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：
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
项目类别：
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

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在适当的条件下变成功能齐全的棕色脂肪细胞，高水平 UCP1和非常高的代谢率。这些单元格是我们用来开发用于开发的独特工具识别具有招募新蝙蝠的能力的化合物。我们最近将此测定法用于高通量筛选并获得了几次高质量的命中，具有良好的活动，效能和类似性。我们现在有创建了一系列具有出色活性和理想的物理化学和理想性的最佳热门歌曲的新型类似物 Adme属性。在拟议的工作中，我们旨在通过研究这一系列类似物来证明体内概念证明在高质量的肥胖和胰岛素模型中，化合物的药代动力学和功效反抗。我们还将研究化合物系列的分子机制。如果这项工作是成功，我们计划进步进行复合优化，选择候选人和备份，以及生成辅助安全数据。