REV-ERB ligands for treatment of anxiety disorders

描述（由申请人提供）：昼夜节律失调与几种神经系统疾病有关，包括抑郁症、焦虑症、精神分裂症和睡眠障碍。对于治疗这些病症的其他类别的治疗剂存在明显未满足的医学需求。焦虑症是一种严重的医学疾病，影响着美国约4000万成年人。苯二氮卓类是最常用的抗焦虑药物，但其使用与显著的副作用相关，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，但这些药物也不是最佳的。这项拟议的研究是基于我们最近的发现，我们可以调节体内的昼夜节律与合成配体的一个特定的核受体（NR），REV-ERB。REV-ERBa是一种NR，在昼夜节律的调节中具有良好的表征作用。我们发现，我们设计的REV-ERB激动剂SR 9011能够调节体内昼夜节律，也在小鼠中表现出抗焦虑活性。有趣的是，SR9011在表现出抗焦虑活性的剂量下不显示镇静活性。SR9011是第一个REV-ERB配体，其体内暴露足以评估其在动物中的作用;然而，其药效学和药代动力学特性远非最佳。我们假设，优化的合成REV-ERB配体将在治疗焦虑症的效用。我们将通过关注以下具体目标来解决这一假设：1）优化用于CNS的合成REV-ERB配体的药效学和药代动力学特性，2）评价合成REV-ERB配体调节体内昼夜节律行为/生理学的能力，3）优化REV-ERB激动剂的体内抗焦虑活性并表征其镇静活性和滥用潜力。我们现在已经开发了一系列非常强效和有效的REV-ERB激动剂以及拮抗剂，其具有允许在疾病动物模型中评价这些化合物的特性。因此，我们提出的研究是高度创新的，并有可能产生很大的影响，因为这项工作可能导致治疗焦虑症以及其他行为障碍的新药。 公共卫生相关性：我们发现核受体REV-ERB是配体调节的，并且已经表征了该受体的合成激动剂和拮抗剂。该受体是昼夜节律的关键调节剂，昼夜节律的失调与包括焦虑症在内的几种神经系统疾病相关。我们已经发现REV-ERB激动剂显示出抗焦虑活性，并且该提议的目标是开发具有优化的药效学和药代动力学性质的REV-ERB激动剂以用作抗焦虑剂。

DESCRIPTION (provided by applicant): Dysregulation of the circadian rhythm is associated with several disorders of the nervous system including depression, anxiety, schizophrenia and sleep disorders. There is a clear unmet medical need for additional classes of therapeutics to treat these 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. 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-ERBa is an NR that has a well characterized role in the regulation of the circadian rhythm. We have found that a REV-ERB agonist that we have designed, SR9011,that has the ability to modulate the circadian rhythm in vivo also displays anxiolytic activity in mice. Interestingly, SR9011 displayed no sedative activity at a dose that exhibited anxiolytic activity. SR9011 is the first REV-ERB ligand with sufficient in vivo exposure to allow evaluation of its effects in animals; however, its 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 in the CNS, 2) Evaluate the ability of synthetic REV-ERB ligands for their ability 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 as well as antagonists 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. PUBLIC HEALTH RELEVANCE: We discovered that the nuclear receptor REV-ERB is ligand regulated and have characterized both synthetic agonists and antagonists of this receptor. This receptor is a key regulator of the circadian rhythm and dysregulation of the circadian rhythm is associated with several disorders of the nervous system including anxiety disorders. We have discovered that REV-ERB agonists display anxiolytic activity and the goal of this proposal is to develop REV-ERB agonists with optimized pharmacodynamic and pharmacokinetic properties for use as anxiolytic agents.