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：
8962739
负责人：
John D Imig
金额：
$ 48.51万
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/8962739
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 Fatty acid glycerol esters Functional disorder Generations Glucose Goals High Density Lipoprotein Cholesterol 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 new therapeutic target novel prevent prototype public health relevance 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（由适用提供）：糖尿病和代谢综合征（Mets）苦难接近7000万美国人和糖尿病，占所有新肾脏衰竭病例的一半。寻找针对多种危险因素的治疗靶标和疗法的兴趣越来越大，从而最大程度地减少了与Mets和2型糖尿病患者中多药治疗方案相关的问题。在MetS和2型糖尿病患者中，类eicosanoid代谢组改变了。在MetS和2型糖尿病中，类花生酸代谢组发生了变化，并且已证明这种改变会影响多种因素，包括血压，脂质水平和胰岛素信号传导。我们已经开发了一种新型的化学实体，4-（苯基-3- {3 - [ - （4-三氟甲基 - 苯基）-URIDO] -URIDO] -propyl} -pyrazol-1-基） - 苯甲苯磺甲酰胺（PTUPB），它均无效地抑制了固体固体水解酶（SEH）和cy氧化物酶（SEH）的（SEH）ASHASITASE（SEH）（SEH）（SEH）（SEH）。大都会，2型糖尿病和相关的肾衰竭。我们的长期目标是朝着对新型化学实体进行研究新药（IND）应用的最终目标的重要步骤，该实体唯一地改变了eicosanoid代谢物，并证明了对2型糖尿病的MetS治疗的潜力。该应用程序的总体目标是实现我们长期目标的下一步，是药物测试以及基于PTUPB的COX-2/SEH抑制剂的开发和优化，作为对MetS和2型糖尿病的新型疗法。我们的中心假设是，抑制COX-2和SEH将唯一改变类固醇代谢物，以改善MetS和2型糖尿病中的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具有治疗MetS多种危险因素，2型糖尿病和相关肾衰竭的多种危险因素。在强大的初步数据的指导下，我们的中心假设将通过追求三个具体目标来检验：1）优化PTUPB化学支架以增强药代动力学特征和治疗潜力； 2）检验以下假设：COX-2/SEH抑制剂将操纵类固醇代谢物以改善胰岛素信号传导和胰腺功能，并减少MetS的肾脏损伤； 3）检验以下假设：COX-2/SEH抑制剂将操纵类固醇代谢物以改善胰岛素信号传导和胰腺功能，并减少2型糖尿病的肾脏损伤。该项目将在Mets和2型糖尿病的相关动物模型中对原型小分子进行药物测试。该建议的主要部分是利用药物化学和计算方法来优化我们早期的治疗前铅PTUPB。这项贡献将是重要的，因为它将为鉴定和进一步开发COX-2/SEH抑制剂开辟大门。