DICATIONIC DRUGS--METABOLISM AND TOXICITY

这个节目的目的是为了了解动作的机制(S)， 三七的构效关系及毒性机制(S) 抗菌剂(五烷双胺类似物)的阳离子类。《词典》 分子是重要的治疗(或潜在治疗)药物 与艾滋病有关的机会主义代理人的治疗。这一类人 药物此前已经证明了对卡氏肺孢子虫的效力， 艾滋病患者中最严重的感染，最近显示 对另外两种与艾滋病相关的条件致病菌的活性；弓形虫 Gondii和微小隐孢子虫。尽管阳离子试剂是 在艾滋病患者的临床管理中被认为是重要的，这 在不了解他们的行动模式的情况下获得了地位， 新陈代谢，或毒性。在这项提案中，我们在合成方面的专业知识 并将使用五烷双胺类似物的化疗应用 了解分子间的相互作用和代谢的命运 感染病人体内的这些化合物。这是对 论判断性代理人对待机会主义代理人的作用模式(S) 将允许合理设计具有更好治疗效果的新药 使用的指数和光谱。上述问题将分三个阶段加以解决 不同的项目。 以下项目标题清楚地表明了该计划的重点为 一个整体和每个项目的责任领域：项目一。 二性药物：新陈代谢和毒性；项目二.二性药物： 作用机理(S)；方案III.双阳离子分子抗微小隐孢子虫 和弓形虫。项目I将确定体外和体内的 戊二甲双胺及其选择性的结构/毒性研究进展 类比。此外，这个项目将继续我们的初步工作 五烷双胺的药代动力学/代谢研究，并启动类似的 对已显示毒性模式的选定类似物的研究 和/或与母药不同的活性。项目II将 关注之前描述的两种药剂的活动，DNA 多种生化方法对DNA拓扑异构酶的结合和抑制 技巧。这些研究将试图确定上述药物是否- 靶向相互作用具有治疗意义。此外，项目 Ii将使用放射性标记的配体结合分析和抗独特型抗体 针对抗药物抗体以确定其他药物的特征 病原体和人类细胞中的结合位点。项目III将依赖于 两名高级调查人员建立药物模型的专业知识 针对弓形虫和微小弧菌的检测，并为 项目二研究。项目III将使用放射性标记的药物和电子设备 显微技术用于鉴定五烷双胺类似物和 确定它们的生理意义。双方之间的密切互动 将确保三个项目并监测方案的进展 通过一个积极的管理核心。藤泽药业公司 (FPC)将担任企业赞助商。因此，FPC将获得专利和 由团队开发关键发现，每年投入135,000美元 预算和提供选定动物的全面动物毒性研究 化合物。

The goal of this program is to understand the mechanism(s) of action, structure/activity relationships, and mechanism(s) of toxicity of the dicationic class of antimicrobial agents (pentamidine analogs). Dicationic molecules are important therapeutic (or potential therapeutic) agents in the treatment of opportunistic agents associated with AIDS. This class of agents has previously demonstrated potency against Pneumocystis carinii, the most serious infection in AIDS patients, and has recently demonstrated activity against two other AIDS-related opportunistic pathogens; Toxoplasma gondii, and Cryptosporidium parvum. Although dicationic agents are accepted as important in the clinical management of the AIDS patient, this status has been achieved with no understanding of their mode of action, metabolism, or toxicity. In this proposal, our expertise in the synthesis and chemotherapeutic applications of pentamidine analogs will be used to obtain an understanding of the molecular interactions and metabolic fate of these compounds in the infected patient. This basic understanding of the mode(s) of action of dicationic agents in treating opportunistic agents will allow the rational design of new drugs with improved therapeutic indices and spectra of use. The above questions will be addressed in three separate projects. The following project titles clearly indicate the focus of the program as a whole and the areas of responsibility for each project: Project I. Dicationic Drugs: Metabolism and Toxicity; Project II. Dicationic Drugs: Mechanism(s) of Action; Project III. Dicationic Molecules Against C. parvum and T. gondii. Project I will determine the in vitro and in vivo structure/toxicity profiles for pentamidine and selected pentamidine analogs. In addition, this project will continue our preliminary pharmacokinetic/metabolism studies for pentamidine, and initiate similar studies on selected analogs that have demonstrated patterns of toxicity and/or activity different from those of the parent drug. Project II will focus on two previously described activities of dicationic agents, DNA binding and inhibition of DNA topoisomerases using a variety of biochemical techniques. Such studies will attempt to determine if the above drug- target interactions are of therapeutic significance. In addition, Project II will use radiolabeled ligand binding assays and antiidiotype antibodies directed toward anti-drug antibodies to characterize additional drug binding sites in both pathogens and human cells. Project III will rely on the expertise of the two senior investigators to establish models for drug testing against T. gondii and C. parvum and to provide organisms for Project II studies. Projects III will use radiolabeled drug and electron microscopy to identify binding sites of the pentamidine analogs and determine their physiological significance. Close interaction between the three Projects will be assured and the progress of the Program monitored through an active Administrative Core. Fujisawa Pharmaceutical Company (FPC) will serve as the corporate sponsor. As such, FPC will patent and develop key discoveries by the group, commit $135,000/yr to the total budget and provide comprehensive animal toxicity studies on selected compounds.