EFFICACY OF A-73209, A POTENT ORALLY-ACTIVE AGENT AGAINST VZV AND HSVINFECTIONS

A-73209 is a novel oxetanocin derivative with potent in vitro and in v ivo activity against VZV, HSV-1, and HSV-2. A-73209 was two logs more potent than acyclovir against five thymidine kinase positive (TK+) str ains of VZV in vitro (mean EC(50) 0.01 VS. 1.22 mu g/ml). The activity of A-73209 was one log more potent than acyclovir against TK+ HSV-1 s trains in vitro (EC(50) = 0.03 VS. 0.32 mu g/ml). A-73209 yielded a me an EC(50) of 2.2 mu g/ml compared to a mean EC(50) Of 0.37 mu g/ml for acyclovir against a panel of TK+ HSV-2 strains in vitro. The in vitro activity of A-73209 against thymidine kinase negative or deficient st rains of VZV, HSV-1 and HSV-2 was much lower than for the correspondin g TK+ strains. A-73209 produced efficacy superior to acyclovir against lethal systemic or intracerebral HSV-1 infections in mice. The greate r efficacy of A-73209 relative to acyclovir was especially apparent wi th oral dosing. Against HSV-2 infections in mice, the efficacy of A-73 209 ranged from equal to 1.7 times less active relative to acyclovir w ith oral dosing. A-73209 was orally bioavailable in mice, with maximal serum concentrations well in excess of in vitro inhibitory concentrat ions. A-73209 appears to be a potent and selective agent against varic ella-zoster virus and herpes simplex virus infections.