Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives
Identifieur interne : 000608 ( PascalFrancis/Curation ); précédent : 000607; suivant : 000609Application 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.
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 :
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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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives</title>
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<sZ>14 aut.</sZ>
<sZ>15 aut.</sZ>
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<country>États-Unis</country>
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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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<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
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<sZ>10 aut.</sZ>
<sZ>11 aut.</sZ>
<sZ>12 aut.</sZ>
<sZ>13 aut.</sZ>
<sZ>14 aut.</sZ>
<sZ>15 aut.</sZ>
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<country>États-Unis</country>
</affiliation>
</author>
<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>
<s2>Research Triangle Park, North Carolina 27709</s2>
<s3>USA</s3>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
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<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
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<sZ>12 aut.</sZ>
<sZ>13 aut.</sZ>
<sZ>14 aut.</sZ>
<sZ>15 aut.</sZ>
</inist:fA14>
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</affiliation>
</author>
<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>
<s2>Research Triangle Park, North Carolina 27709</s2>
<s3>USA</s3>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>11 aut.</sZ>
<sZ>12 aut.</sZ>
<sZ>13 aut.</sZ>
<sZ>14 aut.</sZ>
<sZ>15 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<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>
<s3>USA</s3>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>11 aut.</sZ>
<sZ>12 aut.</sZ>
<sZ>13 aut.</sZ>
<sZ>14 aut.</sZ>
<sZ>15 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Balzarini, Jan" sort="Balzarini, Jan" uniqKey="Balzarini J" first="Jan" last="Balzarini">Jan Balzarini</name>
<affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Rega Institute for Medical Research, Katholieke Universiteit Leuven</s1>
<s2>3000 Leuven</s2>
<s3>BEL</s3>
<sZ>16 aut.</sZ>
</inist:fA14>
<country>Belgique</country>
</affiliation>
</author>
</analytic>
<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>
</imprint>
</series>
</biblStruct>
</sourceDesc>
<seriesStmt><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>
</seriesStmt>
</fileDesc>
<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>
</keywords>
<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>
<term>Carbanucléoside</term>
</keywords>
</textClass>
</profileDesc>
</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>
<inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0022-2623</s0>
</fA01>
<fA02 i1="01"><s0>JMCMAR</s0>
</fA02>
<fA03 i2="1"><s0>J. med. chem. : (Print)</s0>
</fA03>
<fA05><s2>49</s2>
</fA05>
<fA06><s2>24</s2>
</fA06>
<fA08 i1="01" i2="1" l="ENG"><s1>Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives</s1>
