Zidampidine, an aryl phosphate derivative of AZT: in vivo pharmacokinetics, metabolism, toxicity, and anti-viral efficacy against hemorrhagic fever caused by Lassa virus

The pharmacokinetics, metabolism, and toxicity of Zidampidine, an aryl phosphate derivative of AZT, 3′-azidothymidine-5′-[p-bromophenyl methoxyalaninyl phosphate] were investigated in CD-1 mice. Following iv injection, Zidampidine was rapidly converted to its metabolites Ala-AZT-MP and AZT. Zidampidine was not toxic to mice at doses up to 250 mg/kg. We next examined the therapeutic effect of Zidampidine in CBA mice challenged with intracerebral injections of the Josiah strain of Lassa virus. Mice were treated either with vehicle or non-toxic doses of Zidampidine administered intraperitoneally 24 h prior, 1 h prior, and 24, 48, 72, and 96 h after virus inoculation. The probability of survival following the Lassa challenge was significantly improved for Zidampidine-treated mice (Kaplan Meier, Log-Rank p value < 0.0001). This pilot study provides the basis for future preclinical evaluation of Zidampidine and its potential as a new agent for the treatment of viral hemorrhagic fevers caused by Lassa virus.

We examined the therapeutic effect of the aryl phosphate derivative of AZT, 3′-azidothymidine-5′-[p-bromophenyl methoxyalaninyl phosphate] (Zidampidine) in CBA mice inoculated with intracerebral injections of the Josiah strain of Lassa virus. The probability of survival following the Lassa challenge was significantly improved for Zidampidine-treated mice (25 mg/kg) (Kaplan Meier, Log-Rank p value ≫ 0.0001). The pharmacokinetics, metabolism, and toxicity of Zidampidine were also investigated in CD-1 mice. Zidampidine was rapidly converted to metabolite Ala-AZT-MP and AZT, both of them have been identified by NMR and LC–MS in comparison with authentic synthetic compounds.Figure optionsDownload as PowerPoint slide