Development of ferroptosis inhibitors for Huntington Disease

亨廷顿病铁死亡抑制剂的开发

• 批准号: 9810193
• 负责人: Brent R Stockwell
• 金额: $ 40.03万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9810193
• 关键词: Adult; Aftercare; Animal Model; Apoptosis; Autopsy; Biological; Biological Availability; Blood - brain barrier anatomy; Brain; CAG repeat; Cell Death; Cells; Computer software; Corpus striatum structure; Cytochrome P450; Degenerative Disorder; Development; Disease; Disease model; Dose; Drug Kinetics; Effectiveness; Endoplasmic Reticulum; Enzymes; Esters; Flowcharts; Foundations; Gap Junctions; Gastrointestinal tract structure; Genes; Genetic Diseases; Glutamates; Human; Huntington Disease; Huntington gene; Image; Immune; In Vitro; Inflammation Mediators; Inflammatory; Investigation; Lipid Peroxidation; Liver Microsomes; Mass Spectrum Analysis; Measures; Metabolic; Modeling; Monitor; Mus; N-terminal; Nerve Degeneration; Neurologic; Oral; Pathway interactions; Patients; Penetration; Pharmacodynamics; Phase; Plasma; Polyunsaturated Fatty Acids; Production; Property; Reporting; Role; Safety; Sampling; Series; Slice; Solubility; Structure-Activity Relationship; Testing; Therapeutic Agents; Toxic effect; analog; fatty acid metabolism; improved; in vivo; inhibitor/antagonist; lipophilicity; mouse model; neuroinflammation; neuron loss; neurotoxicity; novel therapeutic intervention; prevent

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.

项目概要 Ferrostatin 是一种有效的铁死亡抑制剂。这是一种非凋亡形式的细胞死亡，可能涉及 一些退行性疾病。我们已经展示了 Fer-1 在脑切片模型中的有效性 亨廷顿病 (HD) 和谷氨酸毒性。然而，铁他汀的药代动力学/药效学 (PK/PD) 特性使其不适合在动物模型中使用以进一步测试铁死亡在这些疾病中的作用 疾病。我们制备了一系列铁他汀类似物来探索铁他汀的构效关系 (SAR) 并改善活性、代谢和血浆稳定性。虽然我们在以下方面取得了重大进展 创造具有良好效力和血浆稳定性的代谢稳定类似物，额外的改进是 预计这可能会产生可在体内给药的高效、稳定的化合物。这样的结果 研究将是一组用于体内使用的优化化合物，以研究脂质过氧化在体内的作用 亨廷顿病小鼠模型。从长远来看，我们将能够使用这些优化的化合物 探讨脂质过氧化和铁死亡在多种退行性疾病中的作用。