In vivo antiherpesvirus activity of N-7-substituted acyclic nucleoside analog 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine

Abstract

The efficacy of 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (S2242) was evaluated in several animal models for herpesvirus infections. Compound S2242 was more effective than acyclovir (i) when administered subcutaneously in a model for herpes simplex virus type 1 (HSV-1)-induced mortality in immunocompetent mice and (ii) when applied topically to hairless (hr/hr) mice that had been infected intracutaneously with HSV-2. In SCID (severe combined immune deficient) mice that had been infected with a thymidine kinasedeficient HSV-1 strain, S2242 (administered subcutaneously at a dosage of 50 mg/kg/day) completely protected against virus-induced mortality whereas foscarnet was less effective and acyclovir had no or little protective effect. Compound S2242 was far more effective than ganciclovir in preventing or delaying murine cytomegalovirus-induced mortality in immunocompetent and SCID mice. The compound was more effective when a given dose was fractionated and administered on subsequent days than when this dose was administered in one single injection. A 5-day treatment course with S2242 (10 and 50 mg/kg/day) for newborn mice that had been infected with a lethal dose of murine cytomegalovirus suppressed virus-induced mortality. Compound S2242 had no inhibitory effect on the growth of weanling (at 50 mg/kg for 5 days) and 3-to 4-week-old mice (at doses of 50 to 200 mg/kg for 6 weeks). However, akin to ganciclovir, compound S2242 significantly reduced testicle weight, testicle morphology, and spermatogenesis.A major goal of the search for new antiviral drugs is the development of antiherpesvirus agents that have resistance and toxicity profiles that are different from those of the currently available drugs. Little attention has so far been paid to the synthesis of purine nucleoside analogs with the side chain substituted at the purine N-7 position. Recently we reported on the synthesis of a series of N-7-substituted acyclic nucleoside analogs (6). Of this class of compounds, 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (S2242) was shown to be a potent inhibitor of herpesvirus replication in vitro. Of special interest is the potent activity of the compound against cytomegalovirus (CMV) and thymidine kinase-deficient (TK Ϫ ) strains of herpes simplex virus (HSV) and varicella-zoster virus (7). We report here on the antiherpesvirus activity of compound S2242 in several animal models for herpesvirus infection. MATERIALS AND METHODSCompounds. Acyclovir (ACV) (Zovirax) was obtained from Wellcome Research Laboratories (Aalst, Belgium), ganciclovir (GCV) (Cymevene) was obtained from Sarva-Syntex (Brussels, Belgium), and foscarnet (PFA) (Foscavir) was obtained from Astra Pharmaceutical Products, Inc. (Södertalje, Sweden). The synthesis of 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (compound S2242) has been reported elsewhere (6).Mice. The animals used throughout the experiments were (i) NMRI (Naval Medical Research Institute) mice, which were housed under conventional conditions during the experiments; (ii) ...

Mouse Adenovirus Type 1 Infection in SCID Mice: an Experimental Model for Antiviral Therapy of Systemic Adenovirus Infections

“…Cidofovir and S-2242 have similar in vitro activities against MAV-1, and the in vitro sensitivity of MAV-1 to cidofovir and S-2242 is comparable to those of several herpesviruses. Although the doses in our in vivo studies are comparable to those used in animal studies with herpesviruses, it seems that cidofovir and S-2242 are less effective in inhibiting mortality in the MAV-1/SCID model than in the herpesvirus models (40)(41)(42). It is rather unlikely that the limited effectiveness of cidofovir and S-2242 in our MAV-1 model is due to poor disposition, since both antiviral drugs are supposed to have different pharmacokinetics and organ distribution.…”

Vaccinia Virus Inhibitors as a Paradigm for the Chemotherapy of Poxvirus Infections

“…This compound is a potent and selective inhibitor of virtually all herpesviruses (83) and inhibits VV replication at an IC 50 of 0.4 g/ml (Table 1). In vivo, S2242 was more effective than acyclovir against HSV infection and far more effective than ganciclovir against cytomegalovirus (CMV) infection (84). Recently, this agent was shown to be fully protective against VV infection when given as its diacetate ester prodrug (H961) in both immunocompetent and SCID (severe combined immunodeficient) mice (86) (see Table 2).…”

The N-7-substituted acyclic nucleoside analog 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine is a potent and selective inhibitor of herpesvirus replication

“…For the acyclic nucleoside phosphonate analogs this long-lasting antiviral activity has also been observed in several animal models for virus infections as well as in the clinical setting (14,15,20,(25)(26)(27). However, although S2242 has a more pronounced in vivo activity than DHPG and ACV against several herpesvirus infections, it does not seem to cause as prolonged an antiviral response in vivo as the acyclic nucleoside phosphonate analogs (17).…”