Structurally engineered furan fatty acids for the treatment of dyslipidemia and cardiovascular disease

1项目概要 2血脂异常患者的心血管风险通常通过使用他汀类药物降低LDL-C水平来控制。 3然而，在伴有其他并发风险因素的患者中， 4.肥胖、糖尿病、胰岛素抵抗和高脂血症。鉴于多方面的 5心血管疾病的潜在病理学，应用多种药物治疗方法以针对个体风险 6个因素，但由于各种药物副作用、缺乏协同作用和患者依从性低，成功有限。 7鱼油有效降低高脂血症，基于omega-3脂肪酸的治疗方法获得FDA批准 8、治疗这种情况。我们发现了鱼油的一种微量成分，也存在于FDA批准的omega-3脂肪酸中， 9为基础的药物，这是更有效地引发这些影响。使用药物化学方法，我们设计了， 10合成，测试和优化了一系列具有改善的代谢稳定性和治疗效果的化合物。 11力量先导化合物FA-1011在高脂饮食的NAFLD小鼠中表现出显著的保护作用 12模型，降低循环胆固醇，甘油三酯，肝脂肪变性，炎症标志物引起的 13例显著的肝代谢重连。保护、抗炎作用和改善循环 14脂质谱使我们假设FA-1011可以通过降低血脂水平来治疗多因素心血管疾病。 15斑块形成，正常化血脂异常，减轻胰岛素抵抗，并征求抗炎 16个答案具体而言，将通过追求以下具体目标来检验假设： 目的1：评价FA-1011的吸收、分布和代谢。 目的2：确定FA-1011对ApoE-/-小鼠动脉粥样硬化的保护作用。 19该项目涉及的多学科方法包括合成化学、基于质谱仪的 20分析，动物药代动力学和药理学将明确揭示ADME，验证抗 21动脉粥样硬化的影响和表征的先导化合物FA-1011的作用模式。成功 该项目的22项成果将为IND启动研究提供可靠的临床前候选药物， 23加速其转化为对心血管风险负担过大的患者的真实的临床价值。 24领导这项工作的团队经验丰富，参与了几项临床前和临床研究（5 25个I期和2个II期）。此外，该团队还得到了重要合作者的支持 26和顾问成功地执行拟议的研究计划。 27

1 Project Summary 2 Cardiovascular risks in dyslipidemia patients are commonly controlled by lowering the LDL-C level using statins. 3 However, a significant residual cardiovascular risk persists in patients with additional concurrent risk factors such 4 as obesity, diabetes, insulin resistance, and elevated triglyceride-rich lipoproteins. Given the multifaceted 5 underlying pathology of cardiovascular disease, polypharmacy approaches are applied to target individual risk 6 factors but with limited success due to various drug side effects, lack of synergy, and low patient adherence. 7 Fish oils effectively lower hypertriglyceridemia, and omega-3 fatty acids-based treatments are approved by FDA 8 to treat this condition. We discovered a minor component of fish oil, also present in FDA-approved omega-3- 9 based drugs, that is more potent in eliciting these effects. Using a medicinal chemistry approach, we designed, 10 synthesized, tested, and optimized a series of compounds with improved metabolic stability and therapeutic 11 potency. The lead compound, FA-1011, demonstrated significant protection in a high-fat diet NAFLD mouse 12 model, reducing circulating cholesterol, triglycerides, hepatic steatosis, inflammatory markers caused by a 13 significant hepatic metabolic rewiring. The protective, anti-inflammatory effect and the improvement in circulating 14 lipid profile led us to hypothesize that FA-1011 could tackle the multifactorial cardiovascular disease by reducing 15 plaque formation, normalizing dyslipidemia, alleviating insulin resistance, and soliciting anti-inflammatory 16 responses. In particular, the hypothesis will be tested by pursuing the following Specific Aims: 17 Aim 1: Evaluate the absorption, distribution, and metabolism of FA-1011. 18 Aim 2: Define the protection of FA-1011 against atherosclerosis in ApoE–/– mice. 19 The multidisciplinary approach involved in the project including synthetic chemistry, mass spectrometer-based 20 analytics, and animal pharmacokinetics and pharmacology will definitively reveal the ADME, validate the anti- 21 atherosclerotic impact and characterize the modes of action of the lead compound FA-1011. The successful 22 outcomes of this project will result in a solid preclinical candidate ready for IND-enabling studies, and greatly 23 accelerate its translation to real clinical value for patients with excessive cardiovascular risk burden. 24 The team leading this effort is experienced and has participated in several preclinical and clinical studies (5 25 Phase I and 2 Phase II) in related disease areas. In addition, the team is supported by significant collaborators 26 and consultants to successfully execute the proposed research plan. 27