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

结构工程呋喃脂肪酸用于治疗血脂异常和心血管疾病

基本信息

批准号：
10603408
负责人：
Francisco Jose Schopfer
金额：
$ 29.92万
依托单位：
FURANICA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10603408
关键词：
Acceleration Address Adherence Agonist Animal Model Animals Anti-Inflammatory Agents Antiatherogenic Antiinflammatory Effect Apolipoprotein E Area Atherogenic Diet Atherosclerosis Benchmarking Biochemical Biological Availability Biological Markers Blood Vessels Cardiovascular Diseases Cardiovascular Pathology Cardiovascular system Cessation of life Cholesterol Clinical Clinical Research Coenzyme A Combined Modality Therapy Complex Data Development Diabetes Mellitus Disease Dose Drug Kinetics Drug Prescriptions Drug Side Effects Dyslipidemias Engineering Enzymes Event Exposure to FDA approved Fatty Acids Fatty Liver Fenofibrate Fish Oils Foundations Functional disorder Furans Future Glycolysis Half-Life Hepatic High Density Lipoprotein Cholesterol High Fat Diet Hypertension Hypertriglyceridemia Immune Incidence Individual Inflammation Inflammatory Inflammatory Response Insulin Insulin Resistance Investigation Lead Libraries Lipids Lipoproteins Low-Density Lipoproteins Medicine Metabolic Metabolic Diseases Metabolic dysfunction Metabolic syndrome Metabolism Minor Modeling Morbidity - disease rate Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Oils Omega-3 Fatty Acids Outcome Pathway Analysis Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacology Study Phase Phase II Clinical Trials Plasma Polypharmacy Property Research Residual state Risk Risk Factors Rodent Route Series Solid Synthesis Chemistry Testing Therapeutic Tissues Translations Triglycerides Underserved Population absorption analytical method bench-to-bedside translation blood glucose regulation cardiovascular disorder prevention cardiovascular risk factor comorbidity compliance behavior course development design diabetic patient drug candidate drug development experience fasting glucose fatty acid analog fatty acid metabolism fatty acid oxidation holistic approach improved in vivo inflammatory marker interdisciplinary approach marine mass spectrometer mimetics mortality mouse model nitroalkene non-alcoholic fatty liver disease novel novel strategies novel therapeutic intervention pharmacodynamic biomarker pre-clinical preclinical development preclinical study primary endpoint response rosuvastatin secondary endpoint stem success synergism transcriptome sequencing

项目摘要

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

1个项目摘要血脂异常患者的2个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，患有其他并发风险因素的患者存在明显的残留心血管风险 4作为肥胖，糖尿病，胰岛素抵抗和富含甘油三酸酯的脂蛋白升高。给定多方面 5心血管疾病的潜在病理，多药方法用于针对个人风险 6个因素，但由于各种药物副作用，缺乏协同作用和患者依从性较低而取得成功的因素有限。 7鱼油有效降低高甘油三酯血症和欧米茄3的基于omega-3脂肪酸的疗法得到FDA的批准 8治疗这种情况。我们发现了鱼油的次要成分，也存在于FDA批准的Omega-3-中 9种基于药物，这在引起这些作用方面具有更大的潜力。我们使用医学化学方法，设计了 10合成，测试和优化了一系列具有改善代谢稳定性和治疗的化合物 11效力。铅化合物FA-1011在高脂饮食NAFLD小鼠中显示出明显的保护 12个模型，减少循环胆固醇，甘油三酸酯，肝脂肪变性，由A引起的炎症标记 13重大的肝脏代谢重新布线。受保护的，抗炎作用和循环的改善 14脂质轮廓使我们假设FA-1011可以通过减少来解决多因素心血管疾病 15颗粒形成，使血脂异常归一化，减轻胰岛素抵抗和征求抗炎 16个回应。特别是，该假设将通过追求以下特定目的来检验： 17 AIM 1：评估FA-1011的抽象，分布和代谢。 18 AIM 2：定义FA-1011对APOE –/ - 小鼠的动脉粥样硬化的保护。 19项目中涉及的多学科方法，包括基于质谱仪的合成化学 20分析，动物药代动力学和药理学将明确揭示ADME，验证抗抗药性 21动脉粥样硬化的影响并表征铅化合物FA-1011的作用模式。成功该项目的22个结果将导致一个可靠的临床前候选者准备进行辅助研究，并大量 23加速其转化为过度心血管风险伯恩患者的实际临床价值。 24领导这项工作的团队经验丰富，并参加了几项临床前和临床研究（5个 25阶段I和2期II）在相关疾病地区。此外，团队得到了重要的合作者的支持 26和顾问成功执行拟议的研究计划。 27