey="Johnson L" first="Lance" last="Johnson">Lance Johnson</name>
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<series><title level="j" type="main">Journal of medicinal chemistry : (Print)</title>
<title level="j" type="abbreviated">J. med. chem. : (Print)</title>
<idno type="ISSN">0022-2623</idno>
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<seriesStmt><title level="j" type="main">Journal of medicinal chemistry : (Print)</title>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adenine derivatives</term>
<term>Aminoester</term>
<term>Antiviral</term>
<term>Carbanucleoside</term>
<term>Chemical synthesis</term>
<term>Hepatitis B virus</term>
<term>Human immunodeficiency virus</term>
<term>Hydrolysis resistance</term>
<term>In vitro</term>
<term>Monocyclic compound</term>
<term>Organic amidophosphate</term>
<term>Prodrug</term>
<term>Purine nucleotide</term>
<term>Structure activity relation</term>
<term>α-Aminoacid</term>
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<keywords scheme="Pascal" xml:lang="fr"><term>Phosphoramidate organique</term>
<term>Antiviral</term>
<term>Composé monocyclique</term>
<term>Relation structure activité</term>
<term>Promédicament</term>
<term>Purine nucléotide</term>
<term>α-Aminoacide</term>
<term>Aminoester</term>
<term>Virus immunodéficience humaine</term>
<term>Virus hépatite B</term>
<term>Synthèse chimique</term>
<term>In vitro</term>
<term>Résistance hydrolyse</term>
<term>Adénine dérivé</term>
<term>Cyclopentaneméthanol dérivé</term>
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<front><div type="abstract" xml:lang="en">We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinct SARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4A and the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potency improvements over the parent drug. In conclusion, the ProTide approach is highly successful when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinical candidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinal S9 fractions.</div>
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<fA11 i1="01" i2="1"><s1>MCGUIGAN (Christopher)</s1>
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<fA11 i1="04" i2="1"><s1>YIKANG WANG</s1>
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<fA11 i1="08" i2="1"><s1>HUIQIANG ZHOU</s1>
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<fA11 i1="09" i2="1"><s1>MCLEAN (Ed W.)</s1>
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<fA11 i1="10" i2="1"><s1>PECKHAM (Jennifer P.)</s1>
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<fA11 i1="16" i2="1"><s1>BALZARINI (Jan)</s1>
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<fC01 i1="01" l="ENG"><s0>We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinct SARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4A and the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potency improvements over the parent drug. In conclusion, the ProTide approach is highly successful when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinical candidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinal S9 fractions.</s0>
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<fC02 i1="01" i2="X"><s0>002B02S05</s0>
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</fC03>
<fC03 i1="05" i2="X" l="SPA"><s0>Promedicamento</s0>
<s5>05</s5>
</fC03>
<fC03 i1="06" i2="X" l="FRE"><s0>Purine nucléotide</s0>
<s5>06</s5>
</fC03>
<fC03 i1="06" i2="X" l="ENG"><s0>Purine nucleotide</s0>
<s5>06</s5>
</fC03>
<fC03 i1="06" i2="X" l="SPA"><s0>Purina nucleótido</s0>
<s5>06</s5>
</fC03>
<fC03 i1="07" i2="X" l="FRE"><s0>α-Aminoacide</s0>
<s5>07</s5>
<s6>«α»-Aminoacide</s6>
</fC03>
<fC03 i1="07" i2="X" l="ENG"><s0>α-Aminoacid</s0>
<s5>07</s5>
<s6>«α»-Aminoacid</s6>
</fC03>
<fC03 i1="07" i2="X" l="SPA"><s0>α-Aminoácido</s0>
<s5>07</s5>
<s6>«α»-Aminoácido</s6>
</fC03>
<fC03 i1="08" i2="X" l="FRE"><s0>Aminoester</s0>
<s5>09</s5>
</fC03>
