Development of Novel Brown Adipocyte Recruiters for the Treatment of Obesity

开发用于治疗肥胖症的新型棕色脂肪细胞招募剂

• 批准号: 10081602
• 负责人: Olivier Boss
• 金额: $ 29.54万
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081602
• 关键词: Acids; Adipocytes; Adult; Antidiabetic Drugs; Artificial Membranes; Arts; Atrophic; Award; Biological Assay; Biological Availability; Body Temperature; Body Weight decreased; Brown Fat; Cardiovascular Diseases; Cell Membrane Permeability; Cells; Chemistry; Collaborations; Data; Desire for food; Development; Diabetes Mellitus; Dose; Dyslipidemias; Energy Intake; Energy Metabolism; Epidemic; Evaluation; Fatty acid glycerol esters; Generations; Glucose; Goals; Human; In Vitro; Individual; Investments; Lead; Libraries; Link; Lipolysis; Liver; Maintenance; Measures; Mediating; Medical; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Natural Products; Non-Insulin-Dependent Diabetes Mellitus; Normal tissue morphology; Obesity; Oral; Parents; Patients; Performance; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Physiology; Play; Probability; Property; Proteins; Provider; Publishing; Resistance; Resources; Rodent; Rodent Model; Role; Safety; Series; Skeletal Muscle; Solubility; Structure; Structure-Activity Relationship; Temperature; Testing; Thermogenesis; Thinness; Time; Tissues; Toxicology; Translational Research; Translations; Weight maintenance regimen; Weight-Loss Drugs; Work; absorption; analog; base; design; drug candidate; efficacy study; energy balance; experience; flexibility; genomic locus; human data; improved; in vitro Assay; in vitro Bioassay; in vitro activity; in vivo; in vivo evaluation; insulin sensitivity; lead candidate; lead optimization; lipid biosynthesis; metabolic rate; mitochondrial uncoupling protein; novel; obesity treatment; pharmacophore; preservation; progenitor; programs; recruit; response; scaffold; screening; small molecule; stem cells; tool; 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 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.

项目摘要/摘要 肥胖在美国已经达到了流行病，并在2型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 手术治疗。虽然大多数当前的减肥剂通过抑制食欲而采取行动，但可以 安全地增强能量消耗有效治疗肥胖。棕色脂肪组织（蝙蝠） 是一种唯一表达线粒体解偶联蛋白1（UCP1）的热组织。该蛋白质 以受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中起着重要作用 啮齿动物和人类。蝙蝠是一种柔性组织，通常会随着时间的流逝而扩大或萎缩 环境温度。在许多不同的啮齿动物模型中，蝙蝠质量的增强令人信服 已显示导致体重减轻和糖尿病耐药性。直到最近被认为是 在过去几年中获得的数据实际上已经有效地表明，成人的数据实际上已经 明显的蝙蝠，并且该组织具有功能。人们已经确定了更高数量的活跃 个体中的蝙蝠与苗条密切相关。人类的冷暴露会导致蝙蝠增加 形成，热生成，胰岛素敏感性和脂解，证明可以募集蝙蝠并铅 代谢益处。此外，遗传基因座最紧密地与一般肥胖有关导致缺陷 招募新的棕色脂肪细胞。 直到最近，还没有鉴定出棕色脂肪细胞干细胞。我们发现了人类棕色脂肪细胞 祖细胞驻留在适当条件下的骨骼肌中 脂肪细胞，UCP1水平高，代谢率很高。这些单元是我们的独特工具 用于开发用于识别具有招募新蝙蝠的化合物的测定法。我们最近 将此测定法转换为高吞吐量格式，并将其用于屏幕7000多种化合物。我们验证了 筛选命中，并根据效力，最大活动和 创建改进的类似物的潜力。 在拟议的工作中，我们旨在调查其中最喜欢的结构活动关系 通过购买和合成一系列新颖的类似物并在体外评估它们来进行化合物。我们将 确定基于活动和理化和ADME的发展潜力最高的人 特性。将选择铅化合物和备份，如果这项工作成功，我们计划进步 进行PK和体内功效研究。随后将进行铅优化，选择开发 候选人和生成辅助安全数据。