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 & 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.
