Synthesis and biological activation of an ethylene glycol-linked amino acid conjugate of cyclic cidofovir.
Basic Information
ID: ALA1146335
Journal: Bioorg Med Chem Lett
Title: Synthesis and biological activation of an ethylene glycol-linked amino acid conjugate of cyclic cidofovir.
Authors: Eriksson U, Hilfinger JM, Kim JS, Mitchell S, Kijek P, Borysko KZ, Breitenbach JM, Drach JC, Kashemirov BA, McKenna CE.
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.
CiteXplore: 17161946
DOI: 10.1016/j.bmcl.2006.11.012
Patent ID: ┄