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，过量的脂肪在肝脏中积聚，损害 肝细胞并引起炎症。该疾病的进展进一步导致纤维化、肝细胞性肝硬化、肝纤维化、肝硬化、肝硬化、肝纤维化、肝硬化。 癌症和肝功能衰竭。在单一药物治疗的临床试验中多次失败后， 方法已逐渐转向使用涉及代谢调节剂和 抗纤维化剂。然而，迄今为止取得的进展有限。我们最近发现， 在NASH中，脂质代谢以及氨基酸代谢被破坏，导致脂肪酸- 与两种代谢途径交叉的氨基酸缀合物（NAA）用于治疗NASH。小鼠 用内源性NAA治疗的已建立的NASH表现出减少的脂肪性肝炎和纤维化。使用 一种药物化学方法，我们设计，合成，测试和优化了一系列新的NAA。我们 目前的先导化合物FAL-113获得了上级的理化性质、口服生物利用度和功效 初步的细胞和动物模型。假设FAL-113可以通过以下方式降低脂毒性： 同时增加脂肪酸氧化和减少其生物合成，同时提供抗纤维化 与内源性NAA一起出现。此外，新的结构修饰改善了化合物的口服 生物利用度和半衰期，使得否则不可能的口服给药成为可能。FAL-113的代谢 还释放二级生物活性脂肪酸，通过代谢改善能量平衡 重编程，其随后有益于通常与NASH相关的合并症。大大 新型NAA的药代动力学和疗效的改善使我们假设FAL-113可以治疗NASH， 通过多重机制-协同代谢修饰和抗- 炎症/纤维化特性。将通过追求以下具体目标来检验这一假设： 目的1：利用生物正交化学确定FAL-113的作用机制。 目的2：建立FAL-113在啮齿动物中的药代动力学。 目的3：确定FAL-113在NASH小鼠模型中的药理学。 该项目涉及的多学科方法，包括生物正交化学，质谱仪- 基于分析，动物药代动力学和药理学，将明确揭示ADME，验证 保护免受NASH，并表征先导化合物FAL-113的作用模式。成功 该项目的成果将产生一个坚实的临床前候选人准备IND使能研究， 加速其转化为NASH患者的真实的临床价值。 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。 病区。此外，该团队还得到经验丰富的合作者和顾问的支持， 成功提出研究计划。

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.