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

1个项目摘要 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低密度脂蛋白水平来控制。 然而，在同时存在其他危险因素的患者中，仍然存在显著的心血管风险。 4肥胖、糖尿病、胰岛素抵抗和富含甘油三酯的脂蛋白升高。考虑到多方面的 5心血管疾病的基本病理，多药联用方法被应用于针对个人风险 6个因素，但由于各种药物副作用，缺乏协同作用，患者依从性低，疗效有限。 7种鱼油有效降低高甘油三酯血症，基于omega-3脂肪酸的治疗方法被FDA批准 8治疗这种情况。我们发现了鱼油中的一种很小的成分，也存在于FDA批准的omega-3中- 以9为基础的药物，在引起这些影响方面更有效。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化合物，提高了代谢稳定性和治疗效果 11效力。先导化合物FA-1011在高脂饮食的NAFLD小鼠中显示出显著的保护作用 12模型，降低循环胆固醇、甘油三酯、肝脏脂肪变性、炎症标记物引起的 13显著的肝脏代谢重排。保护、抗炎作用与改善血液循环 14血脂谱使我们假设FA-1011可以通过减少 15斑块形成，正常血脂，缓解胰岛素抵抗，并寻求抗炎 16份回复。特别是，将通过追求以下具体目标来检验这一假设： 17目的1：评价FA-1011的吸收、分布和代谢。 18目的2：明确FA-1011对载脂蛋白E-/-小鼠动脉粥样硬化的保护作用。 19参与该项目的多学科方法，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最终揭示ADME，验证抗- 21对动脉粥样硬化的影响，并表征铅化合物FA-1011的作用模式。成功者 该项目的22项成果将产生一个坚实的临床前候选人，为IND支持研究做好准备，并极大地 23对于心血管风险负担过重的患者，加速将其转化为真正的临床价值。 24领导这项工作的团队经验丰富，并参与了几项临床前和临床研究(5 25个第一阶段和2个第二阶段)在相关疾病地区。此外，该团队还得到了重要合作者的支持 26和顾问成功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