Evaluation of PPARgam-sparing TZDs for Treating Non-Alcoholic Fatty Liver Disease

描述（由申请人提供）：非酒精性脂肪性肝病（NAFLD）是美国最常见的肝脏疾病。这种情况包括肝脂肪变性和更严重的非酒精性脂肪性肝炎。目前估计有14-24%的普通人群和高达80%的病态肥胖患者感染过NAFLD。未经治疗的疾病可能发展为肝硬化并导致肝癌。肝硬化现在占糖尿病相关死亡的12.5%。尽管在文献中有公认的需求和兴趣程度，但目前还没有批准的治疗NAFLD的药物，这种未满足的医疗需求可能会随着肥胖的流行而继续增加。拟议研究的总体目标是发现一种PPAR？-保留噻唑烷二酮（TZD），在非酒精性脂肪性肝病（NAFLD）的啮齿动物模型中显示出疗效，并显示出必要的药物样品质，成为人类治疗的潜在临床候选药物。TZD类胰岛素增敏剂通常被认为是通过与PPAR结合而起作用的。受体。然而，该提案的作者强烈认为TZDs的不良影响是通过与PPAR结合介导的。受体。此外，最近有人建议罗格列酮，典型的PPAR？激活剂，可产生不良的急性心血管效应。与流行的科学观点相反，本提案的作者认为非ppar介导的机制负责胰岛素增敏药理学。代谢解决方案开发公司（MSDC）的联合创始人已经设想了与PPAR结合最少或不结合的tzd。并在细胞模型（棕色脂肪前体细胞分化）和2型糖尿病啮齿动物模型中广泛评估了它们的活性。在I期研究中，我们在啮齿动物NAFLD模型上评估了一种PPAR-sparing类似物，结果清楚地表明，它可以改善胰岛素敏感性，同时增加肝脏氧化和清除脂肪的能力。因此，该项目的顺利完成为PPAR的选择和开发提供了良好的基础。-保留TZD用于治疗NAFLD，没有与此类药物相关的典型副作用。二期计划的实验工作将建立并扩展该技术，以实现NAFLD治疗类似物的选择和初步临床前开发，以及可能用于检测早期疾病和监测临床试验中治疗进展的生物标志物的潜在鉴定。

DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in the United States. This condition encompasses both hepatic steatosis and the more severe non-alcoholic steatohepatitis. It is now estimated that 14-24% of the general population and up to 80% of morbidly obese subjects have contracted NAFLD. Untreated disease may progress to cirrhosis and lead to hepatic cancer. Cirrhosis now accounts for 12.5% of diabetes related deaths. In spite of the recognized need and degree of interest in the literature, there are no currently approved therapeutic agents for treatment of NAFLD and this unmet medical need will likely continue to increase in concert with the epidemic of obesity. The overall objective of the proposed research is to discover a PPAR?-sparing thiazolidinedione (TZD) which displays efficacy in a rodent model of non-alcoholic fatty liver disease (NAFLD) and demonstrates the necessary drug-like qualities to become a potential clinical candidate for human therapeutics. The TZD class of insulin sensitizing agents are conventionally thought to operate through binding to PPAR? receptors. However, it is the strong contention of the authors of this proposal that the undesirable effects of the TZDs are mediated by binding to PPAR? receptors. Moreover, it has recently been suggested that rosiglitazone, the prototypical PPAR? activator, could exert untoward acute cardiovascular effects. Contrary to the prevailing scientific view, the authors of this proposal believe that non-PPAR mediated mechanisms are responsible for the insulin sensitizing pharmacology. The co-founders of the Metabolic Solutions Development Company (MSDC) have conceived of TZDs which should display minimal or no binding to the PPAR? receptor and has extensively evaluated their activity in cellular models (brown adipose precursor cell differentiation) and in rodent models of Type 2 diabetes. In Phase I studies, we evaluated a PPAR-sparing analog on a rodent model of NAFLD and the results clearly show that it improves insulin sensitivity accompanied by increased ability of the liver to oxidize and clear fat. Thus, the positive completion of this project provides an excellent foundation for selecting and developing a PPAR?- sparing TZD for treatment of NAFLD devoid of the side effects typically associated with this class of medications. The experimental work planned for Phase II would build on and extend this technology to achieve the selection and initial preclinical development of an analog for treatment of NAFLD as well as the potential identification of a biomarker which could be useful for detection of early disease and to monitor therapeutic progress in clinical trials. PUBLIC HEALTH RELEVANCE: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in the U.S. and the incidence of this disease has risen concomitantly with the epidemic of obesity. There is currently no approved therapeutic treatment for this liver disease. It is the overall goal of the proposed research to identify a candidate drug from the thiazolidinedione class which can be submitted to a development program for therapeutic use in treatment of NAFLD.