DESIGN & SYNTHESIS OF BRAIN-SPECIFIC ANTIHERPETIC AGENT

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Phase I results have demonstrated the feasibility of synthesizing brain- enhanced chemical delivery systems (CDS) for a select group of antiherpetic agents. Based on the successful completion of Phase I studies, analogs of these Carrier systems have been proposed for Phase II studies, in order to determine the optimal drug-CDS (D-CDS) combination for delivery to the brain for the purpose of treating herpes encephalitis. The Carrier system functions on the basis of an interconversion (analogous to the NAD+ NADH system) between a lipophilic dihydropyridine derivative (which crosses the BBB) to a hydrophilic pyridinium salt which gets locked in the brain. Advantages of such a system are 1) clinically effective cerebral concentrations of the active drug are achieved rapidly resulting in greater efficacy; 2) reduced systemic toxicity due to lowered peripheral concentrations of the active agent. Objectives of this proposal are 1) synthesis of additional analogs of CDS for the antiherpetic agents, 2) in vitro stability determinations in various matrices, evaluation of lipophilicity and neurotoxicity of these antiviral-CDS, 3) elucidation of in vivo distribution pattern of these D-CDS in rat and dog models, 4) evaluation of different vehicles for i.v. dosing of D-CDS and 5) activity evaluations in a rat model of herpes encephalitis using HSV-1 strain. Successful completion of these objectives will identify a candidate drug for clinical and commercial development.