Development of Novel Brown Adipocyte Recruiters for the Treatment of Obesity

项目摘要/摘要 肥胖症在美国已经达到流行的程度，并在2型肥胖症的发展中发挥着重要作用 糖尿病、血脂异常和心血管疾病。仍然有非常重要的需求，需要更好的非 外科治疗。虽然目前大多数减肥剂的作用是抑制食欲，但可以 安全提高能量消耗有可能有效治疗肥胖症。棕色脂肪组织(BAT) 是一种唯一表达线粒体解偶联蛋白-1(UCP1)的生热组织。这种蛋白质 以一种受调控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。蝙蝠是一种灵活的组织，通常会随着时间的推移而增大或萎缩，这取决于 环境温度。在许多不同的啮齿动物模型中，蝙蝠质量的增加令人信服 已被证明有助于减肥和抵抗糖尿病。而直到最近，蝙蝠还被认为是 过去几年获得的数据表明，成年人实际上并不存在于成年人中。 重要的蝙蝠，这个组织是有功能的。已经很好地确定了较高的活跃量 个体的BAT与苗条有很强的相关性。人体暴露寒冷会导致蝙蝠数量增加 形成、产热、胰岛素敏感性和脂肪分解，证明BAT可以被招募和领导 对新陈代谢的益处。此外，与普遍肥胖联系最紧密的遗传基因会导致缺陷。 新的棕色脂肪细胞的募集。 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 存在于骨骼肌中的祖细胞，在适当的条件下会变成完全功能的棕色 脂肪细胞，高水平的UCP1和非常高的代谢率。这些细胞是我们唯一的工具 用于开发一种分析方法，用于鉴定具有招募新蝙蝠能力的化合物。我们最近 将该方法转化为高通量形式，并用于筛选7000+个化合物。我们验证了 筛选命中，并根据效力、最大活性和 创造改进的类比的潜力。 在拟议的工作中，我们的目标是研究其中最受欢迎的这些化合物的构效关系 通过购买和合成一系列新的类似物并在体外对它们进行评估。我们会 根据活性、物理化学和ADME确定最有发展潜力的项目 属性。将选择先导化合物和后备化合物，如果这项工作成功，我们计划推进 对PK和体内疗效进行研究。这些将紧随其后的是领先的优化，选择一个发展 候选，并生成启用IND的安全数据。

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.