Evaluation of anti-herpesvirus activity of (1 ' S,2 ' R)-9-[[1 ',2 '-bis(hydroxymethyl)cycloprop-1 '-yl]methyl]guanine (A-5021) in mice

The anti-herpesvirus activity of (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)cycl oprop-1'-yl]methyl]guanine (A-5021) was evaluated in murine cells and in se veral murine models of herpes simplex virus (HSV) infection. Against HSV ty pe 1 (HSV-1), A-5021 was 15-30- and 30-60-fold more active, and against HSV type 2 (HSV-2), it was 2- and 8-fold more active than acyclovir and pencic lovir in Balb/3T3 cells, respectively. When antiviral compounds were admini stered orally (once daily) to mice infected intraperitoneally with HSV-1 (T omioka), A-5021 was more active than acyclovir or famciclovir in spite of i ts relatively low oral bioavailability. A-5021 was as active as penciclovir when the antiviral compounds were given intravenously (three times daily) to mice infected intraperitoneally with HSV-2 (186). In mice with a cutaneo us HSV-1 (KOS) infection, three times daily oral therapy with A-5021 at 25 mg/kg per day produced more significant reduction in severity of skin lesio ns than equivalent treatment with acyclovir or famciclovir. In mice infecte d intracerebrally with HSV-1 (Tomioka), complete survival was observed in t he group treated intravenously with A-5021 at 25 mg/kg per day (three times daily), while more than 50% of mice died in the groups treated intravenous ly with acyclovir of up to 100 mg/kg per day (three times daily). Moreover, A-5021 was more effective than acyclovir in clearing infectious virus from the brain. These findings demonstrate that A-5021 has potent anti-HSV acti vity in several murine models. (C) 1999 Elsevier Science B.V. All rights re served.