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、胰岛素抵抗和 2 型糖尿病日益流行，我们需要针对这些严重疾病采取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 型糖尿病分子机制的了解存在重大差距，这限制了我们开发完全有效和安全的疗法来治疗这些代谢疾病的能力。在此应用中，我们致力于开发一类新型抗糖尿病疗法，其基础是我们最近发现的一种结构新颖的生物活性脂质，称为羟基脂肪酸脂肪酸酯（FAHFAs）。 FAHFA 家族——羟基硬脂酸棕榈酸酯 (PAHSA) 的表征表明，这些脂质具有一系列显着的活性，可改善葡萄糖代谢和减少炎症。 PAHSA 刺激胰岛素分泌和 GLP1 分泌，提高全身胰岛素敏感性（即它们是胰岛素增敏剂），并减少肥胖小鼠脂肪组织中促炎细胞因子的分泌。作为天然化合物，PAHSA 并不是针对特定目标而设计的。相反，这些脂质通过至少两个 G 蛋白偶联受体 (GPCR) 利用多种途径。这种有益活性和受体靶标的强大组合使 PAHSA 成为治疗糖尿病的一类令人兴奋的新型化合物。在目标 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，这个过程将是迭代的，我们将在目标 1 和 2 中的生物测定和代谢稳定性研究中测试它们，并使用这些信息来设计具有改进特性的下一代类似物。在目标 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、口服利用度、安全性和活性。这些实验的信息还将有助于目标 1 中新的 PAHSA 类似物的设计。然后在目标 3 中，我们将使用敲除小鼠和这些组织中的生物测定来确定 GPR40 和 GPR120 在体内介导 PAHSA 生物效应中的作用。老鼠。药物进入临床需要明确的作用机制，而 PAHSA 靶向两个备受追捧的抗糖尿病 GPCR 药物靶点的发现将增强开发基于 PAHSA 的药物的兴趣。我们还将进行广泛的靶点筛选，因为 PAHSA 可能有其他受体或途径。结合目标 3 中获得的数据将提供对 GPR40、GPR120 和其他 PAHSA 靶点对体内 PAHSA 生物学的贡献的全面了解。该申请将提供将 PAHSA 或 PAHSA 类似物开发成新型抗糖尿病疗法所需的结构、药代动力学、毒理学和机制数据。