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    J Med Chem. 2011 Aug 25;54(16):5680-93. Epub 2011 Aug 3.

    Tyrosine-based 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine and -adenine ((S)-HPMPC and (S)-HPMPA) prodrugs: synthesis, stability, antiviral activity, and in vivo transport studies.

    Zakharova VM, Serpi M, Krylov IS, Peterson LW, Breitenbach JM, Borysko KZ, Drach JC, Collins M, Hilfinger JM, Kashemirov BA, McKenna CE.

    Source

    Department of Chemistry, University of Southern California, Los Angeles, California 90089-0744, USA.

    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

    PMID:
    21812420
    [PubMed - indexed for MEDLINE]
    PMCID:
    PMC3166236
    [Available on 2012/8/25]

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