New Agents That Inhibit Fatty Acid Accumulation

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。虽然减肥是治疗2型糖尿病最有效的方法，但目前的减肥方法通常不足以长期减肥。AdipoGenix, Inc.的使命是发现、开发和许可在脂肪细胞（脂肪细胞）水平上作用的新型治疗方法，用于治疗肥胖和相关疾病。目前缺乏有效的治疗方法，特别是对脂肪细胞有效的治疗方法。AdipoGenix已经开发出了培养和分化人类前脂肪细胞的先进方法，并建立并验证了一种监测这些细胞中脂质积累的初级筛选试验。使用该方法筛选了70,000种化合物，并鉴定了一类新的化合物，这些化合物可以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积累的作用机制，以促进这类化合物的进一步开发，并扩大我们的领先产品的专有保护。在目标1中，将合成足够数量的铅和两种相关化合物，用于目标2和目标3的工作。放射性标记的先导化合物也将被合成用于Aim 2。在Aim 2中，将使用Aim 1中生成的未标记和放射性标记的化合物来确定分化的人前脂肪细胞匀浆的特异性结合。一般受体和作用机制筛选也将进行，以确定受体和阐明细胞靶机制，通过这些化合物减少脂肪细胞中的脂质积累。Aim 3将进行代谢途径分析。使用这种新方法

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.