Eicosanoid-based Therapy for Diabetes

基于类二十烷酸的糖尿病疗法

基本信息

批准号：
9129716
负责人：
John D Imig
金额：
$ 47.44万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-20 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9129716
关键词：
Accounting Acids Address Adverse effects Affect American Animal Model Anti-Inflammatory Agents Anti-inflammatory Attenuated Biological Availability Blood Pressure Blood Vessels Cardiovascular system Central obesity Chemicals Chronic Disease Coagulation Process Complex Complication Coxibs Cyclooxygenase Inhibitors Data Development Diabetes Mellitus Diagnosis Diet Dinoprostone Disease Dose Drug Kinetics Eicosanoid Modulation Eicosanoids Epoprostenol Epoxide hydrolase Event Functional disorder Generations Glucose Goals Health High Density Lipoprotein Cholesterol High Fat Diet Human Hypertension Hypertriglyceridemia Inbred SHR Rats Incidence Inflammation Inflammatory Injury Insulin Insulin Resistance Investigational New Drug Application Kidney Kidney Diseases Kidney Failure Lead Leptin Lipids Metabolic syndrome Mission Mucous Membrane Myocardial Infarction National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Obesity Outcome PTGS2 gene Pain Pancreas Patients Pharmaceutical Chemistry Pharmaceutical Preparations Production Prostaglandin-Endoperoxide Synthase Prostaglandins I Public Health Regimen Renal function Research Research Project Grants Risk Risk Factors Rodent Model Role Safety Signal Transduction Staging Stroke Testing Therapeutic Thromboxanes Ulcer United States National Institutes of Health Validation base benzenesulfonamide cyclooxygenase 2 design diabetes mellitus therapy diabetic diabetic patient diabetic rat effective therapy eicosanoid metabolism feeding gastrointestinal improved inhibitor/antagonist insulin signaling interest metabolome new therapeutic target novel novel therapeutics prevent prototype research study scaffold single molecule small molecule targeted treatment therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Diabetes and metabolic syndrome (MetS) afflicts close to 70 million Americans and diabetes accounts for close to half of all new cases of kidney failure. There is increasing interest in finding therapeutic targets and therapies that target multiple risk factors, thereby minimizing problems associated with multi-drug regimens in MetS and type 2 diabetic patients. The eicosanoid metabolome is altered in MetS and type 2 diabetes patients. The eicosanoid metabolome is altered in MetS and type 2 diabetes, and such alterations have been demonstrated to affect multiple factors including blood pressure, lipid levels, and insulin signaling. We have developed a novel chemical entity, 4-(phenyl-3-{3-[-(4-trifluoromethyl-phenyl)-ureido]-propyl}-pyrazol-1-yl)- benzenesulfonamide (PTUPB), that uniquely inhibits both soluble epoxide hydrolase (sEH) and cyclooxygenase (COX) and demonstrates potential as a therapeutic for MetS, type 2 diabetes and the associated kidney failure. Our long-term objective is to make significant steps towards an ultimate goal of an Investigational New Drug (IND) application for a novel chemical entity that uniquely alters eicosanoid metabolites and demonstrates potential as a therapeutic for MetS, type 2 diabetes. The overall objective of this application, which is the next step toward attainment of our long-term goal, is the pharmacological testing and the development and optimization of PTUPB-based COX-2/sEH inhibitors as a novel therapy for MetS and type 2 diabetes. Our central hypothesis is that inhibition of both COX-2 and sEH will uniquely alter eicosanoid metabolites to improve insulin signaling and renal function in MetS and type 2 diabetes. Our preliminary experiments demonstrate that the COX-2/sEH inhibitor, PTUPB has great therapeutic potential for treating multiple risk factors of MetS, type 2 diabetes and the associated kidney failure. Guided by strong preliminary data, our central hypothesis will be tested by pursuing three specific aims: 1) Optimize the PTUPB chemical scaffold to enhance the pharmacokinetic profile and the therapeutic potential; 2) Test the hypothesis that COX- 2/sEH inhibitors will manipulate eicosanoid metabolites to improve insulin signaling and pancreatic function, and decrease renal injury in MetS; 3) Test the hypothesis that COX-2/sEH inhibitors will manipulate eicosanoid metabolites to improve insulin signaling and pancreatic function, and decrease renal injury in type 2 diabetes. This project will conduct pharmacological testing of prototype small molecules in relevant animal models of MetS and type 2 diabetes. A major part of this proposal will be to utilize medicinal chemistry and computational approaches to optimize our early pre-therapeutic lead PTUPB. This contribution will be significant because it will open the door for identification and further development of COX-2/sEH inhibitors towards a therapeutic for diabetes and kidney disease.

描述（由申请人提供）：糖尿病和代谢综合征 (MetS) 困扰着近 7000 万美国人，糖尿病占所有新发肾衰竭病例的近一半。人们越来越有兴趣寻找针对多种危险因素的治疗靶点和疗法。，从而最大限度地减少与 MetS 和 2 型糖尿病患者的多药治疗相关的问题。 MetS 和 2 型糖尿病患者的类二十烷酸代谢组发生了改变。在 MetS 和 2 型糖尿病中，这种改变已被证明会影响多种因素，包括血压、血脂水平和胰岛素信号传导。我们开发了一种新的化学实体 4-(苯基-3-{3-[-)。 (4-三氟甲基-苯基)-脲基]-丙基}-吡唑-1-基)-苯磺酰胺 (PTUPB)，独特地抑制可溶性环氧化物水解酶(sEH) 和环氧合酶 (COX)，并展示出治疗 MetS、2 型糖尿病和相关肾衰竭的潜力。我们的长期目标是朝着研究性新药 (IND) 申请的最终目标迈出重要一步。一种新型化学实体，可以独特地改变类二十烷酸代谢物，并显示出治疗 MetS、2 型糖尿病的潜力。该应用的总体目标是实现我们长期目标的下一步，即药理学测试。基于 PTUPB 的 COX-2/sEH 抑制剂作为 MetS 和 2 型糖尿病的新型疗法的开发和优化我们的中心假设是，抑制 COX-2 和 sEH 将独特地改变类二十烷酸代谢，从而改善胰岛素信号传导和肾功能。我们的初步实验表明，COX-2/sEH 抑制剂 PTUPB 对于治疗 MetS、2 型糖尿病和相关肾脏的多种危险因素具有巨大的治疗潜力。在强有力的初步数据的指导下，我们的中心假设将通过三个具体目标进行检验：1) 优化 PTUPB 化学支架以增强药代动力学特征和治疗潜力；2) 检验 COX-2/sEH 抑制剂的假设。操纵类二十烷酸代谢物以改善胰岛素信号传导和胰腺功能，并减少 MetS 中的肾损伤 3) 检验 COX-2/sEH 抑制剂将操纵类二十烷酸代谢物以改善胰岛素的假设；该项目将在 MetS 和 2 型糖尿病的相关动物模型中进行原型小分子的药理学测试。优化我们的早期治疗前先导药物 PTUPB，这一贡献将意义重大，因为它将为识别和进一步开发 COX-2/sEH 抑制剂以治疗糖尿病和肾脏疾病打开大门。