VOL. 46, 2002
INHIBITION OF POXVIRUS BY CIDOFOVIR ANALOGS
995
vious experience utilizing this technology for improving the
activity of nucleosides such as acyclovir, ganciclovir, penciclo-
vir, and azidothymidine (14–16).
4. Collins, D. J., D. C. Quenelle, and E. R. Kern. 2001. Systemic and cutaneous
infections of mice with vaccinia and cowpox viruses and efficacy of cidofovir.
Antiviral Res. 50:A70.
5. Cundy, K. C., A. M. Bidgood, G. Lynch, J.-P. Shaw, L. Griffin, and W. A. Lee.
1
996. Pharmacokinetics, bioavailability, metabolism and tissue distribution
Earlier studies indicated that 1-0-hexadecylpropanediol-P-
ganciclovir provided greater oral bioavailability in mice than
ganciclovir and provided good oral activity against herpes sim-
plex virus type 1 and murine CMV infections in mice (16). In
addition, it was demonstrated that oral 1-0-hexadecyl-pro-
panediol-P-acyclovir at 20 mg/kg of body weight daily lowered
woodchuck hepatitis virus DNA levels by nearly 2 log units
after 4 weeks of administration. Acyclovir at a fivefold-higher
molar dose was not effective (15). To determine if a similar
strategy could be employed with phosphonate nucleotides, we
synthesized the 1-0-hexadecylpropanediol and the 1-0-octade-
cylethanediol esters of CDV and cCDV. As demonstrated in
these studies, the new analogs were not only active against VV
and CV replication in vitro, they were considerably more active
than the parent compounds. Although there are no published
reports of the efficacy of CDV for experimental variola virus
infections, it was recently determined that CDV and cCDV
inhibited the replication of variola virus strain Bangladesh in
vitro at levels of about 25 M. Importantly, the alkoxyalkyl
analogs of CDV and cCDV were Ͼ100-fold more active than
the unmodified compounds (John Huggins, unpublished re-
sults). The mechanism of action through which these analogs
exhibit greater antiviral activity and selectivity is currently not
well understood. However, preliminary studies using radiola-
of cidofovir (HPMPC) and cyclic HPMPC in rats. Drug Metab. Disp. 24:
45–752.
6. Cundy, K. C., Z.-H. Li, M. J. M. Hitchcock, and W. A. Lee. 1996. Pharma-
cokinetics of cidofovir in monkeys. Evidence for a prolonged elimination
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490.
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and A. Hol ´y . 1987. Antiviral activity of phosphonylmethoxyalkyl derivatives
of purine and pyrimidines. Antiviral Res. 8:261–272.
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7
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8
1
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1
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3. Hitchcock, M. J. M., H. S. Jaffe, J. C. Martin, and R. J. Stagg. 1996.
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4. Hostetler, K. Y., J. R. Beadle, G. D. Kini, M. F. Gardner, K. N. Wright, T.-H.
Wu, and B. E. Korba. 1997. Enhanced oral absorption and antiviral activity
of 1-O-octadecyl-sn-glycero-3-phospho-acyclovir in hepatitis B virus infec-
tion, in vitro. Biochem. Pharmacol. 53:1815–1822.
5. Hostetler, K. Y., J. R. Beadle, W. E. Hornbuckle, C. A. Bellezza, I. A.
Tochkov, P. J. Cote, J. L. Gerin, B. E. Korba, and B. C. Tennant. 2000.
Antiviral activities of oral 1-O-hexadecylpropanediol-3-phosphoacyclovir
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1
1
4
beled HDP-[ C]CDV, have indicated that cellular uptake of
1
4
the drug is many-fold greater than that observed with [ C]
CDV in human lung fibroblast cells (unpublished observations).
In summary, we have synthesized several alkoxyalkyl esters
of CDV and cCDV which exhibited greatly enhanced antiviral
activity and selectivity against two members of the orthopox-
virus group in tissue culture cells. Based upon our previous
experiments with analogs of this type, we anticipate that these
new compounds will exhibit significant oral activity compared
with the parent compounds, and they now need to be evaluated
in animal model systems for oral pharmacokinetics, toxicity,
and antiviral efficacy against members of the orthopoxviruses.
1
6. Hostetler, K. Y., R. J. Rybak, J. R. Beadle, M. F. Gardner, K. A. Aldern,
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3
-phospho-penciclovir in cytomegalovirus and herpes simplex virus infec-
tions. Antivir. Chem. Chemother. 12:61–70.
17. Hutin, Y. J., R. J. Williams, P. Malfait, R. Pebody, V. N. Loparev, S. L. Ropp,
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2
1
997. HPMPC (cidofovir), PMEA (adefovir) and related acyclic nucleoside
phosphonate analogues: a review of their pharmacology and clinical poten-
tial in the treatment of viral infections. Antivir. Chem. Chemother. 8:1–23.
1. Nettleton, P. F., J. A. Gilray, H. W. Reid, and A. A. Mercer. 2000. Parapox-
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ACKNOWLEDGMENTS
2
2
These studies were supported in part by NIH grant EY11832 from
the National Eye Institute to the University of California, San Diego
K.Y.H.), and contract NO1-AI-85347 from the Antiviral Research
Branch, NIAID, NIH, to the University of Alabama at Birmingham
E.R.K.).
(
(
2
3. Neyts, J., and E. De Clercq. 2001. Efficacy of 2-amino-7-(1,3-dihydroxy-2-
propoxymethyl) purine for treatment of vaccinia virus (orthopoxvirus) infec-
tions in mice. Antimicrob. Agents Chemother. 45:84–87.
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