Structurally engineered N-acyl amino acids for the treatment of NASH

项目摘要 非酒精性脂肪性肝炎(NASH)发生时，肝脏中过多的脂肪积聚，损害 肝细胞和引起炎症。疾病的发展进一步导致纤维化，肝细胞 癌症和肝功能衰竭。在单剂疗法的临床试验多次失败后，治疗性的 方法逐渐转向使用联合疗法，既包括代谢调节剂，也包括 一种抗纤维化的药剂。然而，到目前为止，进展有限。我们最近发现，不仅 NASH不仅脂肪代谢紊乱，而且氨基酸代谢紊乱，导致脂肪酸的发展- 氨基酸结合物(NaAs)交叉于两条代谢途径，用于治疗NASH。小鼠带有 确诊的NASH患者接受内源性NaAS治疗后，脂肪性肝炎和纤维化程度降低。vbl.使用 作为一种药物化学方法，我们设计、合成、测试和优化了一系列新型的NaAs。我们的 目前的先导化合物FAL-113获得了优异的物理化学性质、口服生物利用度和有效性 在初步的细胞和动物模型中。推测FAL-113可通过以下途径降低脂毒性 同时增加脂肪酸的氧化和减少其生物合成，同时提供抗纤维化 与内源性NAA一起观察。此外，新的结构修饰提高了化合物的口服力 生物利用度和半衰期，使原本不可能的口服。FAL-113的代谢 还会释放一种次级生物活性脂肪酸，通过代谢改善能量动态平衡 重新编程，这随后有利于通常与NASH相关的合并症。大名鼎鼎 新型NAAS的药代动力学和疗效的改善使我们假设FAL-113可以对付NASH 通过一种多元化的机制--协同新陈代谢修饰和抗衰老的益处 炎症/纤维化性质。这一假设将通过追求以下具体目标来检验： 目的1：用生物正交化学方法确定FAL-113的作用机制。 目的：建立FAL-113在啮齿动物体内的药代动力学。 目的3：明确FAL-113在NASH小鼠模型中的药理作用。 该项目涉及多学科方法，包括生物正交化学、质谱仪- 基于分析，以及动物药代动力学和药理学，将最终揭示ADME，验证 防止NASH并表征先导化合物FAL-113的作用模式。成功者 该项目的结果将产生一个坚实的临床前候选人，为IND-Enabling研究做好准备，并大大 加速将其转化为对NASH患者的真正临床价值。 领导这项工作的团队经历并参与了相关的几项临床前和临床研究 疫区。此外，团队还得到经验丰富的合作者和顾问的支持，以执行 成功地提出了研究计划。

Project Summary Nonalcoholic steatohepatitis (NASH) occurs when excessive amounts of fat build up in the liver, damaging hepatocytes and causing inflammation. The progression of the disease further leads to fibrosis, hepatocellular carcinoma, and liver failure. After numerous failures in clinical trials with single-agent therapies, the therapeutic approach has gradually shifted toward using combination therapies that involve both a metabolic modifier and an anti-fibrotic agent. However, limited progress has been made so far. We recently discovered that not only lipid metabolism but also amino acid metabolism is disrupted in NASH, leading to the development of fatty acid- amino acid conjugates (NAAs) intersecting both metabolic pathways for the treatment of NASH. Mice with established NASH that were treated with endogenous NAAs exhibited reduced steatohepatitis and fibrosis. Using a medicinal chemistry approach, we designed, synthesized, tested, and optimized a series of novel NAAs. Our current lead compound, FAL-113, obtained superior physicochemical properties, oral bioavailability, and efficacy in preliminary cellular and animal models. It is hypothesized that FAL-113 could reduce lipotoxicity by simultaneously increasing fatty acid oxidation and decreasing its biosynthesis while providing the anti-fibrosis seen with the endogenous NAAs. In addition, the novel structural modification improved the compound’s oral bioavailability and half-life, enabling an otherwise impossible oral administration. The metabolism of FAL-113 also releases a secondary bioactive fatty acid that improves energy homeostasis through metabolic reprogramming, which subsequently benefits the comorbidities commonly associated with NASH. The greatly improved pharmacokinetics and efficacy of novel NAAs led us to hypothesize that FAL-113 could tackle NASH through a multiplexed mechanism – synergizing the benefits of metabolic modification and anti- inflammatory/fibrotic properties. This hypothesis will be tested by pursuing the following Specific Aims: Aim 1: Determine the mechanisms of action of FAL-113 using bioorthogonal chemistry. Aim 2: Establish the pharmacokinetics of FAL-113 in rodents. Aim 3: Define the pharmacology of FAL-113 in a NASH mouse model. The multidisciplinary approach involved in the project, including bioorthogonal chemistry, mass spectrometer- based analytics, and animal pharmacokinetics and pharmacology, will definitively reveal the ADME, validate the protection against NASH and characterize the modes of action of the lead compound FAL-113. The successful outcomes of this project will result in a solid preclinical candidate ready for IND-enabling studies and greatly accelerate its translation to real clinical value for NASH patients. The team leading this effort has experienced and participated in several preclinical and clinical studies in related disease areas. In addition, the team is supported by experienced collaborators and consultants to execute the proposed research plan successfully.