Antiviral activity of 9-[[(ethoxyhydroxyphosphinyl)-methoxy]methoxy]guanine against cytomegalovirus and herpes simplex virus

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 μg/ml, respectively. The in vitro EC₅₀ value of SKI 1008 against HCMV was comparable to that of ganciclovir (0.24 vs 0.16 μg/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.