Eicosanoid-based Therapy for Diabetes

 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，糖尿病占所有肾衰竭新发病例的近一半。人们越来越关注寻找靶向多种风险因素的治疗靶点和疗法，从而最大限度地减少与MetS和2型糖尿病患者中的多药物方案相关的问题。代谢综合征和2型糖尿病患者的类花生酸代谢组发生改变。类花生酸代谢组在代谢综合征和2型糖尿病中发生改变，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。我们已经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），其独特地抑制可溶性环氧化物水解酶（sEH）和环氧合酶（考克斯），并显示出作为MetS、2型糖尿病和相关肾衰竭的治疗剂的潜力。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的一步，该新药申请是一种独特地改变类花生酸代谢物的新型化学实体，并显示出作为MetS（2型糖尿病）治疗药物的潜力。本申请的总体目标是实现我们长期目标的下一步，即药理学测试以及基于PTUPB的考克斯-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考克斯-2和sEH将独特地改变类花生酸代谢物，以改善代谢综合征和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，考克斯-2/sEH抑制剂PTUPB对治疗代谢综合征、2型糖尿病和相关肾衰竭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）检验考克斯- 2/sEH抑制剂将操纵类花生酸代谢物以改善胰岛素信号传导和胰腺功能并减少MetS中的肾损伤的假设; 3）验证考克斯-2/sEH抑制剂将操纵类花生酸代谢物以改善胰岛素信号传导和胰腺功能并减少2型糖尿病中的肾损伤的假设。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。该提案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的早期治疗前铅PTUPB。这一贡献将是重要的，因为它将为考克斯-2/sEH抑制剂的鉴定和进一步开发打开大门，以治疗糖尿病和肾脏疾病。

 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.