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Synthesis and biological activation of an ethylene glycol-linked amino acid conjugate of cyclic cidofovir.


ABSTRACT: Cidofovir (HPMPC) is a broad-spectrum anti-viral agent whose potential, particularly in biodefense scenarios, is limited by its low oral bioavailability. Two prodrugs (3 and 4) created by conjugating ethylene glycol-linked amino acids (L-Val, L-Phe) with the cyclic form of cidofovir (cHPMPC) via a P-O ester bond were synthesized and their pH-dependent stability (3 and 4), potential for in vivo reconversion to drug (3), and oral bioavailability (3) were evaluated. The prodrugs were stable in buffer between pH 3 and 5, but underwent rapid hydrolysis in liver (t(1/2) = 3.7 min), intestinal (t(1/2) = 12.5 min), and Caco-2 cell homogenates (t(1/2) = 20.2 min). In vivo (rat), prodrug 3 was >90% reconverted to cHPMPC. The prodrug was 4x more active than ganciclovir (IC50 value, 0.68 microM vs 3.0 microM) in a HCMV plaque reduction assay. However, its oral bioavailability in a rat model was similar to the parent drug. The contrast between the promising activation properties and unenhanced transport of the prodrug is briefly discussed.

SUBMITTER: Eriksson U 

PROVIDER: S-EPMC1899532 | biostudies-literature | 2007 Feb

REPOSITORIES: biostudies-literature

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Synthesis and biological activation of an ethylene glycol-linked amino acid conjugate of cyclic cidofovir.

Eriksson Ulrika U   Hilfinger John M JM   Kim Jae-Seung JS   Mitchell Stefanie S   Kijek Paul P   Borysko Katherine Z KZ   Breitenbach Julie M JM   Drach John C JC   Kashemirov Boris A BA   McKenna Charles E CE  

Bioorganic & medicinal chemistry letters 20061110 3


Cidofovir (HPMPC) is a broad-spectrum anti-viral agent whose potential, particularly in biodefense scenarios, is limited by its low oral bioavailability. Two prodrugs (3 and 4) created by conjugating ethylene glycol-linked amino acids (L-Val, L-Phe) with the cyclic form of cidofovir (cHPMPC) via a P-O ester bond were synthesized and their pH-dependent stability (3 and 4), potential for in vivo reconversion to drug (3), and oral bioavailability (3) were evaluated. The prodrugs were stable in buff  ...[more]

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