SrasV1, Main, Exploration, bibRecordById, pubmed:17125274

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

Identifieur interne : 004474 ( Main/Exploration ); précédent : 004473; suivant : 004475

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

KwdFr :
- Adénosine (analogues et dérivés), Adénosine (pharmacologie), Adénosine (synthèse chimique), Agents antiVIH (pharmacologie), Agents antiVIH (synthèse chimique), Animaux, Antiviraux (pharmacologie), Antiviraux (synthèse chimique), Composés organiques du phosphore (pharmacologie), Composés organiques du phosphore (synthèse chimique), Foie (métabolisme), Humains, Lignée cellulaire, Muqueuse intestinale (métabolisme), Nucléotides (pharmacologie), Nucléotides (synthèse chimique), Relation structure-activité, Techniques in vitro, VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (), VIH-2 (Virus de l'Immunodéficience Humaine de type 2) (), Virus de l'hépatite B ().
MESH :
- analogues et dérivés : Adénosine.
- métabolisme : Foie, Muqueuse intestinale.
- pharmacologie : Adénosine, Agents antiVIH, Antiviraux, Composés organiques du phosphore, Nucléotides.
- synthèse chimique : Adénosine, Agents antiVIH, Antiviraux, Composés organiques du phosphore, Nucléotides.
Pascal (Inist)
- Animaux, Humains, Lignée cellulaire, Phosphoramidate organique, Antiviral, Composé monocyclique, Relation structure activité, Promédicament, Purine nucléotide, Relation structure-activité, Techniques in vitro, VIH-1 (Virus de l'Immunodéficience Humaine de type 1), VIH-2 (Virus de l'Immunodéficience Humaine de type 2), Virus de l'hépatite B, 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, Adenosine (analogs & derivatives), Adenosine (chemical synthesis), Adenosine (pharmacology), Aminoester, Animals, Anti-HIV Agents (chemical synthesis), Anti-HIV Agents (pharmacology), Antiviral, Antiviral Agents (chemical synthesis), Antiviral Agents (pharmacology), Carbanucleoside, Cell Line, Chemical synthesis, HIV-1 (drug effects), HIV-2 (drug effects), Hepatitis B virus, Hepatitis B virus (drug effects), Human immunodeficiency virus, Humans, Hydrolysis resistance, In Vitro Techniques, In vitro, Intestinal Mucosa (metabolism), Liver (metabolism), Monocyclic compound, Nucleotides (chemical synthesis), Nucleotides (pharmacology), Organic amidophosphate, Organophosphorus Compounds (chemical synthesis), Organophosphorus Compounds (pharmacology), Prodrug, Purine nucleotide, Structure activity relation, Structure-Activity Relationship, α-Aminoacid.
MESH :
- chemical , analogs & derivatives : Adenosine.
- chemical , chemical synthesis : Adenosine, Anti-HIV Agents, Antiviral Agents, Nucleotides, Organophosphorus Compounds.
- chemical , pharmacology : Adenosine, Anti-HIV Agents, Antiviral Agents, Nucleotides, Organophosphorus Compounds.
- drug effects : HIV-1, HIV-2, Hepatitis B virus.
- metabolism : Intestinal Mucosa, Liver.
- Animals, Cell Line, Humans, In Vitro Techniques, Structure-Activity Relationship.

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.

Affiliations:

