Efficacy of A-73209, a potent orally active agent against VZV and HSV infections

Abstract

A-73209 is a novel oxetanocin derivative with potent in vitro and in vivo activity against VZV, HSV-1, and HSV-2. A-73209 was two logs more potent than acyclovir against five thymidine kinase positive (TK +) strains of VZV in vitro (mean EC 50 0.01 vs. 1.22 μg/ml). The activity of A-73209 was one log more potent than acyclovir against TK + HSV-1 strains in vitro (EC 50 = 0.03 vs. 0.32 μg/ml). A-73209 yielded a mean EC 50 of 2.2 μg/ml compared to a mean EC 50 of 0.37 μg/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 strains of VZV, HSV-1 and HSV-2 was much lower than for the corresponding TK + strains. A-73209 produced efficacy superior to acyclovir against lethal systemic or intracerebral HSV-1 infections in mice. The greater efficacy of A-73209 relative to acyclovir was especially apparent with oral dosing. Against HSV-2 infections in mice, the efficacy of A-73209 ranged from equal to 1.7 times less active relative to acyclovir with oral dosing. A-73209 was orally bioavailable in mice, with maximal serum concentrations well in excess of in vitro inhibitory concentrations. A-73209 appears to be a potent and selective agent against varicella-zoster virus and herpes simplex virus infections.