ARF6 Inhibitors for Treatment of Acute Lung Injury

项目摘要 急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）是由共同的病原体引起的， 过程：肺损伤或感染引发压倒性的炎症反应（"细胞因子风暴"）， 导致内皮和上皮渗透性增加以及炎性细胞、蛋白质和水的流出 从血管系统进入肺泡腔。炎症因子从受损肺中的进一步释放 组织经常触发全身炎症反应综合征（SIRS）和终末器官衰竭， ALI/ARDS死亡。ALI和ARDS由多种病因引起，包括吸入性损伤，吸入性损伤， 细菌性和病毒性肺炎、创伤、烧伤、输血、败血症和其他因素。事实上，生物 并且化学战剂通常因其引起ALI/ARDS的破坏性作用的能力而被选择。 据估计，ALI的发病率约为79例/100，000人年。改善 在过去的十年中，由于机械通气策略的改进， 一般性支助措施的进展。不幸的是，即使在今天， 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，并分享了建立潜在的 抑制ARF6对治疗ALI/ARDS的治疗价值。我们第一阶段申请的具体目标是 鉴定具有所需效力和溶解度的许多ARF6抑制剂，以表征药代动力学 (PK)这些化合物的少数性质，并获得令人信服的体内概念验证功效 在LPS诱导的ALI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。自从提交了我们的第二阶段申请 2016年1月，我们已经取得了重大进展，并确定了一个主要候选人，NAV-5093，携带 进入第二阶段。NAV-5093是NAV-4424的水溶性赖氨酸前药（二盐酸盐），NAV-4424本身是一种 在第一阶段确定的主要5名候选人中。NAV-5093具有高水溶性的优点， 适合于在医院环境中静脉内（IV）给药以治疗ALI/ARDS的制剂。 NAV-5093在体内被快速切割以释放亲本NAV-4424，并且在LPS-4424的小鼠模型中是有效的。 诱导的ALI以及在鲍曼不动杆菌（AB）诱导的肺炎中。在未来 在II期的两年中，我们建议完成以下内容：（1）证明NAV-5093在两只大鼠中的功效 使用公认的结果测量的ALI模型，（2）表征体外ADME和体内PK特性 （3）在大鼠中进行NAV-5093的初始毒性研究，（4）生产NAV-5093并优化其毒性。 IV给药的NAV-5093水性制剂，和（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.