New Agents That Inhibit Fatty Acid Accumulation

抑制脂肪酸积累的新药物

• 批准号: 6582264
• 负责人: CYDNEY C BROOKS
• 金额: $ 9.99万
• 依托单位: ADIPOGENIX, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6582264
• 关键词: adipocytes; biological signal transduction; biotherapeutic agent; cardiovascular disorder risk; chemical synthesis; clinical research; diabetes risk; fatty acids; human tissue; lead; liquid chromatography mass spectrometry; nuclear magnetic resonance spectroscopy; obesity; pharmacokinetics; polymerase chain reaction; prostaglandins; radiotracer; receptor; technology /technique development; tissue /cell culture

DESCRIPTION (provided by applicant): Obesity is a well-established risk factor for a number of diseases, including type 2 diabetes and coronary heart disease. Although weight loss is the most effective treatment for type 2 diabetes, current methods for reducing weight typically are insufficient for long-term weight loss. The mission of AdipoGenix, Inc. is to discover, develop and license novel therapeutics acting at the level of the fat cell (adipocyte) for the treatment of obesity and related disorders. Effective therapeutics, particularly those acting on the fat cell, is lacking. AdipoGenix already has developed advanced methods for culturing and differentiating human preadipocytes, and has established and validated a primary screening assay to monitor lipid accumulation in these cells. Using this assay 70,000 compounds were screened, and a new class of compounds that reduces lipid accumulation in differentiated human preadipocytes was identified. The present goal is to determine the mechanism of action by which these new compounds reduce lipid accumulation in order to facilitate further development of this class of compounds and to expand proprietary protection of our leads. In Aim 1 sufficient quantities of the lead and two related compounds will be synthesized for work in Aims 2 and 3. Radiolabeled lead compound also will be synthesized for use in Aim 2. In Aim 2 specific binding in homogenates from differentiated human preadipocytes using the unlabeled and radiolabeled compounds generated in Aim 1 will be determined. General receptor and mechanism of action screens also will be performed to identify the receptor and elucidate the cellular target mechanism by which these compounds reduce lipid accumulation in human adipocytes. In Aim 3 metabolic pathway analysis will be performed. Using this approach this new class of compounds has been shown not to act through PPARgamma or by stimulating lipolysis. Also in Aim 3, signaling pathways will be defined by analysis of focused signaling-pathway expression arrays using mRNA from differentiated human preadipocytes treated with our compounds. This work will produce key information to expedite receptor identification, determine mechanism of action, facilitate full lead optimization for the further development of this class of compounds, and to develop additional, new antiobesity drugs acting at the level of the fat cell.

描述（由申请人提供）：肥胖是许多疾病的公认危险因素，包括2型糖尿病和冠心病。虽然减肥是2型糖尿病最有效的治疗方法，但目前的减肥方法通常不足以长期减肥。AdipoGenix公司的使命是发现，开发和许可在脂肪细胞（脂肪细胞）水平作用的新疗法，用于治疗肥胖症和相关疾病。缺乏有效的治疗方法，特别是那些作用于脂肪细胞的治疗方法。AdipoGenix已经开发出了培养和分化人类前脂肪细胞的先进方法，并建立和验证了一种初步筛选试验，以监测这些细胞中的脂质积累。使用该测定筛选了70，000种化合物，并鉴定了一类新的化合物，其减少分化的人前脂肪细胞中的脂质积累。目前的目标是确定这些新化合物减少脂质蓄积的作用机制，以促进这类化合物的进一步开发，并扩大对我们的电极导线的专有保护。在目标1中，将合成足够量的铅和两种相关化合物，用于目标2和3的工作。还将合成用于目标2的放射性标记的先导化合物。在目标2中，将使用目标1中生成的未标记和放射性标记化合物测定分化人前脂肪细胞匀浆中的特异性结合。还将进行一般受体和作用机制筛选，以鉴定受体并阐明这些化合物减少人脂肪细胞中脂质蓄积的细胞靶向机制。在目标3中，将进行代谢途径分析。使用这种方法，新 已经证明这类化合物不通过PPARgamma或刺激脂解起作用。同样在目标3中，将通过使用来自用我们的化合物处理的分化的人前脂肪细胞的mRNA分析聚焦信号传导途径表达阵列来定义信号传导途径。这项工作将产生关键信息，以加快受体鉴定，确定作用机制，促进这类化合物的进一步开发的全面优化，并开发在脂肪细胞水平上起作用的其他新的减肥药物。