REV-ERB ligands for treatment of anxiety disorders

描述（由申请人提供）：昼夜节律失调与包括焦虑症在内的几种神经系统疾病有关。焦虑症是一种严重的医学疾病，影响着美国大约4000万成年人。苯二氮卓类药物是最常用的抗焦虑药物，但其使用与显著的副作用有关，包括镇静、耐受性和滥用的可能性。现在有许多抗焦虑药物可用，但它们也不是最理想的。因此，有一个明确的未满足的医疗需求，需要额外的治疗类来治疗这些疾病。这项研究是基于我们最近的发现，我们可以通过合成一种特定核受体（NR）的配体REV-ERB来调节体内的昼夜节律。REV-ERBalpha是一种NR，在昼夜节律调节中具有良好的特征。我们发现，我们设计的REV-ERB激动剂具有调节体内昼夜节律的能力，在小鼠中也显示出抗焦虑活性。有趣的是，这些化合物在抗焦虑剂量下没有镇静活性。我们开发的REV-ERB激动剂是第一个具有充分体内暴露的药物，可以评估其在动物中的作用；然而，它们的药效学和药代动力学性能远未达到最佳。我们假设优化的合成REV-ERB配体将在治疗焦虑症方面具有实用价值。我们将通过以下具体目标来解决这一假设：1)优化合成REV-ERB配体作为抗焦虑药物的药效学和药代动力学特性，2)评估合成REV-ERB配体在体内调节昼夜行为/生理的能力，3)优化REV-ERB激动剂在体内的抗焦虑活性，并表征其镇静活性和滥用的可能性。我们现在已经开发了一系列非常有效的REV-ERB激动剂，其特性将允许在动物疾病模型中评估这些化合物。因此，我们提出的研究是高度创新的，并且有可能产生很高的影响，因为这项工作可能会导致治疗焦虑症以及其他行为障碍的新药。

DESCRIPTION (provided by applicant): Dysregulation of the circadian rhythm is associated with several disorders of the nervous system including anxiety disorders. Anxiety disorders are a serious medical illness affecting approximately 40 million adults in the United States. Benzodiazepenes are the most commonly utilized anxiolytic drugs, but their use is associated with significant side effects including sedation, tolerance and potential for abuse. There are a number of anxiolytic drugs that are now available, but these also are less than optimal. Thus, there is a clear unmet medical need for additional classes of therapeutics to treat these disorders. This proposed research is based on our recent discovery that we can modulate the circadian rhythm in vivo with synthetic ligands for a particular nuclear receptor (NR), REV-ERB. REV-ERBalpha is an NR that has a well-characterized role in the regulation of the circadian rhythm. We have found that REV-ERB agonists that we have designed that has the ability to modulate the circadian rhythm in vivo also display anxiolytic activity in mice. Interestingly, thes compounds display no sedative activity at anxiolytic doses. The REV-ERB agonists we have developed are the first with sufficient in vivo exposure to allow evaluation of its effects in animals; however, their pharmacodynamic and pharmcokinetic properties are far from optimal. We hypothesize that optimized synthetic REV-ERB ligands will have utility in treatment of anxiety disorders. We will address this hypothesis by focusing on the following specific aims: 1) Optimize the pharmacodynamic and pharmacokinetic properties of synthetic REV-ERB ligands for use as anxiolytic agents, 2) Evaluate the ability of synthetic REV- ERB ligands for their abiliy to modulate circadian behavior/physiology in vivo, 3) Optimize the anxiolytic activity of REV-ERB agonists in vivo and characterize their sedative activity and potential for abuse. We have now developed a series of very potent and efficacious REV-ERB agonists that have properties that will allow for evaluation of these compounds in animal models of disease. Thus, our proposed research is highly innovative and has the potential to have high impact since this work may lead to novel drugs for the treatment of anxiety disorders as well as other behavioral disorders.