Preclinical Studies of Novel Anti-Diabetic Lipids

新型抗糖尿病脂质的临床前研究

• 批准号: 9515379
• 负责人: BARBARA B. KAHN
• 金额: $ 90.31万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-04 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9515379
• 关键词: Acute; Adipocytes; Adipose tissue; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Antidiabetic Drugs; Biological; Biological Assay; Biological Availability; Biology; Blood Glucose; Cells; Chemicals; Chronic; Clinic; Clinical Data; Clinical Trials; Data; Dendritic Cells; Development; Diabetes Mellitus; Diabetes prevention; Disease; Dose; Drug Kinetics; Drug Targeting; Effectiveness; Epidemic; Esters; Family; Fasting; Fatty Acids; G-Protein-Coupled Receptors; GCG gene; Genetically Engineered Mouse; Glucose; Goals; Half-Life; High Fat Diet; Human; Inflammation; Insulin; Insulin Resistance; Islets of Langerhans; Isomerism; Knockout Mice; Knowledge; Lead; Ligands; Lipids; Measurement; Mediating; Metabolic; Metabolic Diseases; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Oral; Palmitic Acids; Pathway interactions; Pharmaceutical Preparations; Positioning Attribute; Prevention strategy; Process; Property; Role; Safety; Schedule; Serum; Solubility; Stearic Acids; Structure; Structure-Activity Relationship; Testing; Therapeutic; Tissues; Toxic effect; Toxicology; Work; analog; base; clinical development; cytokine; design; diabetic; drug development; effective therapy; experimental study; glucose metabolism; glucose tolerance; glucose transport; hydroxy fatty acid; improved; in vivo; insight; insulin secretagogues; insulin secretion; insulin sensitivity; insulin sensitizing drugs; interest; macrophage; metabolic abnormality assessment; next generation; novel; pre-clinical; preclinical study; prevent; receptor; screening; small molecule; treatment strategy

Because of the growing epidemic of obesity, insulin resistance, and Type 2 diabetes, we need more effective and sustainable prevention and treatment strategies for these serious disorders. Significant gaps exist in our knowledge of the molecular mechanisms underlying insulin resistance and Type 2 diabetes, which limit our ability to develop fully effective and safe therapies to treat these metabolic diseases. In this application, we strive to develop a new class of antidiabetic therapeutics based on a structurally novel class of bioactive lipids we recently discovered called Fatty Acid esters of Hydroxy Fatty Acids (FAHFAs). Characterization of one family of FAHFAs, Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs), revealed that these lipids possess a remarkable range of activities that improve glucose metabolism and reduce inflammation. PAHSAs stimulate insulin secretion and GLP1 secretion, improve systemic insulin sensitivity (i.e. they are insulin sensitizers), and reduce proinflammatory cytokine secretion in adipose tissue of obese mice. As natural compounds, PAHSAs were not designed for a particular target. Instead, these lipids utilize multiple pathways through at least two G protein coupled receptors (GPCRs). This powerful combination of beneficial activities and receptor targets uniquely positions PAHSAs as an exciting new class of compounds for the treatment of diabetes. In Aim 1, we will design, synthesize, and test PAHSAs and PAHSA analogs to enhance solubility, biological activity, and metabolic stability. This process will be iterative as we synthesize PAHSA analogs we will test them in biologic assays and metabolic stability studies in Aims 1 and 2 and use this information to design the next generation of analogs with improved properties. In Aim 2, we will investigate pharmacokinetics, efficacy, and toxicity of PAHSAs and PAHSA analogs to determine which compounds have the ideal stability, oral availability, safety, and activity. The information from these experiments will also assist in the design of new PAHSA analogs in Aim 1. Then in Aim 3, we will determine the roles of GPR40 and GPR120 in mediating PAHSA biological effects in vivo using knockout mice and biologic assays in tissues from these mice. A clear mechanism of action is required for drugs moving into the clinic, and the finding that PAHSAs target two intensely pursued anti-diabetic GPCR drug targets will amplify interest in developing PAHSA-based drugs. We will also perform broad target screening since PAHSAs might have additional receptors or pathways. The combination of the data obtained in Aim 3 will provide a comprehensive understanding of the contribution of GPR40, GPR120, and other PAHSA targets to PAHSA biology in vivo. This application will provide the structural, pharmacokinetic, toxicology, and mechanistic data needed to develop PAHSAs or PAHSA analogs into novel anti-diabetes therapeutics.

由于肥胖症，胰岛素抵抗和2型糖尿病的流行病，我们需要对这些严重疾病的更有效和可持续的预防和治疗策略。我们对胰岛素抵抗和2型糖尿病的分子机制的了解存在很大的差距，这限制了我们开发完全有效且安全的治疗这些代谢疾病的能力。在此应用中，我们努力根据我们最近发现的称为羟基脂肪酸（Fahfas）的脂肪酸酯（FAHFAS）的结构新型生物活性脂质开发新的抗糖尿病治疗剂。羟基酸（PAHSA）的一个Fahfas，棕榈酸酯的表征表明，这些脂质具有改善葡萄糖代谢并减少炎症的显着活性。 PAHSA刺激胰岛素分泌和GLP1分泌，提高全身性胰岛素敏感性（即它们是胰岛素敏感性），并减少肥胖小鼠脂肪组织中促炎细胞因子分泌。作为天然化合物，PAHSA不是为特定目标设计的。相反，这些脂质通过至少两个G蛋白偶联受体（GPCR）利用多个途径。这种有益的活动和受体的强大组合将PAHSA唯一的位置作为一种令人兴奋的新化合物，用于治疗糖尿病。在AIM 1中，我们将设计，合成和测试PAHSA和PAHSA类似物，以增强溶解度，生物活性和代谢稳定性。当我们合成PAHSA类似物时，我们将在AIMS 1和2中的生物学测定和代谢稳定性研究中对其进行测试，这将是迭代的。在AIM 2中，我们将研究PAHSA和PAHSA类似物的药代动力学，功效和毒性，以确定哪些化合物具有理想的稳定性，口服可用性，安全性和活性。这些实验的信息还将在AIM 1中有助于设计新的PAHSA类似物。然后，在AIM 3中，我们将确定GPR40和GPR120在使用基因敲除小鼠中使用敲除小鼠和生物学测定中的PAHSA生物学作用在这些小鼠中的生物学分析中的作用。进入诊所的药物需要一种明确的作用机理，而PAHSA的目标是两个强烈追求抗糖尿病GPCR药物靶标的发现将扩大对开发基于PAHSA的药物的兴趣。我们还将进行广泛的目标筛选，因为PAHSA可能具有其他受体或途径。 AIM 3中获得的数据的组合将对GPR40，GPR120和其他PAHSA靶标的对PAHSA生物学的贡献进行全面了解。该应用将提供结构性，药代动力学，毒理学以及将PAHSA或PAHSA类似物开发为新型抗糖尿病疗法所需的机械数据。