Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives.
Identifieur interne : 001774 ( Ncbi/Curation ); précédent : 001773; suivant : 001775Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives.
Auteurs : Christopher Mcguigan [Royaume-Uni] ; Alshaimaa Hassan-Abdallah ; Sheila Srinivasan ; Yikang Wang ; Adam Siddiqui ; Susan M. Daluge ; Kristjan S. Gudmundsson ; Huiqiang Zhou ; Ed W. Mclean ; Jennifer P. Peckham ; Thimysta C. Burnette ; Harry Marr ; Richard Hazen ; Lynn D. Condreay ; Lance Johnson ; Jan BalzariniSource :
- Journal of medicinal chemistry [ 0022-2623 ] ; 2006.
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.
- Animaux, Humains, Lignée cellulaire, 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.
English descriptors
- KwdEn :
- Adenosine (analogs & derivatives), Adenosine (chemical synthesis), Adenosine (pharmacology), Animals, Anti-HIV Agents (chemical synthesis), Anti-HIV Agents (pharmacology), Antiviral Agents (chemical synthesis), Antiviral Agents (pharmacology), Cell Line, HIV-1 (drug effects), HIV-2 (drug effects), Hepatitis B virus (drug effects), Humans, In Vitro Techniques, Intestinal Mucosa (metabolism), Liver (metabolism), Nucleotides (chemical synthesis), Nucleotides (pharmacology), Organophosphorus Compounds (chemical synthesis), Organophosphorus Compounds (pharmacology), Structure-Activity Relationship.
- 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.
DOI: 10.1021/jm060776w
PubMed: 17125274
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pubmed:17125274Le document en format XML
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<author><name sortKey="Hassan Abdallah, Alshaimaa" sort="Hassan Abdallah, Alshaimaa" uniqKey="Hassan Abdallah A" first="Alshaimaa" last="Hassan-Abdallah">Alshaimaa Hassan-Abdallah</name>
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<term>Adenosine (chemical synthesis)</term>
<term>Adenosine (pharmacology)</term>
<term>Animals</term>
<term>Anti-HIV Agents (chemical synthesis)</term>
<term>Anti-HIV Agents (pharmacology)</term>
<term>Antiviral Agents (chemical synthesis)</term>
<term>Antiviral Agents (pharmacology)</term>
<term>Cell Line</term>
<term>HIV-1 (drug effects)</term>
<term>HIV-2 (drug effects)</term>
<term>Hepatitis B virus (drug effects)</term>
<term>Humans</term>
<term>In Vitro Techniques</term>
<term>Intestinal Mucosa (metabolism)</term>
<term>Liver (metabolism)</term>
<term>Nucleotides (chemical synthesis)</term>
<term>Nucleotides (pharmacology)</term>
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<term>Organophosphorus Compounds (pharmacology)</term>
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<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>
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<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>
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<term>Organophosphorus Compounds</term>
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<term>Nucléotides</term>
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<term>Humains</term>
<term>Lignée cellulaire</term>
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<term>Techniques in vitro</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>
</front>
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