An isosteric analog of 9-[2-(phosphonomethoxy)ethyl]
guanine (
PMEG), 9-[[(ethoxyhydroxyphosphinyl)methoxy]methoxy]
guanine (
SKI 1008), was evaluated for its in vitro
antiviral activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), murine cytomegalovirus (MCMV), and human cytomegalovirus (HCMV), and its in vivo
antiviral efficacy against MCMV in mice. The in vitro anti-HSV activity of
SKI 1008 was much lower than that of
acyclovir, even though
SKI 1008 showed similar
antiviral activity against
thymidine kinase positive (TK+) and
thymidine kinase negative (TK-) strains. Like
ganciclovir and
PMEG,
SKI 1008 selectively inhibited plaque formation of MCMV; the 50% effective concentration (EC50) and the 50% cytotoxic concentration (CC50) of
SKI 1008,
ganciclovir, and
PMEG being 0.51 and 600, 1.65 and 461, and 0.06 and 12.1 micrograms/ml, respectively. The in vitro EC50 value of
SKI 1008 against HCMV was comparable to that of
ganciclovir (0.24 vs 0.16 microgram/ml) and was 12-fold higher than that of
PMEG in a plaque reduction assay, but the therapeutic indices (the ratios of CC50 to EC50) of
SKI 1008 and
ganciclovir were higher than that of
PMEG. The in vivo
antiviral efficacy of
SKI 1008 in MCMV-infected normal BALB/c and
severe combined immunodeficiency (SCID) mice was lower than that of
ganciclovir in terms of mortality and mean survival time.