APJ receptor agonism for metabolic syndrome

APJ 受体激动剂治疗代谢综合征

• 批准号: 9239698
• 负责人: RANGAN MAITRA
• 金额: $ 47.15万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9239698
• 关键词: APLN gene; Adipocytes; Adipose tissue; Adverse effects; Affinity; Agonist; Agreement; American; Animals; Antihypertensive Agents; Binding; Biogenesis; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Blood Glucose; Blood Vessels; Body Weight decreased; Calories; Cardiovascular system; Cells; Centers for Disease Control and Prevention (U.S.); Chronic; Coupled; Critiques; Cyclic AMP; Cytochrome P450; Data; Development; Diet; Disease; Drug Kinetics; Endothelial Cells; Endothelium; Enzymes; Exhibits; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Food; GTP-Binding Protein alpha Subunits, Gs; Glucose Intolerance; Goals; Half-Life; Heart Diseases; Hepatic; High Density Lipoproteins; High Fat Diet; Hormones; Hypertension; Hypertriglyceridemia; In Vitro; Insulin; Insulin Resistance; Knockout Mice; Lead; Libraries; Life; Ligands; Lipolysis; Lymphatic vessel; Metabolic; Metabolic syndrome; Mitochondria; Modality; Modeling; Modification; Monitor; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Oral; Palate; Penetration; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Plasma; Play; Production; Property; Proteins; Reporting; Resistance; Risk; Rodent; Skeletal Muscle; Source; Steatohepatitis; Stroke; Testing; Time; Transgenic Mice; Transport Process; Validation; Work; abdominal fat; absorption; adipokines; analog; cancer type; clinical development; clinically relevant; cytotoxic; design; diabetic patient; disorder prevention; efficacy study; efficacy testing; fasting glucose; fatty acid oxidation; fatty acid transport; hemodynamics; high throughput screening; improved; in vitro Model; in vivo; insulin sensitizing drugs; knockout animal; novel; radioligand; receptor; release of sequestered calcium ion into cytoplasm; response; scaffold; small molecule; tool; uptake

The overall goal of this project is to develop apelin (APJ) receptor agonists to treat diet-induced obesity (DIO) and related metabolic syndrome. Metabolic syndrome can lead to several life threatening conditions including hypertension, heart disease, type II diabetes, steatohepatitis, stroke, and certain types of cancer. Available medications to treat obesity have serious side effects and limited efficacy. Thus, new medications around novel targets are needed. The APJ receptor is a G-protein coupled receptor (GPCR) protein that is activated by apelin peptides and a newly described hormone called TODDLER/ELABELA. It is an emerging multi-modal target for metabolic syndrome that needs pharmacological validation. Apelin is an insulin sensitizer that promotes fatty acid oxidation. Apelin knockout (ko) mice have higher insulin levels and glucose intolerance along with increased abdominal fat and higher bodyweight. Apelin through its interaction with APJ can inhibit maturation of pre-adipocytes and lipolysis in mature adipocytes. Activation of APJ by apelin in the endothelium leads to the formation of large, non-leaky lymphatic and blood vessels that restrict the transport of FA and their uptake in adipose. In agreement with these data, apelin ko mice have vessels that are more amenable to FA transport. Another report has indicated that apelin transgenic mice are resistant to DIO by virtue of increased vascular mass and mitochondrial biogenesis in skeletal muscles. Non-peptide probes of this receptor suitable for in vivo work are not available. We have identified a structurally novel agonist scaffold for further development through high-throughput screening. We propose to refine our early lead compounds to produce in vivo probes of APJ using three iterative specific aims. Through aim 1, synthesis and refinement of APJ probes will continue using medicinal chemistry approaches. Through aim 2, these compounds will be characterized using functional and radioligand displacement assays for APJ. Potent compounds will be then characterized using a battery of ADMET and pharmacokinetic assays. Through aim 3, in vivo testing of the best compounds will be performed in a chronic model of DIO in rodents. Completion of the project will pharmacologically validate APJ as a target for medications development to treat metabolic syndrome and produce advanced lead compounds for eventual clinical development.

该项目的总体目标是开发apelin（APJ）受体激动剂来治疗饮食引起的肥胖 （DIO）和相关的代谢综合征。代谢综合征可导致多种危及生命的疾病 包括高血压、心脏病、二型糖尿病、脂肪性肝炎、中风和某些类型的癌症。 现有的治疗肥胖症的药物具有严重的副作用且疗效有限。因此，新药 需要围绕新的目标。 APJ 受体是一种 G 蛋白偶联受体 (GPCR) 蛋白， 由 apelin 肽和一种新描述的称为 TODDLER/ELABELA 的激素激活。它是一个新兴的 需要药理学验证的代谢综合征的多模式靶点。 Apelin是一种胰岛素 促进脂肪酸氧化的敏化剂。 Apelin 基因敲除 (ko) 小鼠的胰岛素水平和葡萄糖水平更高 不耐受以及腹部脂肪增加和体重增加。 Apelin 通过与 APJ 的互动 可以抑制前脂肪细胞的成熟和成熟脂肪细胞的脂肪分解。 apelin 激活 APJ 内皮导致形成大的、无渗漏的淋巴管和血管，限制运输 FA 及其在脂肪中的摄取。与这些数据一致，apelin ko 小鼠的血管更 适合 FA 运输。另一份报告表明 apelin 转基因小鼠通过以下方式对 DIO 产生抗性： 由于骨骼肌中血管质量和线粒体生物发生的增加。该非肽探针 适合体内工作的受体尚不可用。我们已经确定了一种结构新颖的激动剂支架 通过高通量筛选进一步开发。我们建议改进我们的早期先导化合物 使用三个迭代特定目标产生 APJ 体内探针。通过目标 1，综合和细化 APJ 探针将继续使用药物化学方法。通过目标 2，这些化合物将 使用 APJ 的功能和放射性配体置换测定进行表征。届时将出现有效的化合物 使用一系列 ADMET 和药代动力学测定进行表征。通过目标3，体内测试最佳 化合物将在啮齿类动物的慢性 DIO 模型中进行研究。该项目的完成将 药理学验证 APJ 作为治疗代谢综合征药物开发的靶标 生产用于最终临床开发的先进先导化合物。