Serine peptide phosphoester prodrugs of cyclic cidofovir: synthesis, transport, and antiviral activity.

Abstract

Cidofovir (HPMPC, 1), a broad-spectrum antiviral agent, is currently used to treat AIDS-related human cytomegalovirus (HCMV) retinitis and has recognized therapeutic potential for orthopox virus infections, but is limited by its low oral bioavailability. Cyclic cidofovir (2) displays decreased nephrotoxicity compared to 1, while also exhibiting potent antiviral activity. Here we describe in detail the synthesis and evaluation as prodrugs of four cHPMPC dipeptide conjugates in which the free POH of 2 is esterified by the Ser side chain alcohol group of an X-L-Ser(OMe) dipeptide: 3 (X=L-Ala), 4 (X=L-Val), 5 (X=L-Leu), and 6 (X=L-Phe). Perfusion studies in the rat establish that the mesenteric permeability to 4 is more than 20-fold greater than to 1, and the bioavailability of 4 is increased 6-fold relative to 1 in an in vivo murine model. In gastrointestinal and liver homogenates, the cHPMPC prodrugs are rapidly hydrolyzed to 2. Prodrugs 3, 4, and 5 are nontoxic at 100 microM in HFF and KB cells and in cell-based plaque reduction assays had IC 50 values of 0.1-0.5 microM for HCMV and 10 microM for two orthopox viruses (vaccinia and cowpox). The enhanced transport properties of 3-6, conferred by incorporation of a biologically benign dipeptide moiety, and the facile cleavage of the Ser-O-P linkage suggest that these prodrugs represent a promising new approach to enhancing the bioavailability of 2.

• Authors: Ulrika Eriksson, Larryn W Peterson, Boris A Kashemirov, John M Hilfinger, John C Drach, Katherine Z Borysko, Julie M Breitenbach, Jae Seung Kim, Stefanie Mitchell, Paul Kijek, Charles E McKenna
• Journal: Molecular pharmaceutics (Mol Pharm) 2008 Jul-Aug Vol. 5 Issue 4 Pg. 598-609 ISSN: 1543-8384 [Print] United States
• PMID: 18481868 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antiviral Agents
• Organophosphonates
• Peptides
• Prodrugs
• Serine
• Cytosine
• Cidofovir

Topics

• Animals
• Antiviral Agents (blood, chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cidofovir
• Cytomegalovirus (drug effects)
• Cytosine (analogs & derivatives, blood, chemical synthesis, chemistry, pharmacology)
• Esterification
• Humans
• Hydrolysis
• Intestinal Mucosa (metabolism)
• Male
• Mice
• Models, Molecular
• Molecular Structure
• Organophosphonates (blood, chemical synthesis, chemistry, pharmacology)
• Peptides (chemistry)
• Prodrugs (chemical synthesis, chemistry, metabolism, pharmacology)
• Rats
• Serine (chemistry)
• Static Electricity