6th International AIDS Conference


San Francisco, California, USA — June 20-23, 1990

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Targeting of antiviral agents to the central nervous system: synthesis, stability and bioactivation of prodrugs of phosphonates.

Int Conf AIDS 1990 Jun 20-23; 6:331 (abstract no. 1068)
Mitchell A, Nicholls D, Freeman S, Irwin WJ; Department of Pharmaceutical Sciences, Aston University, Birmingham, UK

OBJECTIVE: To design a stable lipophilic prodrug of phosphonates which will cross the blood-CNS barrier. The potential of the p-substituted benzyl group to confer both lipophilicity and susceptibility to bioactivation with concomitant release of antiviral agent was investigated with phosphonoformate (PF).

METHODS: A series of p-substituted benzyl triesters 1(a-g) of PF were synthesised and their hydrolytic stabilities determined. The bioactivation of diesters 2(f-g) were investigated using purified esterases. FORMULA, SEE ABSTRACT VOLUME.

RESULTS: Triesters 1(a-g) were hydrolysed to their stable diesters 2(a-g) with half-lives between 1 and 30 minutes. Incubation of diesters 2(f-g) with esterase resulted in deesterification and spontaneous decomposition to methyl PF.

CONCLUSION: Para-substituted benzyl triesters of PF are hydrolytically unstable under physiological conditions. The rate of hydrolysis is directly related to the electronic properties of the p-substituent. Studies with other anti-HIV drugs (eg PMEA) will ascertain whether this instability is unique to PF. Susceptibility to bioactivation of the p-substituted benzyl diesters has been demonstrated.

Keywords: AEGIS, Prodrugs, Antiviral Agents, Foscarnet, Anti-HIV Agents, Protein Transport, Biological Transport, Hydrolysis, Solubility, ICA6KWDaegis,prodrugs,antiviralagents,foscarnet,anti-hivagents,proteintransport,biologicaltransport,hydrolysis,solubility,ica6

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