PD2024: A Peripherally Active TNFalpha inhibitor for the treatment of Obesity

PD2024：一种用于治疗肥胖的外周活性 TNFα 抑制剂

基本信息

批准号：
8004629
负责人：
SOMASUNDAR PRASAD GABBITA
金额：
$ 27.21万
依托单位：
P2D, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8004629
关键词：
Adipose tissue Adult Adverse effects Animal Model Antibodies Area Under Curve Binding Biogenesis Body Weight Body Weight decreased Body fat Cardiovascular Diseases Cholesterol Chronic Circadian Rhythms Cleaved cell Comorbidity Consumption Control Animal Control Groups Data Diet Disease Dose Eating Energy Metabolism Enzyme-Linked Immunosorbent Assay Fatty acid glycerol esters Feasibility Studies Flavoring Food Genes Glucose Glucose tolerance test Health Human Inflammation Inflammatory Injectable Insulin Insulin Receptor Insulin Resistance Intake Interleukin-10 Interleukin-6 Knock-out Knockout Mice Lead Leptin Lipomatous neoplasm Lipopolysaccharides Liquid substance Lithium Chloride Measures Membrane Messenger RNA Metabolic Mitochondria Modeling Mus Muscle Myomatous neoplasm Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Oral Oral Administration Overweight Oxygen Consumption Patients Peripheral Pharmaceutical Preparations Phase Plasma Production Proteins Publishing Rattus Receptor Signaling Regression Analysis Research Rheumatoid Arthritis Saccharin Saline Sampling Signal Transduction Skeletal Muscle Small Business Innovation Research Grant Solutions TNF-alpha converting enzyme Taste Perception Testing Thermogenesis Tissues Triglycerides Tumor Necrosis Factor-alpha United States National Institutes of Health Visceral Water Weight Weight Gain clinically significant cytokine energy balance feeding food consumption glucose tolerance human TNFRSF1A protein improved infliximab inhibitor/antagonist insulin sensitivity insulin tolerance male mortality novel obesity treatment paracrine preference public health relevance receptor respiratory small molecule statistics subcutaneous treatment duration tumor necrosis factor alpha receptor tumor necrosis factor-alpha inhibitor water solution

项目摘要

DESCRIPTION (provided by applicant): The purpose of the proposed SBIR Phase 1 feasibility study is to assess the efficacy of our lead tumor necrosis factor- alpha (TNF1) inhibitor for the treatment of obesity. Two-thirds of U.S. adults are obese or overweight according to NIH statistics published in 2006. In addition to increased mortality observed in obesity, it is estimated that 70% of cardiovascular disease and 80% of type II diabetes is directly related to obesity. Thus, oral anti-obesity treatments have tremendous clinical significance. Several lines of recent evidence suggest that chronic low-grade inflammation fueled by adipose tissue-derived TNF1 is an underlying cause of obesity and obesity- related insulin resistance. Studies in human obesity and animal models of obesity strongly implicate TNF1 as target that can be modulated to treat obesity and improve obesity-related disorders. P2D, Inc. is developing small molecule TNF1 inhibitors that are amenable to oral administration to treat obesity and obesity-related insulin resistance. Our Preliminary Studies demonstrate that our lead compound did not elicit any taste aversion. Further, daily oral administration triggered significant weight loss in rats without causing any visceral illness. Our Specific Aims for the proposed studies will confirm and extend these observations employing a diet induced rat model of obesity: Specific Aim 1. To determine whether our lead TNF1 inhibitor results in a conditioned taste aversion across a wide dose range. Specific Aim 2a: To determine the dose-dependent effect of our lead TNF1 inhibitor on food intake, body weight, energy expenditure, circadian activity, and total body fat/lean body mass in high-fat diet-induced obese rats and lean rats fed standard low-fat lab chow. Aim 2b: To determine the effects of diet and our lead TNF1 inhibitor on adipose tissue and muscle TNF1 mRNA and protein levels, and obesity-related co-morbidities such as insulin sensitivity and glucose tolerance. PUBLIC HEALTH RELEVANCE: Obesity is a significant health problem in the U.S. Obesity is a chronic inflammatory condition characterized by elevated levels of inflammation within the fat tissue. The present research aims to develop orally-active compounds that target obesity-associated inflammation to trigger weight loss and improve obesity-related insulin resistance.

描述（由申请人提供）：拟议的 SBIR 1 期可行性研究的目的是评估我们的主要肿瘤坏死因子-α (TNF1) 抑制剂治疗肥胖的功效。根据 NIH 2006 年公布的统计数据，三分之二的美国成年人肥胖或超重。除了肥胖导致的死亡率增加外，据估计，70% 的心血管疾病和 80% 的 II 型糖尿病与肥胖直接相关。因此，口服抗肥胖治疗具有巨大的临床意义。最近的一些证据表明，由脂肪组织来源的 TNF1 引发的慢性低度炎症是肥胖和肥胖相关胰岛素抵抗的根本原因。对人类肥胖和肥胖动物模型的研究强烈表明 TNF1 是可以通过调节来治疗肥胖和改善肥胖相关疾病的靶标。 P2D, Inc. 正在开发小分子 TNF1 抑制剂，可口服治疗肥胖和肥胖相关的胰岛素抵抗。我们的初步研究表明，我们的先导化合物不会引起任何味道厌恶。此外，每天口服给药可使大鼠体重显着减轻，但不会引起任何内脏疾病。我们拟议研究的具体目标将采用饮食诱导的肥胖大鼠模型来证实和扩展这些观察结果：具体目标 1. 确定我们的主要 TNF1 抑制剂是否会在宽剂量范围内导致条件性味觉厌恶。具体目标 2a：确定我们的主要 TNF1 抑制剂对高脂饮食诱导的肥胖大鼠和瘦大鼠的食物摄入、体重、能量消耗、昼夜节律活动和全身脂肪/瘦体重的剂量依赖性影响标准低脂实验室食物。目标 2b：确定饮食和我们的主要 TNF1 抑制剂对脂肪组织和肌肉 TNF1 mRNA 和蛋白质水平以及肥胖相关并发症（如胰岛素敏感性和葡萄糖耐量）的影响。公共卫生相关性：肥胖是美国的一个重大健康问题。肥胖是一种慢性炎症性疾病，其特征是脂肪组织内炎症水平升高。目前的研究旨在开发针对肥胖相关炎症的口服活性化合物，以引发体重减轻并改善肥胖相关的胰岛素抵抗。