Therapeutic Mitochondrial Uncouplers

项目摘要 该项目的目标是开发小分子线粒体解偶联剂，用于治疗非- 酒精性脂肪性肝炎（NASH），非酒精性脂肪性肝病（NAFLD）的晚期形式。约 2600万人（约占美国人口的6-8%）受NASH影响，超过30%的NASH患者- 相关的肝硬化将死于肝衰竭或肝细胞癌。目前还没有FDA批准的药物 临床试验中的顶级药物无效或具有不希望的副作用。纳什 其特征在于肝脏中的脂肪积聚、炎症和组织重塑。线粒体解偶联剂 由于其靶向脂肪积累的作用模式的性质，具有作为NASH治疗剂的强大潜力， 氧化应激线粒体解偶联剂将质子从线粒体膜间隙转运到线粒体膜上。 基质绕过ATP合成酶。这一过程增加了脂肪氧化，降低了线粒体反应性。 氧物质产生;从而，直接靶向作为NASH病理生理学基础的两个途径， 引发炎症和纤维化反应。我们的实验室最近发现了线粒体- 选择性的、安全的和口服生物可利用的线粒体解偶联剂，其具有宽的治疗窗。证明 NASH加速小鼠模型（STAM模型）的原理研究达到了FDA的基准， 通过将NAFLD活动性评分（NAS）降低2分来批准NASH治疗剂，其中至少一个 根据两种不同的NAS标准，并且没有纤维化恶化。这些强有力的初步数据 支持药物化学计划，以改善分子的药物样特性（目标1），并验证 在涉及胰淀素饮食的NASH的生理学和临床上更相关的小鼠模型中，研究了这些分子（目的2）。 我们计划的主要创新是发现了具有不同水平的化学支架， 线粒体解偶联能力是安全的和自限性的。由于目前没有药物 线粒体解偶联作为临床上的主要作用模式，我们的计划可能是第一个提供 用于治疗NASH的线粒体解偶联剂。事实上，该项目解决了一个关键的需求， 对支持调节线粒体解偶联以实现安全和有效性的数据的显著贡献 NASH的有效治疗。

PROJECT SUMMARY The goal of this project is to develop small molecule mitochondrial uncouplers for the treatment of non- alcoholic steatohepatitis (NASH), an advanced form of non-alcoholic fatty liver disease (NAFLD). Approximately 26 million people (~6-8% of US population) are affected by NASH, and more than 30% of patients with NASH- related cirrhosis will die from liver failure or hepatocellular cancer. There are currently no FDA-approved drugs to treat NASH and the top drugs in clinical trials suffer from ineffectiveness or have unwanted side effects. NASH is characterized by fat accumulation in the liver, inflammation, and tissue remodeling. Mitochondrial uncouplers have strong potential as NASH therapeutics by the nature of their mode of action targeting fat accumulation and oxidative stress. Mitochondrial uncouplers transport protons from the mitochondrial intermembrane space into the matrix bypassing ATP synthase. This process increases fat oxidation and decreases mitochondrial reactive oxygen species production; thereby, directly targeting two pathways that underlie NASH pathophysiology that drive inflammation and the fibrogenic response. Our laboratories have recently discovered mitochondria- selective, safe, and orally bioavailable mitochondrial uncouplers that have wide therapeutic window. Proof-of- principle studies in an accelerated mouse model of NASH (STAM model) achieved the FDA benchmark for approval of a NASH therapeutic by decreasing the NAFLD Activity Score (NAS) by 2 points, with at least one point coming from two different NAS criteria, and with no worsening of fibrosis. These strong preliminary data support a medicinal chemistry program to improve the drug-like properties of the molecules (Aim 1) and validate molecules in a more physiologically and clinically relevant mouse model of NASH involving Amylin diet (Aim 2). The major innovation of our program is the discovery of novel chemical scaffolds that have different levels of mitochondrial uncoupling capacity that are safe and self-limiting. As there are currently no drugs with a mitochondrial uncoupling as the primary mode of action in the clinic, our program could be the first to deliver mitochondrial uncouplers for the treatment of NASH. Indeed, this project addresses a critical need and will make significant contribution to data supporting the validity of modulating mitochondrial uncoupling for safe and efficacious treatment of NASH.