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

描述(申请人提供)：非酒精性脂肪性肝病(NAFLD)是美国最常见的肝病。这种情况包括肝脏脂肪变性和更严重的非酒精性脂肪性肝炎。据估计，目前有14%-24%的普通人群和高达80%的病态肥胖受试者患有非酒精性脂肪肝。未经治疗的疾病可能会发展为肝硬变，并导致肝癌。目前，糖尿病相关死亡病例中有12.5%是由肝硬变引起的。尽管文献中认识到了治疗NAFLD的需要和兴趣程度，但目前还没有批准的治疗药物用于治疗NAFLD，这种未得到满足的医疗需求可能会随着肥胖症的流行而继续增加。这项拟议研究的总体目标是发现一种PPAR？节约型噻唑烷二酮(TZD)，它在非酒精性脂肪性肝病(NAFLD)的啮齿动物模型中显示出有效性，并展示了成为潜在的人类疗法临床候选药物所需的类药物特性。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。感受器。然而，这项建议的作者强烈主张，TZD的不良影响是通过与PPAR结合来调节的？感受器。此外，最近有研究表明，PPAR的原型罗格列酮？激活剂，可能会对急性心血管产生不良影响。与流行的科学观点相反，这一建议的作者认为非PPAR介导的机制负责胰岛素增敏的药理作用。代谢解决方案开发公司(MSDC)的联合创始人已经构思出TZD，它应该与PPAR结合最少或没有结合？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。在第一阶段的研究中，我们在NAFLD的啮齿动物模型上评估了一种PPAR保留的类似物，结果清楚地表明，它改善了胰岛素敏感性，同时增加了肝脏氧化和清除脂肪的能力。因此，该项目的积极完成为选择和开发一种无PPAR？的TZD治疗NAFLD提供了良好的基础，该TZD没有通常与此类药物相关的副作用。第二阶段计划的实验工作将建立在这项技术的基础上并加以扩展，以实现用于治疗NAFLD的模拟药物的选择和初步临床前开发，以及可能有助于检测早期疾病和监测临床试验中治疗进展的生物标记物的潜在识别。 公共卫生相关性：非酒精性脂肪性肝病(NAFLD)是美国最常见的肝病，随着肥胖症的流行，该疾病的发病率也随之上升。目前还没有被批准的治疗这种肝病的方法。这项拟议研究的总体目标是从噻唑烷二酮类中确定一种候选药物，该药物可提交给开发计划用于治疗NAFLD。

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.