Abstract
Eight novel single amino acid (6-11) and dipeptide (12, 13) tyrosine P-O esters of cyclic cidofovir ((S)-cHPMPC, 4) and its cyclic adenine analogue ((S)-cHPMPA, 3) were synthesized and evaluated as prodrugs. In vitro IC(50) values for the prodrugs (<0.1-50 μM) vs vaccinia, cowpox, human cytomegalovirus, and herpes simplex type 1 virus were compared to those for the parent drugs ((S)-HPMPC, 2; (S)-HPMPA, 1; IC(50) 0.3-35 μM); there was no cytoxicity with KB or HFF cells at ≤100 μM. The prodrugs exhibited a wide range of half-lives in rat intestinal homogenate at pH 6.5 (<30-1732 min) with differences of 3-10× between phostonate diastereomers. The tyrosine alkylamide derivatives of 3 and 4 were the most stable. (l)-Tyr-NH-i-Bu cHPMPA (11) was converted in rat or mouse plasma solely to two active metabolites and had significantly enhanced oral bioavailability vs parent drug 1 in a mouse model (39% vs <5%).
© 2011 American Chemical Society
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenine / analogs & derivatives*
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Adenine / chemistry
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Adenine / pharmacokinetics
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Adenine / pharmacology
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Animals
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacokinetics
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Antiviral Agents / pharmacology
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Area Under Curve
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Biological Availability
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Cell Line, Tumor
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Cell Survival / drug effects
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Cells, Cultured
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Cidofovir
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Cowpox virus / drug effects
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Cytomegalovirus / drug effects
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Cytosine / analogs & derivatives*
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Cytosine / chemistry
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Cytosine / pharmacokinetics
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Cytosine / pharmacology
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Herpesvirus 1, Human / genetics
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Humans
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Inhibitory Concentration 50
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Mice
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Models, Chemical
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Molecular Structure
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Organophosphonates / chemistry*
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Organophosphonates / pharmacokinetics
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Organophosphonates / pharmacology
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Prodrugs / chemistry*
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Prodrugs / pharmacokinetics
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Prodrugs / pharmacology
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Rats
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Tyrosine / chemistry*
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Vaccinia virus / drug effects
Substances
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Antiviral Agents
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Organophosphonates
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Prodrugs
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Tyrosine
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Cytosine
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9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine
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Adenine
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Cidofovir