ARF6 Inhibitors for Treatment of Acute Lung Injury

ARF6 抑制剂治疗急性肺损伤

• 批准号: 9347749
• 负责人: ALAN L MUELLER
• 金额: $ 88.95万
• 依托单位: NAVIGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9347749
• 关键词: ADME Study; Acinetobacter baumannii; Acute Lung Injury; Adult Respiratory Distress Syndrome; Alveolar; Area Under Curve; Bacterial Pneumonia; Binding Proteins; Biological Assay; Biological Sciences; Biological Warfare; Blood Transfusion; Breathing; Burn injury; Canis familiaris; Cause of Death; Cells; Chemical Warfare Agents; Cleaved cell; Clinical; Data; Development; Dose; Drug Kinetics; Epithelial; Esters; Etiology; Feedback; Formulation; Funding; Goals; Hepatocyte; Hospitals; Hour; Human; In Vitro; Incidence; Infection; Inflammatory; Inflammatory Response; Injury; Intraperitoneal Injections; Intravenous; Lead; Life; Liver Microsomes; Lung; Lysine; Measures; Mechanical ventilation; Modeling; Mus; Organ failure; Oryctolagus cuniculus; Outcome; Outcome Measure; Parents; Pathogenicity; Permeability; Persons; Pharmacology Study; Phase; Plasma; Plasma Proteins; Pneumonia; Polymorph; Process; Prodrugs; Property; Proteins; Pseudomonas aeruginosa; Rattus; Research Design; Rodent; Running; Safety; Sepsis; Sepsis Syndrome; Sodium Chloride; Solubility; Structure of parenchyma of lung; Testing; Therapeutic; Time; Toxic effect; Toxicology; Trauma; United States National Institutes of Health; Vascular System; Viral Pneumonia; Water; analytical method; animal efficacy; aqueous; cytokine; data sharing; experience; improved; in vivo; inhibitor/antagonist; interest; intraperitoneal; irritation; meetings; metabolic profile; method development; mortality; mouse model; programs; response; safety study; screening; small molecule; small molecule inhibitor; treatment effect; water solubility

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.

项目摘要 急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）是由常见致病性引起的 过程：肺损伤或感染会触发压倒性的炎症反应（“细胞因子风暴”） 导致炎症细胞，蛋白质和水的内皮和上皮渗透性以及上皮渗透率增加 从血管系统到肺泡空间。肺部受损的炎症剂进一步释放 组织通常会触发系统性炎症反应综合征（SIRS）和结束器官衰竭，这是 Ali/ards死亡。 Ali和Ards对潜水员的病因是宝贵的，包括抽吸，吸入损伤， 细菌和病毒性肺炎，创伤，烧伤，输血，败血症和其他因素。实际上，生物学 并且通常选择化学战代理，因为它们能够引起ALI/ARDS的毁灭性影响。 据估计，阿里的事件约为每100,000人年的79例。改进 由于改善了机械通气策略和 一般支持措施的进步。不幸的是，即使在今天，对患病者的待遇仍然存在 死亡率约为40％。 Navigen的目标是开发小分子ARF6抑制剂作为ALI/ARDS的治疗方法。在第一阶段， 我们提出了ARF6作为治疗ALI/ARDS的目标，并共享了数据，以确定潜力 抑制ARF6治疗ali/ards的治疗价值。我们阶段应用的具体目的是 识别一些具有所需效力和可溶性的ARF6抑制剂，以表征药代动力学 （PK）少数这些化合物的特性，并获得令人信服的体内概念证明效率 在LPS诱导的ALI的小鼠模型中，探索了剂量反应关系和治疗时间的效果。 我们实现了这些目标，并确定了五种感兴趣的化合物。自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，并确定了一名首席候选人NAV-5093携带 向前进入第二阶段。 NAV-5093是NAV-4424的水溶性赖氨酸前药（二氢盐盐），本身就是一个 在第一阶段确定的5个候选人中，NAV-5093具有高水溶性的优势，使其成为 可以在医院设置ALI/ARDS治疗的医院静脉内（IV）给药。 NAV-5093迅速清除以在体内释放父级NAV-4424，并且在LPS-的小鼠模型中有效 诱导的ALI以及鲍曼尼（AB）诱导的中性小鼠肺炎。在下一个 在第二阶段的两年 使用公认的结果度量的ALI模型，（2）表征体外ADME和体内PK特性 NAV-5093，（3）在大鼠中进行NAV-5093的初始毒性研究，（4）制造NAV-5093并优化 NAV-5093的IV管理水性公式，（5）与FDA举行预先开会。