APJ receptor agonism for metabolic syndrome

APJ 受体激动剂治疗代谢综合征

• 批准号: 9899980
• 负责人: RANGAN MAITRA
• 金额: $ 48.62万
• 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/9899980
• 关键词: APLN gene; Adipocytes; Adipose tissue; Affinity; Agonist; Agreement; American; Animals; Antihypertensive Agents; Binding; Biogenesis; Biological Assay; Biological Markers; Blood Glucose; Blood Vessels; Body Weight decreased; Calories; Cardiovascular system; Cells; Centers for Disease Control and Prevention (U.S.); Chronic; Consumption; 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; G-Protein-Coupled Receptors; 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; Metabolic; Metabolic syndrome; Mitochondria; Modeling; Modification; Monitor; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Oral; Palate; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Plasma; Play; Production; Property; Proteins; Reporting; Resistance; Risk; Rodent; Skeletal Muscle; Source; Steatohepatitis; Stroke; Structure; Testing; Time; Transgenic Mice; Transport Process; Validation; Work; abdominal fat; absorption; adipokines; analog; blood-brain barrier penetration; cancer type; clinical development; clinically relevant; cytotoxic; design; diabetic patient; efficacy study; efficacy testing; fasting glucose; fatty acid oxidation; fatty acid transport; hemodynamics; high throughput screening; improved; in vitro Model; in vivo; in vivo evaluation; insulin sensitizing drugs; knockout animal; lymphatic vessel; multimodality; novel; radioligand; receptor; release of sequestered calcium ion into cytoplasm; response; scaffold; side effect; 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.

本项目的总体目标是开发APJ受体激动剂治疗饮食性肥胖