2-Amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (compound S2242) represents the first antivirally active nucleoside analog with the side chain attached to the N-7 position of the purine ring. Compound S2242 strongly inhibits the in vitro replication of both herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) (50% effective concentration [EC50], 0.1 to 0.2 ,ug/ml), varicella-zoster virus (EC50, 0.01 to 0.02 ,ug/ml) and thymidine kinase (TK)-deficient strains of HSV (EC50, 0.4 ,Lg/ml) and varicella-zoster virus (EC50, 0.2 to 0.5 ,ug/ml). Potent activity was also observed against murine cytomegalovirus (EC50, 1 gig/ml), human cytomegalovirus (HCMV) (EC50, 0.04 to 0.1 ,ug/ml), and human herpesvirus 6 (EC50, 0.0005 ,ug/ml). Compound S2242 (i) was not cytotoxic to confluent Vero, HeLa, or human fibroblast cells at concentrations of > 100 ,ug/ml, (ii) proved somewhat more cytostatic to Vero, HEL, HeLa, and C127I cells than ganciclovir, and (iii) was markedly more cytostatic than ganciclovir to the growth of the human lymphocytic cell lines HSB-2 and CEM°. In contrast to ganciclovir, (i) compound S2242 proved not to be cytocidal to murine mammary carcinoma (FM3A) cells transfected with the HSV-1 or HSV-2 TK gene, (ii) exogenously added thymidine had only a limited effect on its anti-HSV-1 activity, and (iii) the compound was not phosphorylated by HSV-1-encoded TK derived from HSV-1 TK-transfected FM3A cells, indicating that the compound is not activated by a virally encoded TK.Compound S2242 inhibited (i) the expression of late HCMV antigens at an EC50 of 0.07 ,ug/ml (0.6 ,ug/ml for ganciclovir) and (ii) HCMV DNA synthesis at an EC50 of 0.1 ,ug/ml (0.32 ,ug/ml for ganciclovir), i.e., values that are close to the EC50s for inhibition of HCMV-induced cytopathogenicity. Neither ganciclovir nor S2242 had any effect on the expression of immediate-early HCMV antigens, which occurs before viral DNA synthesis. In time-of-addition experiments, S2242 behaved like ganciclovir and acyclovir; i.e., the addition of the drugs could be delayed until the onset of viral DNA synthesis.Agents approved in one or more countries to treat herpesvirus infection include idoxuridine, trifluridine, vidarabine, and acyclovir for the topical treatment of herpetic eye infection; vidarabine and acyclovir for the systemic treatment of herpes encephalitis, acyclovir for the topical and systemic (oral or intravenous) treatment of genital herpes; acyclovir for the systemic (intravenous, oral) treatment of herpes simplex virus (HSV) or varicella-zoster virus (VZV) infections in immunosuppressed patients; and ganciclovir and foscarnet for the systemic (intravenous) treatment of human cytomegalovirus (HCMV) retinitis in patients with AIDS. Foscarnet is effective in the treatment of infections with acyclovir-resistant thymidine kinase-deficient (TK-) HSV or VZV mutants and ganciclovir-resistant HCMV infections (5,16,18,25). However, double resistant viruses (i.e., ganciclovir-and foscarnet-resistant HCMV and acyclovir-and foscarnet-resistant HSV) have b...

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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) ...