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.

项目概要 急性肺损伤 (ALI) 和急性呼吸窘迫综合征 (ARDS) 由常见的病原体引起 过程：肺损伤或感染引发压倒性的炎症反应（“细胞因子风暴”）， 导致内皮和上皮通透性增加以及炎症细胞、蛋白质和水的流出 从血管系统进入肺泡腔。受损肺部进一步释放炎症因子 组织经常引发全身炎症反应综合征（SIRS）和终末器官衰竭，这是 ALI/ARDS 死亡。 ALI 和 ARDS 是由多种病因引起的，包括误吸、吸入性损伤、 细菌性和病毒性肺炎、外伤、烧伤、输血、败血症等因素。事实上，生物 化学战剂通常因其能够造成 ALI/ARDS 的破坏性影响而被选择。 据估计，ALI 的发病率约为每 10 万人年 79 例。改进之处 由于机械通气策略的改进和 总体支持措施取得进展。不幸的是，即使在今天，对那些受苦的人的治疗仍然存在 死亡率约为 40%，很大程度上是支持性的。 Navigen 的目标是开发一种小分子 ARF6 抑制剂来治疗 ALI/ARDS。在第一阶段， 我们提出 ARF6 作为治疗 ALI/ARDS 的靶点，并且我们共享了确定其潜力的数据 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 鉴定许多具有所需效力和溶解度的 ARF6 抑制剂，以表征药代动力学 （PK）少数化合物的特性，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，并确定了主要候选药物 NAV-5093，以携带 进入第二阶段。 NAV-5093是NAV-4424的水溶性赖氨酸前药（二盐酸盐），其本身是一种 I 期确定的领先 5 个候选药物中。NAV-5093 具有高水溶性的优势，使其成为 适合在医院环境中静脉注射 (IV) 给药以治疗 ALI/ARDS。 NAV-5093 在体内快速裂解释放母体 NAV-4424，并且在 LPS-小鼠模型中有效。 诱导 ALI 以及中性粒细胞减少小鼠中鲍曼不动杆菌 (AB) 诱导的肺炎。在接下来的 在第二阶段的两年中，我们建议完成以下任务：（1）在两只大鼠中证明 NAV-5093 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 NAV-5093，(3) 在大鼠中进行 NAV-5093 的初步毒性研究，(4) 制造 NAV-5093 并优化 用于静脉注射的 NAV-5093 水性制剂，以及 (5) 与 FDA 举行 IND 前会议。