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

基本信息

批准号：
10325528
负责人：
Olivier Boss
金额：
$ 101.86万
依托单位：
ENERGESIS PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10325528
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 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 Translational Research 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

项目摘要

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.

项目概要/摘要肥胖在美国已达到流行病的程度，并且在 2 型肥胖的发展中发挥着重要作用糖尿病、血脂异常和心血管疾病。仍然非常需要更好的非手术治疗。虽然目前大多数减肥药都是通过抑制食欲来起作用的，但可以采取的策略安全地增加能量消耗有可能有效治疗肥胖。棕色脂肪组织（BAT）是一种独特表达线粒体解偶联蛋白-1 (UCP1) 的产热组织。这种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量，因此在维持体温和能量平衡方面发挥着重要作用啮齿动物和人类。 BAT 是一种灵活的组织，通常会随着时间的推移而扩大或萎缩，具体取决于环境温度。在许多不同的啮齿动物模型中，BAT 质量的增加令人信服地已被证明可导致体重减轻和抵抗糖尿病。尽管 BAT 直到最近还被认为是过去几年获得的数据表明，成年人实际上不存在这种现象重要的 BAT 并且该组织具有功能。已经明确的是，较高的活性量个体的 BAT 与瘦弱程度密切相关。人类暴露于寒冷会导致 BAT 增加形成、产热、胰岛素敏感性和脂肪分解，证明 BAT 可以被招募并导致新陈代谢的好处。此外，与一般肥胖关系最密切的基因位点会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 UCP1 和非常高的代谢率。这些细胞是我们用来开发检测方法的独特工具识别具有招募新 BAT 能力的化合物。我们最近使用这种测定法来实现高通量筛选并获得了几个具有良好活性、效力和类似性的高质量命中。我们现在有创造了一系列热门产品的新型类似物，具有出色的活性和理想的理化性质， 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反抗。我们还将研究该系列化合物的分子机制。如果这个作品是成功后，我们计划推进复合优化、选择开发候选者和备份，并生成支持 IND 的安全数据。