Modeling, synthesis, and formulation of biguanidines

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The quasi species nature of a human immunodeficiency virus type 1 (HIV-1) infection coupled with the virus's ability to rapidly mutate away from selective drug pressure has led to the use of multiple drugs in combination as the accepted paradigm for treating systemic HIV-1 infections. Therefore it is quite likely that to obtain a safe and effective anti-HIV-1 microbicide a similar approach will be employed. The long-term objectives this "Integrated preclinical program for topical microbicides", is to provide data that will help justify the clinical development and commercialization of polyethylene-hexamethylene biguanide (or PEHMB derived product) alone or in combination regimens, as anti-HIV-1 topical microbicide. The hypotheses that underlie this Program application are that polybiguanide (PBG)-based compounds, and in particular PEHMB, can be easily synthesized and formulated for topical use, are easy to manufacture at low cost (dollars/kg), are non toxic at active concentrations, and provide for an effective inhibition of HIV-1 transmission. In addition, we propose that PEHMB together with an agent or agents that affect HIV-1 via differing mechanisms of action will provide optimal protection against HIV-1 transmission. Specific efforts throughout this preclinical development program and other efforts that are not directly itemized in this application will be used to help define the chemical and biochemical parameters, mechanism of action, and biological profile of PEHMB and like compounds. The Specific Aims of Project I are: 1) to define parameters which facilitate the synthesis of large lots of PEHMB with an acceptable distribution of molecular species in the crude product; 2) optimize biochemical separation and analytical protocols (including the use of 2D NMR to obtain solution structure of PEHMB) to ensure optimum antiviral activity and minimum lot-to-lot variation in the synthesized product; 3) use computer-aided drug design techniques to create a small virtual library of structures based on PEHMB, construct Quantitative Structure-Activity Relationships (QSAR) models from biological feedback, and continue the iterative process of model and compound refinement; 4) provide formulated PEHMB alone or in combination with additional antiviral agents, for use in in vivo efficacy, toxicity and adsorption studies, and 5) identify the maximum tolerated dose for PEHMB via different routes of administration and determine the pharmacokinetic characteristics of PEHMB, including systemic adsorption following topical vaginal application.