Optimal Selective Thyroid Hormone Analogs for Metabolic Syndrome

描述（由申请人提供）：心血管疾病（CVD）和肥胖的联合威胁可以说是影响西方世界最严重的主要健康问题。虽然在降低心血管疾病死亡率方面取得了进展，但死亡率仍然高得令人无法接受。目前治疗肥胖和相关疾病（如2型糖尿病）的方法并没有减少流行；尽管美国正在积极努力改变生活方式；成功需要很多年。开发针对这些疾病的创新治疗方法至关重要。核受体是一类重要的调控分子，也是药物的主要靶点。甲状腺激素（THs）及其同源核受体（TRs 1和TRs 2）是代谢的主要调节因子。虽然过量的TH会导致有害的影响，如心率加快、心律失常、肌肉和骨骼分解代谢，但也有有益的影响，如降低胆固醇和减少脂肪。我们的团队成功地开发了制造选择性TR调节剂（strm）的方法，以安全地引发TH过量状态的有益作用而不会产生有害影响，并且一些生物技术公司已经基于这些原理创造了化合物。strm在临床前动物模型中显示出治疗代谢性疾病的巨大希望，在肥胖和灵长类动物模型中，它们可以不同程度地逆转血脂异常，促进胆固醇逆向转运，降低体脂，降低非酒精性肝脂肪变性啮齿动物模型中的肝脏脂肪，改善糖尿病小鼠的胰岛素敏感性，而没有明显的有害影响。这些化合物中至少有三种已经在人体试验中，在治疗高低密度脂蛋白（LDL）胆固醇和其他致动脉粥样硬化性血脂升高方面取得了非常有希望的结果。然而，我们现在认识到，现有的strm表现出不同选择模式的独特组合；优先结合tr2 -异构体与TR1，肝脏和组织摄取选择性和基因选择性。我们不知道哪种stm对特定适应症是最好的，什么样的选择性作用组合是最理想的，以及治疗心血管疾病和代谢紊乱的不同方面是否需要相同或不同的选择性作用组合。由于数据尚未进入公共领域，通常很难比较不同的化合物。在本研究中，我们将定义现有strm和新概念化合物的作用，并了解其作用和特性的哪些方面将对代谢疾病的不同方面最有用。我们的策略是对现有的和最近发现的具有不同选择性的配体进行头对头比较，并在体外、细胞培养和精心选择的代谢疾病小鼠模型中详细分析机制。结果将有助于快速跟踪一组可能非常有用的化合物进入临床前动物模型和人体试验的后期测试，并将帮助我们确定第二代化合物的选择作用的最佳组合。

DESCRIPTION (provided by applicant): The combined threat of cardiovascular disease (CVD) and obesity is arguably the worst major health problem affecting the western world. While there has been progress in reducing CVD mortality, death rates remain unacceptably high. Current approaches to treatment of obesity and associated diseases such as T2DM have not reduced the epidemics; in spite of aggressive efforts to modify lifestyles in the United States; success will require many years. It is essential to develop innovative treatments for these disorders. Nuclear receptors (NRs) are one of the most important classes of regulatory molecules and major targets for pharmaceuticals. Thyroid hormones (THs) and their cognate nuclear receptors (TRs 1 and 2) are master regulators of metabolism. While TH excess leads to deleterious effects such as elevated heart rate, arrythmias and muscle and bone catabolism there are beneficial effects such as reduced cholesterol and fat loss. Our team successfully developed ways to create selective TR modulators (STRMs) to safely elicit beneficial effects of TH excess states without harmful effects and several biotechnology companies have created compounds based on these principles. The STRMs have shown great promise for treatment of metabolic disease in preclinical animal models, where they variously reverse dyslipidemias, promote reverse cholesterol transport, reduce body fat in rodent models of obesity and primates, reduce liver fat in rodent models of non-alcoholic hepatic steatosis and improve insulin sensitivity in diabetic mice without obvious harmful effects. At least three of these compounds have been in human trials, with very promising results for treatment of high low density lipoprotein (LDL) cholesterol and elevations in other atherogenic serum lipids. We now realize, however, that existing STRMs exhibit distinctive combinations of different modes of selectivity; preferential binding to the TR2-isoform versus TR1, liver and tissue uptake selectivity and gene selectivity. We do not know which STRM is best for particular indications, what combination of selective effects is most desirable and whether the same or different combinations of selective actions are needed to treat different aspects of CVD and metabolic disorders. It is often hard to compare different compounds because data has not entered the public domain. In this study, we will define actions of existing STRMs and novel concept compounds and understand which aspects of their actions and properties will be most useful for different aspects of metabolic disease. Our strategy is to perform head to head comparisons of the existing and recently discovered ligands with distinct selectivity profiles and detailed analysis of mechanism in vitro, in cell culture and in well chosen mouse models of metabolic disease. Results will help fast-track the best of a potentially very useful group of compounds into tests in late-stage pre- clinical animal models and human trials and will help us define the best combination of selective actions for 2nd generation compounds. PUBLIC HEALTH RELEVANCE: Proteins called nuclear receptors play important roles in every major disease that affects the western world and many successful drugs already work through these proteins. We will find drugs that will safely treat high cholesterol and obesity and work through one class of these proteins, thyroid hormone receptors.