Le document en format XML

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<author><name sortKey="Burnette, Thimysta C" sort="Burnette, Thimysta C" uniqKey="Burnette T" first="Thimysta C." last="Burnette">Thimysta C. Burnette</name>
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<author><name sortKey="Marr, Harry" sort="Marr, Harry" uniqKey="Marr H" first="Harry" last="Marr">Harry Marr</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Division of Chemistry MV CEDD; Drug Metabolism and Pharmacokinetics and Virology Departments, GlaxoSmithKline</s1>
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<author><name sortKey="Hazen, Richard" sort="Hazen, Richard" uniqKey="Hazen R" first="Richard" last="Hazen">Richard Hazen</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Division of Chemistry MV CEDD; Drug Metabolism and Pharmacokinetics and Virology Departments, GlaxoSmithKline</s1>
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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>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Division of Chemistry MV CEDD; Drug Metabolism and Pharmacokinetics and Virology Departments, GlaxoSmithKline</s1>
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<author><name sortKey="Johnson, Lance" sort="Johnson, Lance" uniqKey="Johnson L" first="Lance" last="Johnson">Lance Johnson</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Division of Chemistry MV CEDD; Drug Metabolism and Pharmacokinetics and Virology Departments, GlaxoSmithKline</s1>
<s2>Research Triangle Park, North Carolina 27709</s2>
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<author><name sortKey="Balzarini, Jan" sort="Balzarini, Jan" uniqKey="Balzarini J" first="Jan" last="Balzarini">Jan Balzarini</name>
<affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Rega Institute for Medical Research, Katholieke Universiteit Leuven</s1>
<s2>3000 Leuven</s2>
<s3>BEL</s3>
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<country>Belgique</country>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
<orgName type="university">Katholieke Universiteit Leuven</orgName>
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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>
<imprint><date when="2006">2006</date>
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<seriesStmt><title level="j" type="main">Journal of medicinal chemistry : (Print)</title>
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<idno type="ISSN">0022-2623</idno>
</seriesStmt>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adenine derivatives</term>
<term>Adenosine (analogs & derivatives)</term>
<term>Adenosine (chemical synthesis)</term>
<term>Adenosine (pharmacology)</term>
<term>Aminoester</term>
<term>Animals</term>
<term>Anti-HIV Agents (chemical synthesis)</term>
<term>Anti-HIV Agents (pharmacology)</term>
<term>Antiviral</term>
<term>Antiviral Agents (chemical synthesis)</term>
<term>Antiviral Agents (pharmacology)</term>
<term>Carbanucleoside</term>
<term>Cell Line</term>
<term>Chemical synthesis</term>
<term>HIV-1 (drug effects)</term>
<term>HIV-2 (drug effects)</term>
<term>Hepatitis B virus</term>
<term>Hepatitis B virus (drug effects)</term>
<term>Human immunodeficiency virus</term>
<term>Humans</term>
<term>Hydrolysis resistance</term>
<term>In Vitro Techniques</term>
<term>In vitro</term>
<term>Intestinal Mucosa (metabolism)</term>
<term>Liver (metabolism)</term>
<term>Monocyclic compound</term>
<term>Nucleotides (chemical synthesis)</term>
<term>Nucleotides (pharmacology)</term>
<term>Organic amidophosphate</term>
<term>Organophosphorus Compounds (chemical synthesis)</term>
<term>Organophosphorus Compounds (pharmacology)</term>
<term>Prodrug</term>
<term>Purine nucleotide</term>
<term>Structure activity relation</term>
<term>Structure-Activity Relationship</term>
<term>α-Aminoacid</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Adénosine (analogues et dérivés)</term>
<term>Adénosine (pharmacologie)</term>
<term>Adénosine (synthèse chimique)</term>
<term>Agents antiVIH (pharmacologie)</term>
<term>Agents antiVIH (synthèse chimique)</term>
<term>Animaux</term>
<term>Antiviraux (pharmacologie)</term>
<term>Antiviraux (synthèse chimique)</term>
<term>Composés organiques du phosphore (pharmacologie)</term>
<term>Composés organiques du phosphore (synthèse chimique)</term>
<term>Foie (métabolisme)</term>
<term>Humains</term>
<term>Lignée cellulaire</term>
<term>Muqueuse intestinale (métabolisme)</term>
<term>Nucléotides (pharmacologie)</term>
<term>Nucléotides (synthèse chimique)</term>
<term>Relation structure-activité</term>
<term>Techniques in vitro</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ()</term>
<term>VIH-2 (Virus de l'Immunodéficience Humaine de type 2) ()</term>
<term>Virus de l'hépatite B ()</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Adenosine</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Adenosine</term>
