Modeling, synthesis, and formulation of biguanidines

人类免疫缺陷病毒1型(HIV-1)感染的准物种性质，加上该病毒在选择性药物压力下快速变异的能力，导致使用多种药物组合作为治疗系统性HIV-1感染的公认范例。因此，为了获得安全有效的抗艾滋病毒-1杀微生物剂，很可能会采用类似的方法。这项“局部杀微生物剂综合临床前计划”的长期目标是提供数据，帮助证明聚乙烯-六亚甲基双胍(或PEHMB衍生产品)单独或联合治疗方案作为抗HIV-1局部杀菌剂的临床开发和商业化是合理的。作为该程序应用的基础的假设是基于聚双胍(PBG)的化合物，特别是PEHMB， 易于合成和配制以供局部使用，易于以低成本(美元/公斤)制造，在有效浓度下无毒，并有效抑制艾滋病毒-1传播。此外，我们建议PEHMB与通过不同作用机制影响HIV-1的一个或多个试剂一起，将提供针对HIV-1传播的最佳保护。整个临床前开发计划中的具体努力以及本申请中未直接逐项列出的其他努力将用于帮助定义PEHMB和类似化合物的化学和生化参数、作用机制和生物学特性。项目I的具体目标是：1)定义参数以促进 利用计算机辅助药物设计技术建立一个基于PEHMB的小型结构虚拟文库，利用生物反馈构建定量构效关系(QSAR)模型，并继续模型和化合物精制的迭代过程；4)单独提供配方的PEHMB 5)通过不同给药途径确定PEHMB的最大耐受量，并确定PEHMB的药代动力学特征，包括局部阴道给药后的全身吸收。

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.