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

保留 PPARgam 的 TZD 治疗非酒精性脂肪肝的评价

基本信息

批准号：
8124575
负责人：
Brian N Finck
金额：
$ 56.38万
依托单位：
METABOLIC SOLUTIONS DEVELOPMENT CO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8124575
关键词：
2,4-thiazolidinedione Accounting Acute Adipose tissue Adverse effects Affect Agonist American Applications Grants Benchmarking Binding Biological Availability Biological Markers Blood Glucose Cardiovascular system Cell Differentiation process Cell model Cells Cessation of life Cirrhosis Clinical Clinical Trials Contracts Development Diabetes Mellitus Disease Dose Drug Kinetics Drug usage Early Diagnosis Edema Epidemic Evaluation Fasting Fatty Liver Fatty acid glycerol esters Foundations General Population Goals Grant Hepatic High Density Lipoproteins Human Incidence Insulin Intervention Lead Literature Liver Liver diseases Malignant neoplasm of liver Mediating Medical Metabolic Metabolic Diseases Modeling Monitor Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Obesity Peripheral Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Pharmacology Phase Pioglitazone Primary carcinoma of the liver cells Program Development Progress Reports Receptor Activation Relative (related person)Research Risk Rodent Model Small Business Technology Transfer Research Solutions Staging Takeda brand of pioglitazone hydrochloride Technology Therapeutic Therapeutic Agents Therapeutic Uses Thiazolidinediones Tissues Toxicology Treatment Efficacy United States Weight Gain Work analog base drug candidate experience improved in vivo insulin sensitivity insulin sensitizing drugs interest lipid metabolism non-alcoholic fatty liver nonalcoholic steatohepatitis phase 1 study pre-clinical precursor cell receptor response rosiglitazone stem

项目摘要

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.

描述（由申请人提供）：非酒精性脂肪肝病（NAFLD）是美国最常见的肝病。这种病症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 14-24% 的普通人群和高达 80% 的病态肥胖受试者患有 NAFLD。未经治疗的疾病可能会发展为肝硬化并导致肝癌。目前，肝硬化占糖尿病相关死亡的 12.5%。尽管文献中已认识到需求和兴趣程度，但目前尚无批准用于治疗 NAFLD 的治疗药物，并且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保留 PPAR 的噻唑烷二酮 (TZD)，它在非酒精性脂肪肝病 (NAFLD) 啮齿动物模型中显示出功效，并展示了成为潜在临床候选药物所需的类似药物的品质用于人类治疗。通常认为 TZD 类胰岛素增敏剂是通过与 PPAR? 结合来发挥作用的。受体。然而，该提案的作者强烈主张 TZD 的不良反应是通过与 PPAR 结合来介导的？受体。此外，最近有人提出，罗格列酮（PPAR 原型）？激活剂，可能会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) 的联合创始人设想了 TZD 与 PPAR 的结合力最小或没有结合力？受体，并广泛评估了它们在细胞模型（棕色脂肪前体细胞分化）和 2 型糖尿病啮齿动物模型中的活性。在 I 期研究中，我们在 NAFLD 啮齿动物模型上评估了保留 PPAR 的类似物，结果清楚地表明，它可以提高胰岛素敏感性，同时增强肝脏氧化和清除脂肪的能力。因此，该项目的顺利完成为选择和开发用于治疗 NAFLD 的 PPAR 保留 TZD 奠定了良好的基础，且没有此类药物通常带来的副作用。计划进行的第二阶段实验工作将基于并扩展该技术，以实现用于治疗 NAFLD 的类似物的选择和初步临床前开发，以及可用于检测早期疾病和监测的生物标志物的潜在鉴定。临床试验中的治疗进展。公共健康相关性：非酒精性脂肪肝病 (NAFLD) 是美国最常见的肝脏疾病，这种疾病的发病率随着肥胖的流行而上升。目前还没有批准治疗这种肝病的方法。拟议研究的总体目标是从噻唑烷二酮类中鉴定出一种候选药物，该药物可以提交给 NAFLD 治疗用途的开发计划。