Optimizing Small Molecule Lipoxin-Mimicking FPR2 Agonists for the Treatment of Alzheimers Disease

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ABSTRACT Despite tremendous efforts, the development of new therapeutics for Alzheimer’s disease (AD) suffers from the highest failure rates of any disease state. As a result, the identification of novel therapies for novel therapeutic targets for AD is desperately needed. In addition to Aβ deposits and neurofibrillary tangles, neuroinflammation is a major hallmark of AD. Chronic neuroinflammation in AD leads to elevated levels of pro-inflammatory cytokines and oxidative stress which ultimately results in neuronal death, neurodegeneration, and, ultimately, cognitive decline. Under normal physiological conditions, inflammation is resolved by specialized pro-resolving lipid metabolites (SPMs) (e.g. lipoxins, resolvins, maresins, and protectins). Unfortunately, with age, our capacity to produce SPMs decreases leading to an imbalance between pro- and anti-inflammatory lipids. AD patients have significantly higher brain levels of the pro-inflammatory leukotriene B4 (LTB4) and significantly lower levels of the pro-resolving lipoxin A4 (LXA4) in the hippocampus and cerebral spinal fluid as compared to healthy aged individuals. While the pre-clinical data on LXA4 and 15-epi-LXA4 make a compelling case for their use as AD therapeutics, these lipids suffer from metabolic and chemical stability issues and synthetic intractability. In order to overcome these shortcomings, we set out to develop readily synthesizable and stable small molecule LXA4- mimicking FPR2 agonists. From these efforts, RISE-103 was identified as a promising starting point for optimization due to its comparable potency to LXA4, its facile 5-step synthesis, and its physicochemical properties suitable for CNS delivery. Based on our preliminary results and the pre-clinical efficacy of 15-epi-LXA4 in AD models, we hypothesize that RISE-103 can be optimized into an orally dosable and brain penetrant therapy while maintaining its LXA4 mimicking actions. The aims of this SBIR are: 1. To optimize RISE-103 into an orally bioavailable & CNS-penetrant LXA4-mimicking FPR2 agonist and 2. Select lead LXA4-mimicking FPR2 agonist & backup using microglia assays & an AD mouse model. Research proposed herein is in response to PAS-19- 316 to develop and evaluate therapies to “slow and/or reverse” the course of AD and the NIA Strategic Plan translational objectives to support the development of innovative therapies to treat AD/ADRD.