Novel therapeutics for fatty liver disease and type-II diabetes

脂肪肝和 II 型糖尿病的新疗法

基本信息

批准号：
8648389
负责人：
Dave Musso
金额：
$ 90.98万
依托单位：
SOUTHEAST TECHINVENTURES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-05 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8648389
关键词：
Accounting Adult Affect Albumins Animal Model Animals Back Bile Acids Biological Assay Biological Availability Biological Markers Blood Blood Circulation Blood Tests Body Weight decreased Cells Child Cirrhosis Clinic Cytochrome P450 Cytoplasm Data Deposition Development Diet Disease Disease model Drug Kinetics Ensure Enzyme Activation Epidemic Evaluation Exercise Exhibits FDA approved FGF21 gene Fatty Liver Fatty acid glycerol esters Fibrosis Glucose Glucuronosyltransferase Goals Gold Growth Hepatic Hepatocyte Hour Human In Vitro Insulin Resistance Intervention Lactose Lead Life Life Style Lipids Liver Liver diseases Measures Medical Messenger RNA Metabolic Metabolic Diseases Metabolic syndrome Metabolism Metric Modeling Molecular Molecular Target Morphology Non-Insulin-Dependent Diabetes Mellitus Nuclear Obesity Outcome Output Pathogenesis Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phenotype Physiological Production Property Proteins Protocols documentation Reporting Rodent Model Safety Sampling Series Severities Structure-Activity Relationship System Testing Therapeutic Toxic effect Translating Triglycerides Urea Uridine Diphosphate Validation analog annexin A5 base chronic liver disease diabetic drug discovery ex vivo perfusion feeding improved in vitro testing in vivo in vivo Model insight lipid metabolism mouse model non-alcoholic fatty liver non-compliance nonalcoholic steatohepatitis novel novel therapeutics pre-clinical protein metabolite public health relevance scaffold screening small molecule standard care

项目摘要

PROJECT SUMMARY! Western lifestyle and diet have spurred the growth of numerous obesity related disorders in the US, including metabolic syndrome and type 2 diabetes, to epidemic proportions. However, less well known is the rising epidemic of non-alcoholic fatty liver disease (NAFLD). NAFLD ranges from mild hepatosteatosis to severe fibrosis or cirrhosis and is initially characterized by abnormal accumulation of lipids in the liver. The medical significance of NAFLD is reflected in its sheer numbers; NAFLD is the single largest cause of abnormal liver blood tests in the clinic and is the most common chronic liver disease in adults and children. In addition, the majority of type 2 diabetics have some form of NAFLD. Despite the severity of the problem, there is no FDA- approved small molecule drug treatment for NAFLD. Our proposal seeks to translate discovery of a set of promising small molecules that treat the underlying cause of lipid accumulation in an animal model of NAFLD. We propose to further develop these small molecules to advance optimized leads toward the clinic. To achieve this goal, we have established a phenotypic drug discovery platform for fatty liver disease incorporating in vitro and in vivo models. In Phase I, we developed novel small molecules that modulate lipid metabolism and stimulate lipid clearance in lipid-loaded human cells, and demonstrate in vivo efficacy. This Phase II project will develop a series of compounds based on leads with proven in vivo therapeutic value towards increasing efficacy, limiting toxicity and identifying new biomarkers, with the longer-term goal of generating preclinical IND-enabling efficacy and ADME/Tox data. Aim 1 will optimize small molecule efficacy through medicinal chemistry/SAR. Analogs (~200) will be screened in vitro using a suite of metabolically significant protein and mRNA biomarkers (including FGF21, Car3). Aim 2 will evaluate the screened molecules (~50) for efficacy in vivo in the C57-DIO mouse model of NAFLD. The extent of hepatic lipid accumulation/clearing will be measured using conventional triglyceride assay kits and histological scoring. Compounds exhibiting increased efficacy/potency will feed back into Aim 1 to guide further compound derivative synthesis and testing. Aim 3 will establish therapeutic potential and toxicity/metabolic profiling in primary human hepatocytes with evaluation in an ex vivo fatty liver model. Up to 10 molecules will be assessed using primary human hepatocytes, and 2-3 molecules will be evaluated in an ex vivo perfusion model for fatty liver. The output of this aim is to select a preclinical candidate for advancement towards full ADME/Tox studies likely in Phase IIB.

项目概要！西方的生活方式和饮食刺激了美国许多肥胖相关疾病的增长，包括代谢综合征和 2 型糖尿病已达到流行病的程度。然而，不太为人所知的是不断上升的非酒精性脂肪肝（NAFLD）的流行。 NAFLD 范围从轻度肝脂肪变性到重度纤维化或肝硬化，最初的特征是肝脏中脂质异常积聚。医疗方面 NAFLD 的重要性体现在其庞大的数量上； NAFLD 是肝脏异常的最大单一原因临床血液检查是成人和儿童最常见的慢性肝病。此外，大多数 2 型糖尿病患者患有某种形式的 NAFLD。尽管问题很严重，但 FDA 并没有批准治疗 NAFLD 的小分子药物。我们的提案旨在将一组发现转化为有希望的小分子可以治疗 NAFLD 动物模型中脂质积累的根本原因。我们建议进一步开发这些小分子，以将优化的线索推向临床。为了实现这一目标，我们建立了脂肪肝疾病表型药物发现平台结合体外和体内模型。在第一阶段，我们开发了调节脂质的新型小分子代谢并刺激脂质负载的人体细胞中的脂质清除，并证明了体内功效。这二期项目将基于已证实具有体内治疗价值的先导化合物开发一系列化合物提高疗效、限制毒性和识别新的生物标志物，长期目标是生成临床前 IND 功效和 ADME/Tox 数据。目标 1 将优化小分子功效通过药物化学/SAR。将使用一套代谢方法在体外筛选类似物（~200）重要的蛋白质和 mRNA 生物标志物（包括 FGF21、Car3）。目标 2 将评估筛选的分子 (~50) 在 C57-DIO 小鼠 NAFLD 模型中的体内疗效。肝脂质程度将使用常规甘油三酯测定试剂盒和组织学评分来测量积累/清除。表现出增强的功效/效力的化合物将反馈到目标 1 以指导进一步的化合物衍生物合成和测试。目标 3 将确定治疗潜力和毒性/代谢分析原代人肝细胞在离体脂肪肝模型中进行评估。将评估最多 10 个分子使用原代人肝细胞，将在离体脂肪灌注模型中评估 2-3 个分子肝。这一目标的结果是选择一个临床前候选者，以推进全面的 ADME/Tox 研究可能在IIB阶段。