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

• 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
• 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

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项目概述