Although the acyclic nucleoside phosphonates cidofovir, adefovir and tenofovir are approved for treating human cytomegalovirus, hepatitis B and HIV infections, respectively, their utility is limited by low oral bioavailability, renal toxicity and poor cell penetration. Research over the past decade has shown that these undesirable features can be eliminated by esterifying the compounds with an alkoxyalkyl group, in effect disguising them as lysophospholipids. In this modified form, the drugs are readily taken up in the gastrointestinal tract and have a prolonged circulation time in plasma. The active metabolite also has a long half life within cells, permitting infrequent dosing. Because these modified drugs are not recognized by the transport mechanisms that cause the accumulation of acyclic nucleoside phosphonates in renal tubular cells, they lack nephrotoxicity. Alkoxyalkyl esterification also markedly increases the in vitro antiviral activity of acyclic nucleoside phosphonates by improving their delivery into cells. For example, an alkoxyalkyl ester of cyclic-cidofovir, a less soluble compound, retains antiviral activity for 3 months following a single intravitreal injection. Two of these novel compounds, hexadecyloxypropyl-cidofovir (CMX-001) and hexadecyloxypropyl-tenofovir (CMX-157) are now in clinical development. This article focuses on the hexadecyloxypropyl and octadecyloxyethyl esters of cidofovir and (S)-HPMPA, describing their synthesis and the evaluation of their in vitro and in vivo activity against a range of orthopoxviruses, herpesviruses, adenoviruses and other double-stranded DNA viruses. The extension to other nucleoside phosphonate antivirals is highlighted, demonstrating that this novel approach can markedly improve the medicinal properties of these drugs.

The nucleotide phosphonates cidofovir (CDV) and cyclic cidofovir (cCDV) are potent antiviral compounds when administered parenterally but are not well absorbed orally. These compounds have been reported to have activity against orthopoxvirus replication in vitro and in animal models when administered parenterally or by aerosol. To obtain better oral activity, we synthesized a novel series of analogs of CDV and cCDV by esterification with two long-chain alkoxyalkanols, 3-hexadecyloxy-1-propanol (HDP-CDV; HDP-cCDV) or 3-octadecyloxy-1-ethanol (ODE-CDV; ODE-cCDV). Their activities were evaluated and compared with those of CDV and cCDV in human foreskin fibroblast (HFF) cells infected with vaccinia virus (VV) or cowpox virus (CV) using a plaque reduction assay. The 50% effective concentrations (EC 50 s) against VV in HFF cells for CDV and cCDV were 46.2 and 50.6 M compared with 0.84 and 3.8 M for HDP-CDV and HDP-cCDV, respectively. The EC 50 s for ODE-CDV and ODE-cCDV were 0.20 and 1.1 M, respectively. The HDP analogs were 57-and 13-fold more active than the parent nucleotides, whereas the ODE analogs were 231-and 46-fold more active than the unmodified CDV and cCDV. Similar results were obtained using CV. Cytotoxicity studies indicated that although the analogs were more toxic than the parent nucleotides, the selective index was increased by 4-to 13-fold. These results indicate that the alkoxyalkyl esters of CDV and cCDV have enhanced activity in vitro and need to be evaluated for their oral absorption and efficacy in animal models.Since smallpox was considered to be eradicated in the 1970s, there has been little activity in developing antiviral agents for this infection (10). However, in view of the threat of bioterrorism using variola virus or other orthopoxviruses, such as monkeypox virus, which continues to infect humans in central Africa, there is a renewed need to develop antiviral agents for these viruses (3,11,12,17,18,24). For many years the laboratory of Erik De Clercq and other laboratories have utilized in vitro and animal models with vaccinia virus (VV) to screen potential antiviral compounds for activity against poxviruses and have identified a few active agents. Methisazone, ribavirin, idoxuridine, interferon, interferon inducers, S2442, and cidofovir (CDV) have been identified as potential therapies for these infections (7,8,9,20,21,23). Of particular interest was the finding that CDV and other phosphonate nucleotides were inhibitory to this group of viruses, including VV, cowpox virus (CV), camelpox virus, monkeypox virus, and variola virus (J. W. Huggins, personal communication). The activity of CDV is of particular interest as a potential therapy for smallpox, as it is already approved for the treatment of cytomegalovirus (CMV) infections and has been shown to have activity in animal models using VV and CV (2,22,26,27). We have confirmed the activity of CDV against both VV and CV in tissue culture and animal models in our laboratory (4) and report here the results of some new alkoxyalkyl esters o...

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