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

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 andamp; ADME properties of RISE-103 andamp; 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.PROJECT NARRATIVE Acute respiratory distress syndrome (ARDS) is a life-threatening form of respiratory failure with a ~40% mortality rate. Immune and endothelial dysregulation are believed to play a major role in ARDS pathology and specialized pro-resolving lipid metabolites, such as lipoxins, show great promise in reversing this dysfunction in ARDS animal models, but have number of properties that make them poor drugs. The purpose of this study is to further develop our promising small molecule lipoxin mimetic, RISE-103, as a therapeutic for the treatment of ARDS.