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

用于治疗 NASH 的结构工程 N-酰基氨基酸

• 批准号: 10761044
• 负责人: Francisco Jose Schopfer
• 金额: $ 29.35万
• 依托单位: FURANICA, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10761044
• 关键词: Acceleration; Acetyl-CoA Carboxylase; Acids; Address; Affect; Amides; Amino Acids; Anabolism; Animal Model; Animals; Anti-Inflammatory Agents; Area; Binding; Biological; Biological Availability; Cardiovascular Diseases; Cardiovascular system; Cell model; Cellular Stress; Chemicals; Chemistry; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Complex; Development; Development Plans; Disease; Disease Progression; Disease model; Down-Regulation; Drug Kinetics; Economic Burden; Engineering; Enzymes; Exhibits; FDA approved; Failure; Family; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Functional disorder; Glucose; Goals; Hair; Half-Life; Healthcare; Hepatic; Hepatocyte; Homeostasis; Hydrolysis; Individual; Inflammation; Inflammatory; Insulin; Lead; Leucine; Libraries; Lipids; Liver; Liver Failure; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Mitochondria; Modification; Mus; NF-kappa B; Oral; Oral Administration; Outcome; Oxygen Consumption; PPAR alpha; Pathway interactions; Patients; Peptides; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase I/II Clinical Trial; Plasma; Population; Predisposition; Primary carcinoma of the liver cells; Property; Proteins; Proteomics; Protocols documentation; Research; Respiration; Risk; Rodent; Series; Signaling Molecule; Solid; Steatohepatitis; Testing; Therapeutic; Thermogenesis; Translations; Underserved Population; Up-Regulation; absorption; amino acid metabolism; aminoacid biosynthesis; antifibrotic treatment; bench-to-bedside translation; cell injury; comorbidity; crosslink; design; drug candidate; drug development; efficacy evaluation; experience; fatty acid oxidation; improved; indexing; interdisciplinary approach; interest; intraperitoneal; lipid biosynthesis; lipid metabolism; mass spectrometer; mouse model; nitroalkene; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel drug class; oxidation; pharmacologic; pre-clinical; preclinical development; preclinical study; protective effect; screening; therapeutic development; transcriptome sequencing

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.

项目摘要 当肝脏中积聚的脂肪量超过脂肪量时，会发生非酒精性脂肪性肝炎（NASH） 肝细胞并引起感染。疾病的进展进一步导致纤维化，肝细胞 癌和肝衰竭。经过单药治疗的临床试验中的许多失败后，治疗 方法逐渐转向使用涉及代谢修饰符和的组合疗法 抗纤维化剂。但是，到目前为止取得了有限的进展。我们最近发现，不仅 脂质代谢，但氨基酸代谢也被禁用于NASH，导致脂肪酸的发展 氨基酸偶联物（NAAS）与两种代谢途径相交以治疗NASH。老鼠与 已建立的纳什（Nash）接受内源性NAAS治疗，暴露于脂肪性肝炎和纤维化。使用 我们设计，合成，测试和优化了一种医学化学方法，一系列新型NAA。我们的 当前的铅化合物FAL-113获得了出色的物理特性，口服生物利用度和有效性 在初步的细胞和动物模型中。假设FAL-113可以通过 同时增加脂肪酸氧化并减少其生物合成，同时提供抗纤维化 与内源性NAA一起看。此外，新颖的结构修饰改善了化合物的口服 生物利用度和半衰期，使原本不可能的口服给药。 FAL-113的代谢 还释放了二级生物活性脂肪酸，该脂肪酸通过代谢来改善能量稳态 重新编程，随后受益于通常与NASH相关的合并症。很大 新颖的NAAS的改善药代动力学和效率使我们假设FAL-113可以解决NASH 通过多路复用机制 - 协同代谢修饰和抗 - 炎症/纤维化特性。该假设将通过追求以下特定目的来检验： 目标1：使用生物正交化学确定FAL-113的作用机理。 AIM 2：在啮齿动物中建立FAL-113的药代动力学。 AIM 3：在NASH小鼠模型中定义FAL-113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 - 基于的分析，动物药代动力学和药理学，将明确揭示Adme，验证该ADME 防止NASH的保护并表征铅复合FAL-113的作用模式。成功 该项目的结果将导致一个可靠的临床前候选者，准备进行研究，并大量研究 加速其转化为NASH患者的实际临床价值。 领导这项工作的团队已经经历并参与了有关相关的几项临床前和临床研究 疾病地区。此外，团队还得到经验丰富的合作者和顾问的支持 拟议的研究计划成功。