<term>Anti-HIV Agents</term>
<term>Antiviral Agents</term>
<term>Nucleotides</term>
<term>Organophosphorus Compounds</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Adenosine</term>
<term>Anti-HIV Agents</term>
<term>Antiviral Agents</term>
<term>Nucleotides</term>
<term>Organophosphorus Compounds</term>
</keywords>
<keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>Adénosine</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>HIV-1</term>
<term>HIV-2</term>
<term>Hepatitis B virus</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Intestinal Mucosa</term>
<term>Liver</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Foie</term>
<term>Muqueuse intestinale</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Adénosine</term>
<term>Agents antiVIH</term>
<term>Antiviraux</term>
<term>Composés organiques du phosphore</term>
<term>Nucléotides</term>
</keywords>
<keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Adénosine</term>
<term>Agents antiVIH</term>
<term>Antiviraux</term>
<term>Composés organiques du phosphore</term>
<term>Nucléotides</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Cell Line</term>
<term>Humans</term>
<term>In Vitro Techniques</term>
<term>Structure-Activity Relationship</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Animaux</term>
<term>Humains</term>
<term>Lignée cellulaire</term>
<term>Phosphoramidate organique</term>
<term>Antiviral</term>
<term>Composé monocyclique</term>
<term>Relation structure activité</term>
<term>Promédicament</term>
<term>Purine nucléotide</term>
<term>Relation structure-activité</term>
<term>Techniques in vitro</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
<term>VIH-2 (Virus de l'Immunodéficience Humaine de type 2)</term>
<term>Virus de l'hépatite B</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>
<term>Carbanucléoside</term>
</keywords>
</textClass>
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</teiHeader>
<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>
</front>
</TEI>
<affiliations><list><country><li>Belgique</li>
<li>Royaume-Uni</li>
<li>États-Unis</li>
</country>
<region><li>Province du Brabant flamand</li>
</region>
<settlement><li>Louvain</li>
</settlement>
<orgName><li>Katholieke Universiteit Leuven</li>
</orgName>
</list>
<tree><country name="Royaume-Uni"><noRegion><name sortKey="Mcguigan, Christopher" sort="Mcguigan, Christopher" uniqKey="Mcguigan C" first="Christopher" last="Mcguigan">Christopher Mcguigan</name>
</noRegion>
<name sortKey="Hassan Abdallah, Alshaimaa" sort="Hassan Abdallah, Alshaimaa" uniqKey="Hassan Abdallah A" first="Alshaimaa" last="Hassan-Abdallah">Alshaimaa Hassan-Abdallah</name>
<name sortKey="Siddiqui, Adam" sort="Siddiqui, Adam" uniqKey="Siddiqui A" first="Adam" last="Siddiqui">Adam Siddiqui</name>
<name sortKey="Srinivasan, Sheila" sort="Srinivasan, Sheila" uniqKey="Srinivasan S" first="Sheila" last="Srinivasan">Sheila Srinivasan</name>
<name sortKey="Yikang Wang" sort="Yikang Wang" uniqKey="Yikang Wang" last="Yikang Wang">YIKANG WANG</name>
</country>
<country name="États-Unis"><noRegion><name sortKey="Daluge, Susan M" sort="Daluge, Susan M" uniqKey="Daluge S" first="Susan M." last="Daluge">Susan M. Daluge</name>
</noRegion>
<name sortKey="Burnette, Thimysta C" sort="Burnette, Thimysta C" uniqKey="Burnette T" first="Thimysta C." last="Burnette">Thimysta C. Burnette</name>
<name sortKey="Condreay, Lynn D" sort="Condreay, Lynn D" uniqKey="Condreay L" first="Lynn D." last="Condreay">Lynn D. Condreay</name>
<name sortKey="Gudmundsson, Kristjan S" sort="Gudmundsson, Kristjan S" uniqKey="Gudmundsson K" first="Kristjan S." last="Gudmundsson">Kristjan S. Gudmundsson</name>
<name sortKey="Hazen, Richard" sort="Hazen, Richard" uniqKey="Hazen R" first="Richard" last="Hazen">Richard Hazen</name>
<name sortKey="Huiqiang Zhou" sort="Huiqiang Zhou" uniqKey="Huiqiang Zhou" last="Huiqiang Zhou">HUIQIANG ZHOU</name>
<name sortKey="Johnson, Lance" sort="Johnson, Lance" uniqKey="Johnson L" first="Lance" last="Johnson">Lance Johnson</name>
<name sortKey="Marr, Harry" sort="Marr, Harry" uniqKey="Marr H" first="Harry" last="Marr">Harry Marr</name>
<name sortKey="Mclean, Ed W" sort="Mclean, Ed W" uniqKey="Mclean E" first="Ed W." last="Mclean">Ed W. Mclean</name>
<name sortKey="Peckham, Jennifer P" sort="Peckham, Jennifer P" uniqKey="Peckham J" first="Jennifer P." last="Peckham">Jennifer P. Peckham</name>
</country>
<country name="Belgique"><region name="Province du Brabant flamand"><name sortKey="Balzarini, Jan" sort="Balzarini, Jan" uniqKey="Balzarini J" first="Jan" last="Balzarini">Jan Balzarini</name>
</region>
</country>
</tree>
</affiliations>
</record>

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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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