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

• Published in: Bioorganic & medicinal chemistry letters 2007-02, Vol.17 (3), p.583-586
• Main Authors: Eriksson, Ulrika, Hilfinger, John M., Kim, Jae-Seung, Mitchell, Stefanie, Kijek, Paul, Borysko, Katherine Z., Breitenbach, Julie M., Drach, John C., Kashemirov, Boris A., McKenna, Charles E.
• Format: Article
• Language: English
• Subjects: Amino Acids - chemistry; Animals; Anti-viral; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - metabolism; Antiviral Agents - pharmacokinetics; Biodefense; Biological and medical sciences; Biological Availability; Biotransformation; Cell Survival - drug effects; cHPMPC; Cytosine - analogs & derivatives; Cytosine - chemical synthesis; Cytosine - metabolism; Cytosine - pharmacokinetics; Ethylene Glycol - chemistry; Half-Life; HCMV; HPMPC; Human cytomegalovirus; Humans; Hydrolysis; KB Cells; Magnetic Resonance Spectroscopy; Medical sciences; Organophosphonates - chemical synthesis; Organophosphonates - metabolism; Organophosphonates - pharmacokinetics; Peptide Transporter 1; Pharmacology. Drug treatments; Phenylalanine - chemistry; Prodrug; Prodrugs - chemical synthesis; Prodrugs - metabolism; Rats; Symporters - metabolism; Valine - chemistry; Viral Plaque Assay
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.11.012

The synthesis, biological activation and oral bioavailability of an ethylene glycol-linked L-valyl ester conjugate of cyclic cidofovir ( 3) is reported. 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 4× more active than ganciclovir (IC 50 value, 0.68 μM vs 3.0 μM) 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.