In Vivo Proof of Concept and Target Identification Using Small Molecule Stimulators of Brown Adipogenesis

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 在适当的条件下，祖细胞成为功能齐全的棕色脂肪细胞，具有高水平 UCP1和非常高的代谢率。这些细胞是一种独特的工具，我们用来开发一种分析方法 确定具有招募新蝙蝠能力的化合物。我们最近使用了这种方法来实现高通量 经过筛选，获得了几个活性、效价和可比性都很好的高质量目标化合物。我们现在有了 创造了一系列最好的热门药物的新颖类似物，具有出色的活性和理想的物理化学和 ADME属性。 在拟议的工作中，我们的目标是通过研究来演示使用这一系列类似物在体内证明概念 这些化合物在高质量肥胖和胰岛素小鼠模型中的药代动力学和疗效 抵抗。我们还将对该系列化合物的分子机理进行研究。如果这项工作是 成功的我们计划推进复合优化，选择开发候选者和后备， 以及生成启用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 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 used this assay for high throughput screening and obtained several high quality hits with good activity, potency, and analogability. We have now created a series of novel analogs of the best hits with excellent activity and desirable physicochemical and ADME properties. In the proposed work, we aim to demonstrate in vivo proof of concept with this series of analogs by studying the compounds' pharmacokinetics and efficacy in a high quality mouse model of obesity and insulin resistance. We will also investigate the molecular mechanism of the compound series. If this work is successful we plan to advance to compound optimization, selection of a development candidate and backup, and generation of IND-enabling safety data.