Evaluation of prodrugs of 9-beta-D-arabinofuranosyladenine for therapeutic efficacy in the topical treatment of genital herpesvirus infections in guinea pigs

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Abstract
Prodrugs of the antiviral agent 9-beta-D-arabinofuranosyladenine (araA), which were more effective than the parent compound in penetrating vaginal membranes in vitro, were synthesized and examined for efficacy in the topical treatment of genital infections with herpes simplex virus type 2 in female guinea pigs. Treatment with 10% araA-5'-monophosphate or 10% araA-5'-monovalerate twice a day for 7 days, starting 6 h after intravaginal inoculation with virus, completely aborted the primary infection. When initiation of treatment was delayed until 24 h postinfection, araA-5'-monophosphate and araA-5'-monovalerate were no longer effective in reducing the mean lesion scores or mean vaginal virus titers. Treatment with 5% acyclovir, starting at 24 h postinfection, failed to prevent genital lesion development but significantly reduced the peak mean lesion score (approximately 50%). Topical therapy with 10% araA-2',3'-diacetate, initiated at 24 h postinfection, was as effective as, if not more effective than, acyclovir in reducing the severity of herpes genitalis in guinea pigs. Treatment with 10% araA-2',3'-dipropionate or 10% araA-2',3'-dibutyrate was without benefit. Among a series of 5'-monoesters of araA, araA-5'-monobutyrate appeared to be the most effective but was less active than araA-2',3'-diacetate. These data indicate that araA-2',3'-diacetate may be an effective antiviral agent for topical use against genital herpesvirus infections.