Four newly synthesized ether lipid esters of cidofovir (CDV), hexadecyloxypropyl-CDV (HDP-CDV), octadecyloxyethyl-CDV (ODE-CDV), oleyloxypropyl-CDV (OLP-CDV), and oleyloxyethyl-CDV (OLE-CDV), were found to have enhanced activities against vaccinia virus (VV) and cowpox virus (CV) in vitro compared to those of CDV. The compounds were administered orally and were evaluated for their efficacies against lethal CV or VV infections in mice. HDP-CDV, ODE-CDV, and OLE-CDV were effective at preventing mortality from CV infection when treatments were initiated 24 h after viral inoculation, but only HDP-CDV and ODE-CDV maintained efficacy when treatments were initiated as late as 72 h postinfection. Oral pretreatment with HDP-CDV and ODE-CDV were also effective when they were given 5, 3, or 1 day prior to inoculation with CV, even when each compound was administered as a single dose. Both HDP-CDV and ODE-CDV were also effective against VV infections when they were administered orally 24 or 48 h after infection. In animals treated with HDP-CDV or ODE-CDV, the titers of both CV and VV in the liver, spleen, and kidney were reduced 3 to 7 log 10 . In contrast, virus replication in the lungs was not significantly reduced. These data indicate that HDP-CDV or ODE-CDV given orally is as effective as CDV given parenterally for the treatment of experimental CV and VV infections and suggest that these compounds may be useful for the treatment of orthopoxvirus infections in humans.Orthopoxvirus diseases continue to pose challenges to researchers preparing for a bioterrorist release of biological weapons of mass destruction. Rapid diagnostics for smallpox and the development of effective antiviral chemotherapies are two essential components for national preparedness (16,17). The in vitro and in vivo activities of cidofovir (CDV) against orthopoxviruses are well documented (3,4,8,9,15,18,(20)(21)(22)(23)(24); however, its usefulness is limited by the requirement for intravenous administration and dose-limiting nephrotoxicity (14). Orally active compounds with prolonged therapeutic levels in blood and reduced toxicity would be desirable for mass distribution in response to an actual release of the smallpox virus.Results from earlier studies with acyclovir and ganciclovir showed that alkoxyalkyl esters of the monophosphates of ganciclovir or acyclovir have improved oral bioavailabilities compared to those of the unmodified parent compounds and are effective against cytomegalovirus and herpes simplex virus infections (13). To improve the oral bioavailability of CDV, a novel series of analogs were synthesized by esterification with long-chain alkoxyalkanols. Hexadecyloxypropyl-CDV (HDP-CDV) and octadecyloxyethyl-CDV (ODE-CDV) were synthesized and evaluated in vitro for their efficacies against cowpox virus (CV) and vaccinia virus (VV) infections. As reported previously (15), HDP-CDV had 50% effective concentrations (EC 50 s) of 0.52 and 0.62 M against CV and VV, respectively, whereas the EC 50 s of CDV were 42 and 31 M, respectively. ODE-CD...

Orthopoxviruses, including variola and monkeypox, pose risks to human health through natural transmission or potential bioterrorist activities. Since vaccination has not recently been utilized for control of these infections, there is renewed effort in the development of antiviral agents not only for postexposure smallpox therapy but also for treatment of adverse reactions following vaccination. The objectives of this study were to expand on the results of others that cidofovir (CDV) is effective in mice inoculated with cowpox virus (CV) or vaccinia virus (VV) and to document the efficacy of single and interval dosing beginning prior to or after infection, particularly including evaluations using suboptimal doses of CDV. We utilized BALB/c or SCID mice inoculated with CV or VV as models for systemic poxvirus infections. BALB/c mice were inoculated intranasally with CV or VV and treated with CDV prior to or after virus inoculation. CDV, at concentrations as low as 0.7 to 6.7 mg/kg of body weight/day for 5 days, conferred significant protection when treatment was initiated as late as 72 to 96 h postinfection. A single-dose pretreatment or posttreatment with CDV at 3 to 100 mg/kg was effective when given as early as 5 days prior to infection or as late as 3 days after infection with either VV or CV. Interval treatments given every third day beginning 72 h postinfection using 6.7 or 2 mg of CDV/kg also proved effective against CV infections. When SCID mice were inoculated intraperitoneally with CV or VV and treated for 7 to 30 days with CDV, all the mice eventually died during or after cessation of treatment; however, significant delays in time to death and reduction of virus replication in organs occurred in most treated groups, and no resistance to CDV was detected.

