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

描述(申请人提供)：拟议的SBIR第一阶段可行性研究的目的是评估我们的领先肿瘤坏死因子-α(TNF1)抑制剂治疗肥胖症的疗效。根据美国国立卫生研究院2006年发布的统计数据，三分之二的美国成年人肥胖或超重。除了观察到的肥胖死亡率增加外，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，口服减肥治疗具有巨大的临床意义。最近的几条证据表明，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的胰岛素抵抗的潜在原因。对人类肥胖和肥胖动物模型的研究强烈表明，TNF1可以被调节为治疗肥胖和改善肥胖相关疾病的靶点。P2D公司正在开发小分子TNF1抑制剂，这种药物适合口服治疗肥胖症和肥胖相关的胰岛素抵抗。我们的初步研究表明，我们的先导化合物没有引起任何味觉厌恶。此外，每天口服给药可显著减轻大鼠的体重，而不会引起任何内脏疾病。我们在拟议研究中的具体目标将证实并扩大使用饮食诱导的肥胖大鼠模型的观察结果：具体目标1.确定我们的先导TNF1抑制剂是否在广泛的剂量范围内导致条件性味觉厌恶。具体目的2a：确定我们的领先的TNF1抑制剂对高脂饮食诱导的肥胖大鼠和喂饲标准低脂实验室饲料的瘦大鼠的摄食量、体重、能量消耗、昼夜活动和体脂/瘦体重的剂量依赖性影响。目的2b：确定饮食和我们的先导TNF1抑制剂对脂肪组织和肌肉中TNF1基因和蛋白水平的影响，以及与肥胖相关的共病，如胰岛素敏感性和糖耐量。 公共卫生相关性：在美国，肥胖是一个严重的健康问题。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。本研究旨在开发针对肥胖相关炎症的口服活性化合物，以触发减肥并改善肥胖相关的胰岛素抵抗。

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.