Development of ROR ligands for treatment of circadian rhythm disorders

描述（由申请人提供）：核激素受体超家族（NHR）和配体调节的转录因子已被证明是开发针对无数人类疾病的药物的丰富靶标来源。视黄酸受体相关孤儿受体（RORs）是该超家族的成员，并调节多种生理过程，包括昼夜节律、代谢和免疫反应。我们最近发现了第一个选择性合成配体，靶向ROR，一个昼夜节律的关键调节器。我们的长期目标是开发靶向RORs的配体，可用于治疗与昼夜节律失调相关的疾病，如双相情感障碍、睡眠障碍以及精神分裂症。最初的先导化合物（T0901317）作为针对ROR的药物使用的性能不理想，我们的初步数据表明我们可以显着改善其药物样性能。我们假设，基于T0901317化学支架的优化ROR配体，具有改善的药效学、药代动力学和受体选择性特性，将对调节昼夜节律有效。为了解决这一假设，我们将重点关注以下具体目标：1)开发和优化靶向中枢神经系统的具有改进的药代动力学和药效学特性的ROR配体；2)表征ROR配体对动物昼夜节律的作用。我们预测，这项研究将提供新颖的、创新的调节ROR1活性的配体，这将对治疗睡眠障碍以及其他与昼夜节律失调相关的疾病（包括生物极性障碍和精神分裂症）具有潜在的实用价值。

DESCRIPTION (provided by applicant): The nuclear hormone receptor superfamily (NHR) and ligand regulated transcription factors that have proven to be a rich source of targets for development of drugs that target myriad human diseases. The retinoic acid receptor-related orphan receptors (RORs) are members of this superfamily and regulate several physiological processes including the circadian rhythm, metabolism and the immune response. We recently identified the first selective synthetic ligands that target ROR, a critical regulator of the circadian rhythm. Our long-term goal is to develop ligands targeting RORs that can be used to treat diseases associated with dysregulation of the circadian rhythm such as bipolar and sleep disorders as well as schizophrenia. The initial lead compound (T0901317) has less than optimal properties for use as a drug targeting ROR and our preliminary data indicates that we can significantly improve its drug like properties. We hypothesize that optimized ROR ligands, based on the T0901317 chemical scaffold, with improved pharmacodynamic, pharmacokinetic, and receptor selectivity properties will have efficacy in modulation of the circadian rhythm. In order to address this hypothesis we will focus on the following specific aims: 1) Develop and optimize ROR ligands with improved pharmacokinetic and pharmacodynamic properties targeting the central nervous system; 2) Characterize the actions of ROR ligands on the circadian rhythm in animals. We predict that this research will provide novel, innovative ligands that modulate ROR1 activity that will have potential utility to treat sleep disorders as well as other disorders associated with dysregulation of the circadian rhythm including biopolar disorder and schizophrenia.