To improve the oral bioavailability of cidofovir (CDV), a series of ether lipid ester prodrugs were synthesized and evaluated for activity against murine cytomegalovirus (MCMV) infection. Four of these analogs, hexadecyloxypropyl (HDP)-CDV, octadecyloxyethyl (ODE)-CDV, oleyloxyethyl (OLE)-CDV, and oleyloxypropyl (OLP)-CDV, were found to have greater activity than CDV against human CMV and MCMV in vitro. The efficacy of oral treatment with these compounds against MCMV infections in BALB/c mice was then determined. Treatment with HDP-CDV, ODE-CDV, OLE-CDV, or OLP-CDV at 2.0 to 6.7 mg/kg of body weight provided significant protection when daily treatments were initiated 24 to 48 h after viral inoculation. Additionally, HDP-CDV or ODE-CDV administered twice weekly or as a single dose of 1.25 to 10 mg/kg was effective in reducing mortality when treatment was initiated at 24 h, 48 h, or, in some cases, 72 h after viral inoculation. In animals treated daily with HDP-CDV or ODE-CDV, virus titers in lung, liver, spleen, kidney, pancreas, salivary gland, and blood were reduced 3 to 5 log 10 -fold, which was comparable to CDV given intraperitoneally. These results indicated that HDP-CDV or ODE-CDV given orally was as effective as parenteral CDV for the treatment of experimental MCMV infection and suggest that further evaluation for use in CMV infections in humans is warranted.Cytomegalovirus (CMV) infections continue to be a major cause of morbidity in solid organ (35) and stem cell recipients (10, 12). The management of these infections has generally been through the use of prophylaxis or prevention therapy with ganciclovir (GCV) (15) or acyclovir (ACV) (3); however, the lack of activity when they are administered orally has limited their use. While the availability of oral ACV (valacyclovir) (29) and GCV (valganciclovir) (32) has broadened the range of choices for treatment or prevention of CMV infections, a number of problems, including neutropenia, nephrotoxicity, and the selection of drug-resistant mutants, remain (6,8,13,27,28,39). Cidofovir (CDV) has greater activity against CMV in vitro and in vivo than any of the other licensed drugs (16,22,23,40) and retains activity against many of the GCV-and foscarnet (PFA)-resistant mutants (4). However, CDV does not have activity when given orally and may also cause severe nephrotoxicity (25, 37). One approach to overcoming the limitation of the lack of activity of CDV given orally has been to prepare prodrugs of CDV that are bioavailable when administered orally. The synthesis of alkylglycerol phosphate or alkylpropyl phosphate esters of ACV, penciclovir, or GCV provided prodrugs that were active when given orally in animal models of herpes simplex virus, murine CMV (MCMV), and woodchuck hepatitis virus infections (17-19). Using similar methodology, a series of ether lipid ester analogs of CDV or cyclic CDV were prepared and evaluated for activity against CMV and poxviruses (4, 24).It has been reported previously that this series of ether lipid ester prodrugs of CDV, partic...

CMX001, an orally active lipid conjugate of cidofovir (CDV), is 50 times more active in vitro against herpes simplex virus (HSV) replication than acyclovir (ACV) or CDV. These studies compared the efficacy of CMX001 to ACV in BALB/c mice inoculated intranasally with HSV types 1 or 2. CMX001 was effective in reducing mortality using doses of 5 to 1.25 mg/kg administered orally once daily even when treatments were delayed 48-72 h post viral inoculation. Organ samples from mice treated with CMX001 had titers three to five log10 pfu/gram of tissue lower than samples from ACV treated mice, including five different regions of the brain. Detectable concentrations of drug-related radioactivity were documented in the central nervous system of mice following oral administration of 14C-CMX001. These studies indicated that CMX001 penetrates the blood brain barrier, is a potent inhibitor of HSV replication in disseminated and CNS infections and is superior to ACV.

No abstract