Optimal Selective Thyroid Hormone Analogs for Metabolic Syndrome

描述(申请人提供)：心血管疾病(CVD)和肥胖的综合威胁可以说是影响西方世界的最严重的健康问题。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。目前治疗肥胖症和2型糖尿病等相关疾病的方法并没有减少流行病的流行；尽管美国积极努力改变生活方式，但成功将需要多年时间。为这些疾病开发创新的治疗方法是至关重要的。核受体是最重要的调节分子之一，也是药物作用的主要靶点。甲状腺激素(TH)及其同源核受体(TRS1和TR2)是新陈代谢的主要调节因子。虽然过量会导致有害的影响，如心率加快、心律失常、肌肉和骨骼分解代谢，但也有好处，如降低胆固醇和脂肪损失。我们的团队成功地开发了一些方法来创建选择性的tr调节器(STRM)，以安全地引发过量状态的有益影响，而不会产生有害影响，几家生物技术公司已经基于这些原理开发了化合物。在临床前动物模型中，STRM在治疗代谢性疾病方面显示出巨大的前景，它们在不同程度上逆转了血脂异常，促进了胆固醇的反向运输，降低了肥胖和灵长类啮齿动物的体脂，降低了非酒精性肝脂肪变性的啮齿动物的肝脏脂肪，并改善了糖尿病小鼠的胰岛素敏感性，而没有明显的有害影响。其中至少有三种化合物已经进行了人体试验，在治疗高密度脂蛋白(LDL)胆固醇和升高其他导致动脉粥样硬化的血清脂质方面取得了非常有希望的结果。然而，我们现在意识到，现有的STRM表现出不同模式的选择性的独特组合；与TR1相比，与TR2-异构体的优先结合，肝脏和组织摄取的选择性以及基因的选择性。我们不知道哪种STRM对于特定的适应症是最好的，什么选择性效应的组合是最可取的，以及治疗心血管疾病和代谢紊乱的不同方面需要相同还是不同的选择性作用组合。通常很难比较不同的化合物，因为数据还没有进入公共领域。在这项研究中，我们将定义现有的STRM和新概念化合物的作用，并了解它们的作用和性质的哪些方面将对代谢性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特征的配体进行面对面的比较，并在体外、细胞培养和精心挑选的代谢性疾病小鼠模型中详细分析机制。结果将有助于将潜在非常有用的一组化合物中的最好部分快速跟踪到后期临床前动物模型和人体试验中的测试中，并将帮助我们定义第二代化合物的最佳选择性作用组合。 与公共卫生相关：被称为核受体的蛋白质在影响西方世界的每一种重大疾病中都发挥着重要作用，许多成功的药物已经通过这些蛋白质发挥作用。我们将找到安全治疗高胆固醇和肥胖症的药物，并通过这类蛋白质中的一种--甲状腺激素受体发挥作用。

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.