title: 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 EC50 0.01 vs. 1.22 micrograms/ml). The activity of A-73209 was one log more potent than acyclovir against TK+ HSV-1 strains in vitro (EC50 = 0.03 vs. 0.32 micrograms/ml). A-73209 yielded a mean EC50 of 2.2 micrograms/ml compared to a mean EC50 of 0.37 micrograms/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.
authors.affiliation: Abbott Laboratories, Department 47T, Abbott Park, IL 60064-3500.
authors.forename: J
authors.initials: J
authors.lastname: Alder
authors.forename: M
authors.initials: M
authors.lastname: Mitten
authors.forename: D
authors.initials: D
authors.lastname: Norbeck
authors.forename: K
authors.initials: K
authors.lastname: Marsh
authors.forename: E R
authors.initials: ER
authors.lastname: Kern
authors.forename: J
authors.initials: J
authors.lastname: Clement
mesh_terms: D000212:Acyclovir / Q000494:pharmacology / Q000627:therapeutic use; D000284:Administration, Oral; D018138:Alphaherpesvirinae / Q000187:drug effects*; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D006561:Herpes Simplex / Q000188:drug therapy*; D018259:Herpesvirus 1, Human / Q000187:drug effects; D018258:Herpesvirus 2, Human / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects; D007274:Injections, Intraperitoneal; D051379:Mice; D014498:Uracil / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D000998:Antiviral Agents; C086564:A 73209; D014498:Uracil; D000212:Acyclovir