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

摘要 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、吸入）或间接（例如脓毒症、胰腺炎）肺损伤触发。ARDS是 以不受控制的、自我维持的炎症、内皮功能障碍、血管生成增加为特征， 渗透性和肺水肿。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患者仍然面临着约40%的死亡率， 支持性护理仍然是治疗的主要手段。因此，迫切需要新的治疗方法 通过新的治疗靶点来治疗ARDS。近年来，在一系列肺损伤模型中， 已经显示脂氧素促进炎症消退和减少内皮功能障碍。虽然前- 关于脂氧素的临床数据为它们用于治疗ARDS提供了令人信服的理由，这些脂质遭受代谢紊乱， 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 容易合成的和稳定的LXA 4模拟小分子FPR 2激动剂。通过这些努力，小 分子RISE-103由于其与LXA 4相当的效力、其容易的5- 分步合成及理化性质。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LXA 4模拟小分子FPR 2激动剂RISE-103，具有更好的 了解其药理学并增加其稳定性，最终可以优化为口服给药制剂。 对ARDS的治疗非常有效。这项建议采取了第一步，通过测试这一假设， 以下目标：1.评估RISE-103和RISE-103的FPR 2特异性药理学和ADME性质 类似物，2.为了比较我们的LXA 4模拟FPR 2激动剂与LXA 4在以ARDS为重点的 表型测定，和3.为了评估我们的LXA 4模拟FPR 2激动剂在LPS小鼠模型中的功效， ARDS。

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.