<fC03 i1="08" i2="X" l="ENG"><s0>Aminoester</s0>
<s5>09</s5>
</fC03>
<fC03 i1="08" i2="X" l="SPA"><s0>Aminoester</s0>
<s5>09</s5>
</fC03>
<fC03 i1="09" i2="X" l="FRE"><s0>Virus immunodéficience humaine</s0>
<s2>NW</s2>
<s5>10</s5>
</fC03>
<fC03 i1="09" i2="X" l="ENG"><s0>Human immunodeficiency virus</s0>
<s2>NW</s2>
<s5>10</s5>
</fC03>
<fC03 i1="09" i2="X" l="SPA"><s0>Human immunodeficiency virus</s0>
<s2>NW</s2>
<s5>10</s5>
</fC03>
<fC03 i1="10" i2="X" l="FRE"><s0>Virus hépatite B</s0>
<s2>NW</s2>
<s5>11</s5>
</fC03>
<fC03 i1="10" i2="X" l="ENG"><s0>Hepatitis B virus</s0>
<s2>NW</s2>
<s5>11</s5>
</fC03>
<fC03 i1="10" i2="X" l="SPA"><s0>Hepatitis B virus</s0>
<s2>NW</s2>
<s5>11</s5>
</fC03>
<fC03 i1="11" i2="X" l="FRE"><s0>Synthèse chimique</s0>
<s5>12</s5>
</fC03>
<fC03 i1="11" i2="X" l="ENG"><s0>Chemical synthesis</s0>
<s5>12</s5>
</fC03>
<fC03 i1="11" i2="X" l="SPA"><s0>Síntesis química</s0>
<s5>12</s5>
</fC03>
<fC03 i1="12" i2="X" l="FRE"><s0>In vitro</s0>
<s5>13</s5>
</fC03>
<fC03 i1="12" i2="X" l="ENG"><s0>In vitro</s0>
<s5>13</s5>
</fC03>
<fC03 i1="12" i2="X" l="SPA"><s0>In vitro</s0>
<s5>13</s5>
</fC03>
<fC03 i1="13" i2="X" l="FRE"><s0>Résistance hydrolyse</s0>
<s5>14</s5>
</fC03>
<fC03 i1="13" i2="X" l="ENG"><s0>Hydrolysis resistance</s0>
<s5>14</s5>
</fC03>
<fC03 i1="13" i2="X" l="SPA"><s0>Resistencia hidrólisis</s0>
<s5>14</s5>
</fC03>
<fC03 i1="14" i2="X" l="FRE"><s0>Adénine dérivé</s0>
<s5>15</s5>
</fC03>
<fC03 i1="14" i2="X" l="ENG"><s0>Adenine derivatives</s0>
<s5>15</s5>
</fC03>
<fC03 i1="14" i2="X" l="SPA"><s0>Adenina derivado</s0>
<s5>15</s5>
</fC03>
<fC03 i1="15" i2="X" l="FRE"><s0>Cyclopentaneméthanol dérivé</s0>
<s2>NK</s2>
<s4>INC</s4>
<s5>78</s5>
</fC03>
<fC03 i1="16" i2="X" l="FRE"><s0>Carbanucléoside</s0>
<s4>CD</s4>
<s5>96</s5>
</fC03>
<fC03 i1="16" i2="X" l="ENG"><s0>Carbanucleoside</s0>
<s4>CD</s4>
<s5>96</s5>
</fC03>
<fC07 i1="01" i2="X" l="FRE"><s0>Phosphore Composé organique</s0>
<s2>NC</s2>
<s2>NA</s2>
<s5>08</s5>
</fC07>
<fC07 i1="01" i2="X" l="ENG"><s0>Phosphorus Organic compounds</s0>
<s2>NC</s2>
<s2>NA</s2>
<s5>08</s5>
</fC07>
<fC07 i1="01" i2="X" l="SPA"><s0>Fósforo Compuesto orgánico</s0>
<s2>NC</s2>
<s2>NA</s2>
<s5>08</s5>
</fC07>
<fC07 i1="02" i2="X" l="FRE"><s0>Lentivirus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="02" i2="X" l="ENG"><s0>Lentivirus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="02" i2="X" l="SPA"><s0>Lentivirus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="03" i2="X" l="FRE"><s0>Retroviridae</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="03" i2="X" l="ENG"><s0>Retroviridae</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="03" i2="X" l="SPA"><s0>Retroviridae</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="04" i2="X" l="FRE"><s0>Virus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="04" i2="X" l="ENG"><s0>Virus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="04" i2="X" l="SPA"><s0>Virus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="05" i2="X" l="FRE"><s0>Orthohepadnavirus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="05" i2="X" l="ENG"><s0>Orthohepadnavirus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="05" i2="X" l="SPA"><s0>Orthohepadnavirus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="06" i2="X" l="FRE"><s0>Hepadnaviridae</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="06" i2="X" l="ENG"><s0>Hepadnaviridae</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="06" i2="X" l="SPA"><s0>Hepadnaviridae</s0>
<s2>NW</s2>
</fC07>
<fN21><s1>134</s1>
</fN21>
</pA>
</standard>
</inist>
</record>

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   |texte=   Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives
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Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives

Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives

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