Eicosanoid-based Therapy for Diabetes

 描述(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功能衰竭病例的近一半。人们对寻找针对多种危险因素的治疗靶点和治疗方法越来越感兴趣，从而将与METS和2型糖尿病患者的多种药物方案相关的问题降至最低。甲硫氨酸和2型糖尿病患者的二十烷基类代谢组发生改变。二十烷基类代谢组在蛋氨酸和2型糖尿病中发生改变，这种改变已被证明影响包括血压、血脂水平和胰岛素信号在内的多个因素。我们开发了一种新的化学实体，4-(phenyl-3-{3-[-(4-trifluoromethyl-phenyl)-ureido]-propyl}-pyrazol-1-yl)-苯磺酰胺(PTUPB)，它独特地抑制可溶性环氧化物水解酶(SEH)和环氧合酶(COX)，并显示出潜在的治疗蛋氨酸，2型糖尿病和相关的肾功能衰竭。我们的长期目标是朝着研究新药(IND)的最终目标迈出重要的一步，申请一种独特地改变二十烷类代谢物并显示出治疗METS、2型糖尿病的潜力的新化学实体。这项应用的总体目标是药理学测试以及开发和优化基于PTUPB的COX-2/sEH抑制剂，作为治疗甲硫氨酸和2型糖尿病的新疗法。我们的中心假设是，抑制COX-2和sEH将独特地改变二十烷类代谢产物，从而改善蛋氨酸和2型糖尿病患者的胰岛素信号和肾功能。我们的初步实验表明，COX-2/sEH抑制剂PTUPB在治疗蛋氨酸、2型糖尿病和相关肾功能衰竭的多种危险因素方面具有巨大的治疗潜力。在强劲的初步数据指导下，我们的中心假说将通过追求三个特定目标来验证：1)优化PTUPB化学支架，以增强药代动力学和治疗潜力；2)检验COX-2/sEH抑制剂将操纵二十烷类代谢产物以改善胰岛素信号转导和胰腺功能，并减少METS肾脏损伤的假说；3)测试COX-2/sEH抑制剂将操纵二十烷类代谢产物以改善胰岛素信号和胰腺功能，以及减少2型糖尿病肾脏损伤的假说。该项目将在蛋氨酸和2型糖尿病的相关动物模型中对原型小分子进行药理学测试。这项建议的一个主要部分将是利用药物化学和计算方法来优化我们早期治疗前的PTUPB。这一贡献将是重要的，因为它将为COX-2/sEH抑制剂的鉴定和进一步开发成为治疗糖尿病和肾脏疾病的药物打开大门。

 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.