Development of ferroptosis inhibitors for Huntington Disease

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Project Summary Ferrostatin is a potent inhibitor of ferroptosis; which is a non-apoptotic form of cell death potentially involved in a number of degenerative diseases. We have shown the effectiveness of Fer-1 in brain slice models of Huntington's disease (HD) and glutamate toxicity. However, ferrostatin's pharmacokinetic/pharmacodynamic (PK/PD) properties make it unsuitable for use in animal models to further test the role of ferroptosis in these diseases. We have made a series of ferrostatin analogs to explore ferrostatin's structure-activity relationship (SAR) and to improve activity and metabolic and plasma stability. While we have made significant progress in creating metabolically stable analogs with good potency and plasma stability, additional improvements are envisioned that could result in highly potent, stable compounds that could be dosed in vivo. The result of this investigation will be a set of optimized compounds for in vivo use to study the role of lipid peroxidation in a mouse model of Huntington Disease. In the longer term, we will be able to use these optimized compounds to probe the role of lipid peroxidation and ferroptosis in a variety of degenerative diseases.