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

• Published in: Bioorganic & medicinal chemistry Vol. 13; no. 9; pp. 3279 - 3288
• Main Authors: Uckun, F.M., Venkatachalam, T.K., Erbeck, D., Chen, C.L., Petkevich, A.S., Vassilev, A.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 02.05.2005; Elsevier Science
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Dideoxynucleotides; Disease Models, Animal; Female; Hydrolysis; Lassa Fever - drug therapy; Lassa virus - drug effects; Medical sciences; Mice; Mice, Inbred ICR; Molecular Structure; Pharmacology. Drug treatments; Thymine Nucleotides; Time Factors; Zidovudine - analogs & derivatives; Zidovudine - metabolism; Zidovudine - pharmacology; Zidovudine - toxicity; Hemorrhagic fever; Intraperitoneal administration; Toxicity; Lassa virus; Phosphorus Organic compounds; Arbovirus disease; Antiviral; Pyrimidine nucleoside; Organic amidophosphate; Rodentia; Prodrug; Metabolism; Arenavirus; Infection; Virus; In vivo; Vertebrata; Mammalia; Mouse; Viral disease; Animal; Dideoxynucleoside; Pharmacokinetics; Zidovudine; Arenaviridae
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.02.031

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 (25mg/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. 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 250mg/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 24h prior, 1h prior, and 24, 48, 72, and 96h 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.