Selective DAT Inhbitor for the Treatment of Obesity

描述（由申请人提供）：目前SBIR一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PD2007治疗肥胖的疗效。非选择性DAT抑制剂d-安非他明是一种有效的人类抗肥胖治疗药物。然而，d-安非他明尚未被临床批准用于治疗肥胖，主要是由于其显著的滥用和成瘾的潜力。初步研究表明，我们的苯托品类似物PD2007在减少食物摄入方面与d-安非他明一样有效。初步研究还表明，PD2007在临床前研究中没有滥用的可能性。也就是说，PD2007不支持猴子自我给药。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，很少或没有滥用的可能性。

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.