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

使用棕色脂肪生成的小分子刺激剂进行体内概念验证和目标识别

• 批准号: 10454241
• 负责人: Olivier Boss
• 金额: $ 96.99万
• 依托单位: ENERGESIS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454241
• 关键词: Acute; Adipocytes; Adipose tissue; Adrenergic Agents; Adult; Animal Model; Animals; Antidiabetic Drugs; Area; Atrophic; Binding; Biological; Biological Assay; Biological Availability; Biology; Blood; Body Composition; Body Temperature; Body Weight; Body Weight decreased; Brown Fat; Cardiovascular Diseases; Cells; Cellular Assay; Clinical Chemistry; Collaborations; Data; Desire for food; Development; Diabetes Mellitus; Dose; Drug Kinetics; Dyslipidemias; Eating; Energy Intake; Energy Metabolism; Enzymes; Epidemic; Fatty acid glycerol esters; Generations; Glucose; Glucose tolerance test; Half-Life; Harvest; Human; Indirect Calorimetry; Individual; Insulin; Insulin Resistance; Investments; Knowledge; Lead; Leptin; Libraries; Life; Link; Lipolysis; Liver Microsomes; Maintenance; Mediating; Medicine; Metabolic; Mitochondria; Molecular; Molecular Mechanisms of Action; Monitor; Mus; National Center for Advancing Translational Sciences; Natural Products; Non-Insulin-Dependent Diabetes Mellitus; Normal tissue morphology; Obese Mice; Obesity; Oral; PPAR gamma; Pathway Analysis; Patients; Permeability; Pharmaceutical Chemistry; Phase; Phenotype; Physiology; Plasma; Play; Probability; Property; Proteins; Provider; Resistance; Rodent; Rodent Model; Role; Safety; Series; Serum; Solubility; Structure-Activity Relationship; Temperature; Testing; Thermogenesis; Thinness; Time; Tissues; United States National Institutes of Health; Weight; Weight maintenance regimen; Weight-Loss Drugs; Work; analog; base; clinical efficacy; diet-induced obesity; drug discovery; efficacy study; energy balance; experience; flexibility; genomic locus; glucose metabolism; high throughput screening; histopathological examination; human data; improved; in vivo; in vivo evaluation; insulin sensitivity; lipid biosynthesis; liver function; metabolic rate; mitochondrial uncoupling protein; mouse model; network models; novel; obese patients; obesity treatment; pharmacophore; progenitor; programs; receptor; recruit; response; screening; small molecule; stem cells; success; tool; transcriptome sequencing; uncoupling protein 1

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.

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。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 祖细胞在适当的条件下成为功能齐全的棕色脂肪细胞， UCP 1和非常高的代谢率。这些细胞是一种独特的工具，我们用来开发一种检测方法， 确定具有招募新BAT能力的化合物。我们最近使用这种方法进行高通量检测， 筛选并获得了几个高质量的命中，具有良好的活性，效力和相似性。我们现在已经 创造了一系列具有优异活性和理想理化性质的最佳命中物的新型类似物， ADME属性。 在拟议的工作中，我们的目标是通过研究证明这一系列类似物的体内概念证明。 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功效 阻力我们还将探讨该化合物系列的分子机理。如果这项工作是 成功的，我们计划推进到化合物优化，选择一个发展候选人和备份， 和生成IND启用安全性数据。