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

描述（由申请方提供）：拟议SBIR I期可行性研究的目的是评估我们的主要肿瘤坏死因子-α（TNF 1）抑制剂治疗肥胖症的疗效。根据美国国立卫生研究院2006年公布的统计数据，三分之二的美国成年人肥胖或超重。除了在肥胖中观察到的死亡率增加之外，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TNF 1引起的慢性低度炎症是肥胖和肥胖相关的胰岛素抵抗的根本原因。在人类肥胖和肥胖动物模型中的研究强烈暗示TNF 1是可以被调节以治疗肥胖和改善肥胖相关疾病的靶点。 P2 D公司正在开发小分子TNF 1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，我们的先导化合物没有引起任何味觉厌恶。此外，每日经口给药引发大鼠体重显著减轻，而不引起任何内脏疾病。我们提出的研究的具体目标将采用饮食诱导的肥胖大鼠模型证实和扩展这些观察结果：具体目标1。为了确定我们的主要TNF 1抑制剂是否在很宽的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TNF 1抑制剂对高脂饮食诱导的肥胖大鼠和饲喂标准低脂实验室食物的瘦大鼠的摄食量、体重、能量消耗、昼夜节律活动和总体脂/瘦体重的剂量依赖性影响。目标2b：确定饮食和我们的主要TNF 1抑制剂对脂肪组织和肌肉TNF 1 mRNA和蛋白水平以及肥胖相关的合并症（如胰岛素敏感性和葡萄糖耐量）的影响。 公共卫生相关性：肥胖是一种慢性炎症性疾病，其特征在于脂肪组织内炎症水平升高。目前的研究旨在开发口服活性化合物，靶向肥胖相关的炎症，以引发体重减轻和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.