The acyclic
purine nucleoside analog, 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]
purine (
S2242) and its orally active diacetate
ester prodrug (HOE961) were reported to be potent inhibitors of vaccinia virus replication in cell culture and in infected mice. These compounds were evaluated further, using
infections with the related cowpox virus. Against a wild-type (WT) cowpox virus strain in mouse C127I cell culture, 50% effective concentrations (EC(50), determined by plaque reduction assays) of
S2242 and
cidofovir (a positive control) were 3.5 and 1.0 microM, respectively. EC(50) values obtained against a
cidofovir-resistant strain of the virus were 33 and 230 microM, respectively. Compounds were at least ten-fold less potent against WT virus in Vero cells than C127I cells.
S2242 and
cidofovir were 50% inhibitory to the proliferation of uninfected C127I cells at 340 and 180 microM, respectively, but neither compound inhibited Vero cell growth at 1000 microM. Mice were lethally infected with cowpox virus by intranasal inoculation, followed 24 h later by
antiviral treatment for 5 consecutive days. Once or twice daily intraperitoneal (i.p.) treatments with either
S2242 or HOE961 at 100 mg/kg per day resulted in > or = 70 survival compared with no survivors in the placebo group. Lower doses of these compounds (10 and 30 mg/kg per day) were not protective, however.
Cidofovir was 100% protective at 30 mg/kg per day. A 10-day course of treatment gave comparable survival results and demonstrated the oral efficacy of HOE961. Treatments with
S2242 (100 mg/kg per day) and
cidofovir (30 mg/kg per day) each reduced lung and nasal virus titers by approximately ten-fold, whereas, HOE961 (100 mg/kg per day) was less active. Overall,
S2242 and HOE961 were found to be effective against cowpox virus
infections in mice but were less potent than
cidofovir. Since, HOE961 was orally active, it may have advantages over the other parenterally administered compounds for treating
orthopoxvirus infections.