ARF6 Inhibitors for Treatment of Acute Lung Injury

项目总结 急性肺损伤(ALI)和急性呼吸窘迫综合征(ARDS)是由一种常见的 过程：肺损伤或感染引发压倒性炎症反应(“细胞因子风暴”) 导致内皮和上皮通透性增加以及炎细胞、蛋白质和水的外流 从血管系统进入肺泡腔。受损肺中炎性物质的进一步释放 组织经常触发全身炎症反应综合征(SIRS)并最终导致器官衰竭，这是 ALI/ARDS死亡。ALI和ARDS是由各种原因引起的，包括吸入、吸入性损伤、 细菌性和病毒性肺炎、创伤、烧伤、输血、败血症等因素。事实上，生物 而化学战剂之所以被选中，往往是因为它们能够造成ALI/ARDS的毁灭性影响。 据估计，ALI的发病率约为每10万人年79例。改进了 在过去的十年中，由于改进了机械通风和 总体扶持措施取得进展。不幸的是，即使在今天，对这些饱受折磨的遗骸的治疗 很大程度上是支持的，死亡率约为40%。 Navigen的目标是开发一种小分子ARF6抑制剂，用于治疗ALI/ARDS。在第一阶段， 我们提出了ARF6作为治疗ALI/ARDS的靶点，我们分享了建立这种潜力的数据 抑制ARF6对ALI/ARDS的治疗价值我们第一阶段应用程序的具体目标是 确定一系列具有所需效力和溶解度的ARF6抑制剂，以表征其药代动力学 (Pk)少量此类化合物的性质，并在体内获得令人信服的概念验证效果 在脂多糖诱导的急性肺损伤的小鼠模型中，探索剂量-反应关系和治疗时间效应。 我们实现了这些目标，并确定了五种感兴趣的化合物。自从提交我们的第二阶段申请以来 2016年1月，我们取得了重大进展，并确定了一名领先的候选人NAV-5093 NAV-5093是NAV-4424的一种水溶性赖氨酸前药(二盐酸盐)，其本身为 在第一阶段确定的5个主要候选者中，NAV-5093具有高水溶性的优势，使其 适用于在医院环境下静脉注射(IV)治疗ALI/ARDS的制剂。 NAV-5093在体内被迅速切割以释放亲本NAV-4424，并在小鼠内毒素模型中有效。 在中性粒细胞减少的小鼠中诱导ALI和鲍曼不动杆菌(AB)诱导的肺炎。在接下来的时间 在第二阶段的两年中，我们计划完成以下工作：(1)在两只大鼠身上展示NAV-5093的疗效 (2)体外ADME和体内PK特性的研究 NAV-5093的初步毒性研究；(4)NAV-5093的制备和优化 用于静脉给药的NAV-5093水溶液制剂，以及(5)与FDA举行IND前会议。

PROJECT SUMMARY Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) result from a common pathogenic process: pulmonary injury or infection triggers an overwhelming inflammatory response (“cytokine storm”) that results in increased endothelial and epithelial permeability and efflux of inflammatory cells, protein, and water from the vascular system into the alveolar space. The further release of inflammatory agents from damaged lung tissue often triggers systemic inflammatory response syndrome (SIRS) and end organ failure, the main cause of death in ALI/ARDS. ALI and ARDS are precipitated by diverse etiologies including aspiration, inhalation injury, bacterial and viral pneumonias, trauma, burn injury, blood transfusion, sepsis, and other factors. In fact, biologic and chemical warfare agents are often selected for their ability to cause the devastating effects of ALI/ARDS. The incidence of ALI is estimated to be approximately 79 cases per 100,000 person-years. Improvements in outcome have come about over the past decade due to improved strategies of mechanical ventilation and advances in general supportive measures. Unfortunately, even today, the treatment for those afflicted remains largely supportive with a mortality rate of approximately 40%. Navigen’s objective is to develop a small molecule ARF6 inhibitor as a treatment for ALI/ARDS. In Phase I, we presented ARF6 as a target for treatment of ALI/ARDS, and we shared data establishing the potential therapeutic value of inhibiting ARF6 to treat ALI/ARDS. The specific aims of our Phase I application were to identify a number of ARF6 inhibitors with required potency and solubility, to characterize the pharmacokinetic (PK) properties of a small number of these compounds, and to obtain convincing in vivo proof-of-concept efficacy in a mouse model of LPS-induced ALI, exploring both dose-response relationships and time-of-treatment effects. We accomplished these goals and identified five compounds of interest. Since submitting our Phase II application in January, 2016, we have made significant progress and have identified a lead candidate, NAV-5093, to carry forward into Phase II. NAV-5093 is a water-soluble lysine prodrug (dihydrochloride salt) of NAV-4424, itself one of the leading 5 candidates identified in Phase I. NAV-5093 has the advantage of high water solubility, making it amenable to formulation for intravenous (IV) administration in the hospital setting for treatment of ALI/ARDS. NAV-5093 is cleaved rapidly to release parent NAV-4424 in vivo, and is effective in the mouse model of LPS- induced ALI as well as in Acinetobacter baumannii (AB)-induced pneumonia in neutropenic mice. Over the next two years in Phase II, we propose to accomplish the following: (1) demonstrate efficacy of NAV-5093 in two rat models of ALI using accepted outcome measures, (2) characterize the in vitro ADME and in vivo PK properties of NAV-5093, (3) conduct initial toxicity studies of NAV-5093 in rats, (4) manufacture NAV-5093 and optimize an aqueous formulation of NAV-5093 for IV administration, and (5) hold a pre-IND meeting with the FDA.