Selective DAT Inhbitor for the Treatment of Obesity

描述（由申请人提供）：本SBIR I期可行性研究的目的是评估我们的选择性多巴胺转运（DAT）抑制剂PD 2007治疗肥胖症的疗效。非选择性DAT抑制剂，d-安非他明，是一种有效的抗肥胖治疗人类。然而，d-安非他明在临床上没有被批准用于治疗肥胖症，主要是由于其显著的滥用和成瘾潜力。初步研究表明，我们的苯扎托品类似物PD 2007在减少食物摄入方面与d-苯丙胺一样有效。初步研究还表明，PD 2007在临床前研究中没有滥用潜力。也就是说，PD 2007不支持猴自我给药。拟议研究的长期目标是开发一种安全有效的抗肥胖治疗方法，几乎没有滥用的可能性。 广泛的研究表明，DAT抑制是d-苯丙胺的抗肥胖作用机制。苯扎托品是一种选择性高亲和力DAT抑制剂，安全有效，临床应用已超过30年。苯扎托品显示没有明显的滥用潜力，是一种非表列药物。不幸的是，benztropine是一种有效的抗胆碱能药物，这排除了它作为抗肥胖治疗的用途。广泛的先导化合物优化研究已确定苯并托品类似物PD 2007是一种选择性DAT抑制剂，无抗胆碱能特性，在临床前研究中无滥用可能。 拟定的特定目的旨在评估PD 2007对已建立的肥胖症（高脂饮食诱导的肥胖症）临床前模型中的摄食量、体重和体脂的影响，以及确定PD 2007对肥胖症相关合并症的影响。具体目标1：测定PD 2007对高脂饮食诱导的肥胖大鼠和标准实验室食物饮食大鼠的食物摄入、体重、能量消耗、昼夜活动水平和局部体脂/瘦体重的影响。 具体目标二：确定PD 2007对特定目标1动物中肥胖相关合并症的影响（甘油三酯、胆固醇、瘦素、胰岛素和炎性细胞因子水平，以及葡萄糖耐量和胰岛素敏感性）。公共卫生相关性：在本申请中，我们提出了临床前研究来评估我们的专利化合物PD 2007-多巴胺转运蛋白的选择性抑制剂是否是肥胖症的有效治疗。这些临床前研究将评估不同剂量的PD 2007对大鼠以及饲喂标准实验室食物饮食的大鼠中由高脂肪饮食诱导的肥胖症的影响。老鼠，像人类一样，当喂食富含脂肪的饮食时，会增加它们的食物摄入量并变得肥胖。将在两组动物中测定PD 2007减少食物摄入、减少体脂和逆转肥胖相关共病（如胰岛素抵抗和葡萄糖耐受不良）的能力。

DESCRIPTION (provided by applicant): The purpose of the present SBIR Phase 1 feasibility study is to assess the efficacy of our selective dopamine transport (DAT) inhibitor, PD2007, for the treatment of obesity. The non-selective DAT inhibitor, d-amphetamine, is a potent anti-obesity treatment in humans. However, d- amphetamine, is not clinically approved for the treatment of obesity due primarily to its significant abuse and addiction potential. Preliminary Studies indicate that our benztropine analog, PD2007, is as effective as d-amphetamine at decreasing food intake. Preliminary Studies also indicate that PD2007 demonstrates no abuse potential in preclinical studies. That is, PD2007 does not support self- administered in monkeys. The long term goal of the proposed studies is to develop a safe and effective anti-obesity treatment with little or no abuse potential. Extensive research suggests that DAT inhibition is the anti-obesity mechanism of action of d- amphetamine. Benztropine is a selective high affinity DAT inhibitor that is safe and effective and in clinical use for over 30 years. Benztropine demonstrates no significant abuse potential and is a non- Scheduled drug. Unfortunately, benztropine is a potent anticholinergic which precludes it use as an anti-obesity treatment. Extensive lead optimization studies have identified the benzotropine analog, PD2007, as a selective DAT inhibitor with no anticholinergic properties and with no abuse potential in preclinical studies. The purpose of the proposed Specific Aims is to assess PD2007's effect on food intake, body weight and body fat in a well established preclinical model of obesity (high fat diet-induced obesity), as well as, to determine PD2007's effect on obesity related co-morbidities. Specific Aim 1: Determine the effect of PD2007 on food intake, body weight, energy expenditure, circadian activity levels and regional body fat/lean body mass in high-fat diet- induce obesity rats and standard lab chow diet rats. Specific Aim 2: Determine the effects of PD2007 on obesity-related co-morbidities in Specific Aim 1 animals (triglycerides, cholesterol, leptin, insulin and inflammatory cytokines levels, as well as, glucose tolerance and insulin-sensitivity). PUBLIC HEALTH RELEVANCE: In the present application, we propose preclinical studies to assess whether our proprietary compound, PD2007-a selective inhibitor of the dopamine transporter, is an effective treatment for obesity. These preclinical studies will assess the effect of varying doses of PD2007 on obesity induced by a high fat diet in rats as well as in rats fed a standard lab chow diet. Rats, like humans, when fed a diet rich in fats increase their food intake and become obese. The ability of PD2007 to decrease food intake, decrease body fat and to reverse obesity related co-morbidities such as insulin resistance and glucose intolerance will be determined in both groups of animals.