EFFICACY OF EMS-180194 AGAINST EXPERIMENTAL CYTOMEGALOVIRUS INFECTIONS IN IMMUNOCOMPROMISED MICE

A new antiviral nucleoside, BMS-180194 [1R-(1 alpha,2 beta,3 roxymethy l)cyclobutyl]-1,9-dihydro-6H-purin-6-one, is a broad spectrum antivira l agent. The antiviral effectiveness of BMS-180194 against murine cyto megalovirus (MCMV) infection in immunocompromised C57BL/6 mice was inv estigated and was compared to that of ganciclovir (GCV). LP-BM5 murine retrovirus complex-induced immunocompromised C57BL/6 mice were challe nged with MCMV then treated intraperitoneally or per os with various d oses of BMS-180194 ranging from 30 to 3 mg/kg/day. When administered i ntraperitoneally, BMS-180194 was effective against MCMV-mediated morta lity in a dose-dependent manner demonstrating a 50% protective dose (P D50) of 3.12 mg/kg/day which was comparable to that of GCV. There was a marked reduction in organ MCMV titers in BMS-180194-treated animals (10-10 000-fold lower than the placebo controls). Similar findings wer e observed when the compound was administered orally. Interestingly, o ral BMS-180194 demonstrated a similar antiviral efficacy as that obtai ned by the parenteral route of administration suggesting a high oral b ioavailability of the compound. Oral ganciclovir treatment, however, r equired more than a 4-fold higher amount of GCV to confer the same deg ree of protection obtained by a parenteral route of administration. Or al BMS-180194 was also effective in reducing the organ MCMV titer in g enetically severe combined immunodeficient (SCID) mice. The parenteral or oral antiviral efficacy of BMS-180194 was comparable to that of pa renteral ganciclovir against MCMV infection in the present study. Dose s of BMS-180194 employed in the present study showed no toxicity to mi ce. These results suggest that BMS-180194 may be of value as an oral a ntiviral agent for treatment of opportunistic CMV infections in immuno compromised individuals.