Development of Novel Brown Adipocyte Recruiters for the Treatment of Obesity

项目总结/摘要 肥胖在美国已经达到流行病的程度，在2型糖尿病的发展中起着重要作用。 糖尿病、血脂异常和心血管疾病。我们仍然非常需要更好的非... 外科治疗虽然目前大多数减肥药的作用是抑制食欲， 安全地提高能量消耗有可能有效地治疗肥胖症。棕色脂肪组织（BAT） 是唯一表达线粒体解偶联蛋白-1（UCP 1）的产热组织。这种蛋白质 以调节的方式消散棕色脂肪细胞线粒体中的电化学梯度， 热，因此在维持体温和能量平衡方面起着重要作用。 啮齿动物和人类。BAT是一种柔韧的组织，通常会随着时间的推移而扩大或萎缩，这取决于 环境温度在许多不同的啮齿动物模型中，BAT质量的增加令人信服地 被证明可以减肥和抵抗糖尿病。虽然BAT直到最近才被认为是 在成年人中实际上不存在，过去几年获得的数据显示，成年人实际上 重要的BAT并且该组织是功能性的。已经很好地确定，较高量的活性物质 个体的BAT与瘦度密切相关。人类冷暴露导致BAT增加 形成，产热，胰岛素敏感性和脂解，证明BAT可以招募和导致 对新陈代谢有益。此外，与一般肥胖症联系最紧密的遗传位点导致缺陷性肥胖， 募集新的棕色脂肪细胞。 直到最近还没有发现棕色脂肪干细胞。我们发现了人类棕色脂肪细胞 骨骼肌中的祖细胞，在适当的条件下变成功能齐全的棕色 脂肪细胞，具有高水平的UCP 1和非常高的代谢率。这些细胞是我们使用的独特工具 用于开发一种鉴定具有招募新BAT能力的化合物的测定方法。我们最近 将该测定转化为高通量形式并使用其筛选7000+化合物。我们验证 筛选命中，并选择了最有前途的这些基础上的效力，最大活性， 创造改进的类似物的潜力。 在拟议的工作中，我们的目标是调查这些最优选的构效关系 通过购买和合成一系列新的类似物并在体外对其进行评估，我们将 根据活性、理化和ADME确定具有最高发展潜力的药物 特性.将选择一种先导化合物和备用化合物，如果这项工作成功， PK和体内疗效研究。这些都将遵循铅优化，选择一个发展 候选人，并生成IND使能安全性数据。

PROJECT SUMMARY/ABSTRACT Obesity has reached epidemic proportions in the U.S. and plays a major role in the development of type 2 diabetes, dyslipidemia, and cardiovascular disease. There remains a very significant need for better non- surgical treatments. While most current weight loss agents act by suppressing appetite, strategies that can safely enhance energy expenditure have the potential to effectively treat obesity. Brown adipose tissue (BAT) is a thermogenic tissue that uniquely expresses mitochondrial UnCoupling Protein-1 (UCP1). This protein dissipates, in a regulated fashion, the electrochemical gradient in the mitochondria of brown adipocytes as heat, and thus plays an important role in the maintenance of body temperature and energy balance in rodents and humans. BAT is a flexible tissue that normally enlarges or atrophies over time depending on environmental temperature. In many different rodent models, enhancement of BAT mass has convincingly been shown to lead to weight loss and diabetes resistance. While BAT was until recently thought to be effectively nonexistent in adult humans, data obtained in the past several years show that adults in fact have significant BAT and that this tissue is functional. It has been well established that a higher amount of active BAT in individuals is strongly correlated with leanness. Cold exposure in humans leads to increased BAT formation, thermogenesis, insulin sensitivity, and lipolysis, demonstrating that BAT can be recruited and lead to metabolic benefits. Moreover, the genetic locus most tightly linked with general obesity causes defective recruitment of new brown adipocytes. Until recently no brown adipocyte stem cell had been identified. We discovered human brown adipocyte progenitor cells resident in skeletal muscle that under appropriate conditions become fully functional brown adipocytes, with high levels of UCP1 and a very high metabolic rate. These cells are a unique tool that we used to develop an assay for identifying compounds with the capacity to recruit new BAT. We recently converted this assay into high throughput format and employed it to screen 7000+ compounds. We validated the screening hits, and have selected the most promising of these based on potency, maximal activity, and the potential to create improved analogs. In the proposed work, we aim to investigate the Structure Activity Relationship of the most preferred of these compounds by purchasing and synthesizing a series of novel analogs and evaluating them in vitro. We will identify those with the highest potential for advancement based on activity and physicochemical and ADME properties. A lead compound and backup will be selected, and if this work is successful we plan to advance to PK and in vivo efficacy studies. These will be followed by lead optimization, selection of a development candidate, and generation of IND-enabling safety data.