</fA08>
<fA11 i1="01" i2="1"><s1>MCGUIGAN (Christopher)</s1>
</fA11>
<fA11 i1="02" i2="1"><s1>HASSAN-ABDALLAH (Alshaimaa)</s1>
</fA11>
<fA11 i1="03" i2="1"><s1>SRINIVASAN (Sheila)</s1>
</fA11>
<fA11 i1="04" i2="1"><s1>YIKANG WANG</s1>
</fA11>
<fA11 i1="05" i2="1"><s1>SIDDIQUI (Adam)</s1>
</fA11>
<fA11 i1="06" i2="1"><s1>DALUGE (Susan M.)</s1>
</fA11>
<fA11 i1="07" i2="1"><s1>GUDMUNDSSON (Kristjan S.)</s1>
</fA11>
<fA11 i1="08" i2="1"><s1>HUIQIANG ZHOU</s1>
</fA11>
<fA11 i1="09" i2="1"><s1>MCLEAN (Ed W.)</s1>
</fA11>
<fA11 i1="10" i2="1"><s1>PECKHAM (Jennifer P.)</s1>
</fA11>
<fA11 i1="11" i2="1"><s1>BURNETTE (Thimysta C.)</s1>
</fA11>
<fA11 i1="12" i2="1"><s1>MARR (Harry)</s1>
</fA11>
<fA11 i1="13" i2="1"><s1>HAZEN (Richard)</s1>
</fA11>
<fA11 i1="14" i2="1"><s1>CONDREAY (Lynn D.)</s1>
</fA11>
<fA11 i1="15" i2="1"><s1>JOHNSON (Lance)</s1>
</fA11>
<fA11 i1="16" i2="1"><s1>BALZARINI (Jan)</s1>
</fA11>
<fA14 i1="01"><s1>Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue</s1>
<s2>Cardiff CF10 3XF</s2>
<s3>GBR</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>4 aut.</sZ>
<sZ>5 aut.</sZ>
</fA14>
<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>
<s3>USA</s3>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>11 aut.</sZ>
<sZ>12 aut.</sZ>
<sZ>13 aut.</sZ>
<sZ>14 aut.</sZ>
<sZ>15 aut.</sZ>
</fA14>
<fA14 i1="03"><s1>Rega Institute for Medical Research, Katholieke Universiteit Leuven</s1>
<s2>3000 Leuven</s2>
<s3>BEL</s3>
<sZ>16 aut.</sZ>
</fA14>
<fA20><s1>7215-7226</s1>
</fA20>
<fA21><s1>2006</s1>
</fA21>
<fA23 i1="01"><s0>ENG</s0>
</fA23>
<fA43 i1="01"><s1>INIST</s1>
<s2>9165</s2>
<s5>354000145048240300</s5>
</fA43>
<fA44><s0>0000</s0>
<s1>© 2007 INIST-CNRS. All rights reserved.</s1>
</fA44>
<fA45><s0>44 ref.</s0>
</fA45>
<fA47 i1="01" i2="1"><s0>07-0201590</s0>
</fA47>
<fA60><s1>P</s1>
</fA60>
<fA61><s0>A</s0>
</fA61>
<fA64 i1="01" i2="1"><s0>Journal of medicinal chemistry : (Print)</s0>
</fA64>
<fA66 i1="01"><s0>USA</s0>
</fA66>
<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>
</fC01>
<fC02 i1="01" i2="X"><s0>002B02S05</s0>
</fC02>
<fC03 i1="01" i2="X" l="FRE"><s0>Phosphoramidate organique</s0>
<s5>01</s5>
</fC03>
<fC03 i1="01" i2="X" l="ENG"><s0>Organic amidophosphate</s0>
<s5>01</s5>
</fC03>
<fC03 i1="01" i2="X" l="SPA"><s0>Fosforamidato orgánico</s0>
<s5>01</s5>
</fC03>
<fC03 i1="02" i2="X" l="FRE"><s0>Antiviral</s0>
<s5>02</s5>
</fC03>
<fC03 i1="02" i2="X" l="ENG"><s0>Antiviral</s0>
<s5>02</s5>
</fC03>
<fC03 i1="02" i2="X" l="SPA"><s0>Antiviral</s0>
<s5>02</s5>
</fC03>
<fC03 i1="03" i2="X" l="FRE"><s0>Composé monocyclique</s0>
<s5>03</s5>
</fC03>
<fC03 i1="03" i2="X" l="ENG"><s0>Monocyclic compound</s0>
<s5>03</s5>
</fC03>
<fC03 i1="03" i2="X" l="SPA"><s0>Compuesto monocíclico</s0>
<s5>03</s5>
</fC03>
<fC03 i1="04" i2="X" l="FRE"><s0>Relation structure activité</s0>
<s5>04</s5>
</fC03>
<fC03 i1="04" i2="X" l="ENG"><s0>Structure activity relation</s0>
<s5>04</s5>
</fC03>
<fC03 i1="04" i2="X" l="SPA"><s0>Relación estructura actividad</s0>
<s5>04</s5>
</fC03>
<fC03 i1="05" i2="X" l="FRE"><s0>Promédicament</s0>
<s5>05</s5>
</fC03>
<fC03 i1="05" i2="X" l="ENG"><s0>Prodrug</s0>
<s5>05</s5>
</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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