Optimizing Small Molecule Lipoxin-Mimicking FPR2 Agonists for the Treatment of Acute Respiratory Distress Syndrome

优化小分子脂氧素模拟 FPR2 激动剂治疗急性呼吸窘迫综合征

• 批准号: 10325356
• 负责人: Kevin John Gaffney
• 金额: $ 29.8万
• 依托单位: RISERX LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325356
• 关键词: Adult Respiratory Distress Syndrome; Agonist; Animal Model; Anti-Inflammatory Agents; Apoptosis; Aspirin; Biological Assay; Biological Availability; Clinical Data; Collaborations; Development; Dose; Endothelial Cells; Endothelium; Ensure; Escherichia coli; FPR2 gene; Face; Failure; Functional disorder; Human; Hypoxia; Immune; In Vitro; Inflammation; Inflammatory; Injury; Isomerism; Laboratories; Leukocytes; Life; Lipids; Lipoxins; Lung; Malaria; Measures; Metabolic; Modeling; Mus; NF-kappa B; Oleic Acids; Oral; Pancreatitis; Pathologic; Pathology; Patients; Permeability; Phagocytosis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Pneumonia; Production; Property; Pulmonary Edema; Pulmonary Inflammation; Reperfusion Therapy; Resolution; Respiratory Failure; Risk; Role; Safety; Sepsis; Series; Supportive care; Testing; Therapeutic; Translational Research; Vascular Permeabilities; Ventilator; acute hypoxemic respiratory failure; analog; base; chemical stability; commercialization; comparative efficacy; cytokine; drug development; effective therapy; endothelial dysfunction; improved; in vivo; in vivo evaluation; lead series; lipoxin A4; lung injury; macrophage; mimetics; mortality; mouse model; neutrophil; new therapeutic target; novel therapeutics; pre-clinical; preclinical efficacy; programs; recruit; renal ischemia; research clinical testing; respiratory; small molecule

ABSTRACT Acute respiratory distress syndrome (ARDS) is a life-threatening form of acute hypoxemic respiratory failure triggered by direct (e.g. pneumonia, aspiration) or indirect (e.g. sepsis, pancreatitis) pulmonary injury. ARDS is marked by uncontrolled, self-perpetuating inflammation, endothelial dysfunction, increased vascular permeability, and pulmonary edema. While numerous therapeutic strategies for treating ARDS have been explored, unfortunately, despite these tremendous efforts, ARDS patients still face a ~40% mortality rate with supportive care remaining the mainstay of treatment. As a result, there is a desperate need for novel therapies working via novel therapeutic targets for ARDS. Recently, a number of studies in a series of lung injury models have shown lipoxins to promote inflammatory resolution and decrease endothelial dysfunction. While the pre- clinical data on lipoxins make a compelling case for their use to treat ARDS, these lipids suffer from metabolic and chemical stability issues and synthetic intractability. To overcome these shortcomings, we set out to develop readily synthesizable and stable LXA4-mimicking small molecule FPR2 agonists. From these efforts, small molecule RISE-103 was identified as a promising molecule due to its comparable potency to LXA4, its facile 5- step synthesis, and physicochemical properties. Based on our preliminary results and the pre-clinical efficacy of lipoxins, we hypothesize that our LXA4-mimicking small molecule FPR2 agonist RISE-103, with a better understanding of its pharmacology and increases in its stability, can ultimately be optimized into an orally dosable and highly effective therapy for ARDS. This proposal takes the first steps towards testing that hypothesis through the following aims: 1. To assess the FPR2-specific pharmacology & ADME properties of RISE-103 & RISE-103 analogs, 2. To compare the pharmacology of our LXA4-mimicking FPR2 agonists to LXA4 in ARDS-focused phenotypic assays, and 3. To assess the efficacy of our LXA4-mimicking FPR2 agonist in LPS mouse model of ARDS.

抽象的 急性呼吸窘迫综合征（ARDS）是一种危及生命的急性低氧性呼吸衰竭 由直接（例如肺炎、误吸）或间接（例如败血症、胰腺炎）肺损伤引发。 ARDS 是 其特点是不受控制的、自我持续的炎症、内皮功能障碍、血管扩张增加 通透性和肺水肿。尽管已经有许多治疗 ARDS 的治疗策略 不幸的是，尽管做出了这些巨大的努力，ARDS 患者仍然面临约 40% 的死亡率 支持性护理仍然是治疗的支柱。因此，迫切需要新的疗法 通过针对 ARDS 的新治疗靶点开展工作。最近，一系列肺损伤模型的研究 研究表明，脂氧素可以促进炎症消退并减少内皮功能障碍。虽然预 脂氧素的临床数据为治疗急性呼吸窘迫综合征提供了令人信服的理由，这些脂质会遭受代谢障碍 以及化学稳定性问题和合成难处理性。为了克服这些缺点，我们着手开发 易于合成且稳定的 LXA4 模拟小分子 FPR2 激动剂。通过这些努力，小 分子 RISE-103 被认为是一种有前途的分子，因为它的效力与 LXA4 相当，其容易的 5- 步骤合成和物理化学性质。根据我们的初步结果和临床前疗效 脂氧素，我们假设我们的 LXA4 模拟小分子 FPR2 激动剂 RISE-103，具有更好的 了解其药理学并提高其稳定性，最终可以优化为口服剂量 以及 ARDS 的高效治疗方法。该提案迈出了通过以下方式检验该假设的第一步： 目标如下： 1. 评估 RISE-103 和 RISE-103 的 FPR2 特异性药理学和 ADME 特性 类似物，2. 比较我们的 LXA4 模拟 FPR2 激动剂与 LXA4 在 ARDS 中的药理学 表型测定，以及 3. 评估我们的 LXA4 模拟 FPR2 激动剂在 LPS 小鼠模型中的功效 ARDS。