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）是美国最常见的肝病。这种疾病包括肝脂肪变性和更严重的非酒精性脂肪性肝炎。现在估计14-24%的一般人群和高达80%的病态肥胖受试者患有NAFLD。未经治疗的疾病可能进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%。尽管在文献中存在公认的需求和关注度，但目前还没有批准用于治疗NAFLD的治疗剂，并且这种未满足的医疗需求可能会随着肥胖症的流行而继续增加。拟议研究的总体目标是发现一种PPAR？-保留噻唑烷二酮（TZD），其在非酒精性脂肪性肝病（NAFLD）的啮齿动物模型中显示出功效，并证明了成为人类治疗剂的潜在临床候选物所必需的药物样品质。TZD类胰岛素增敏剂通常被认为是通过与过氧化物酶体增殖物激活受体结合而起作用的。受体。然而，这是作者的强烈论点，这一建议，TZDs的不良影响介导的结合到过氧化物酶体增殖物激活受体？受体。此外，最近有人提出，罗格列酮，原型的过氧化物酶体增殖物激活受体？激活剂，可能产生不良的急性心血管作用。与流行的科学观点相反，该提案的作者认为，非PPAR介导的机制是胰岛素增敏药理学的原因。代谢解决方案开发公司（MSDC）的联合创始人已经设想了TZD，它应该显示最低限度或没有结合的过氧化物酶体增殖物激活受体？受体，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其活性。在I期研究中，我们在NAFLD的啮齿动物模型上评估了一种PPAR-sparing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PPAR？提供了良好的基础。避免TZD用于治疗NAFLD，而没有通常与这类药物相关的副作用。II期计划的实验工作将建立并扩展该技术，以实现用于治疗NAFLD的类似物的选择和初始临床前开发，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。 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，并且这种疾病的发病率随着肥胖的流行而上升。目前还没有批准用于这种肝脏疾病的治疗方法。 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.