Development of ROR ligands for treatment of circadian rhythm disorders

开发用于治疗昼夜节律紊乱的 ROR 配体

• 批准号: 8370510
• 负责人: Thomas P Burris
• 金额: $ 71.46万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-22 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8370510
• 关键词: Address; Animals; Biological Assay; Bipolar Disorder; Chemicals; Circadian Dysregulation; Circadian Rhythms; Data; Development; Disease; Drug Kinetics; Drug Targeting; Goals; Health; Human; Immune response; Lead; Ligands; Mental Depression; Metabolism; Mus; Neuraxis; Nuclear Hormone Receptors; Orphan; Pathologic Processes; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Physiological; Physiological Processes; Property; Psychotic Disorders; RORA gene; Regulation; Research; Retinoic Acid Receptor; Role; Scheme; Schizophrenia; Sleep Disorders; Source; Structure-Activity Relationship; Synthesis Chemistry; Testing; base; design; human disease; improved; in vivo; innovation; mRNA Expression; member; nervous system disorder; novel; public health relevance; receptor; scaffold; tool; transcription factor

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.

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，这些转录因子已被证明是针对靶向多种人类疾病的药物的丰富靶标的来源。视黄酸受体相关的孤儿受体（ROR）是该超家族的成员，并调节了几种生理过程，包括昼夜节律，代谢和免疫反应。我们最近确定了靶向ROR的第一个选择性合成配体，该配体是昼夜节律的关键调节剂。我们的长期目标是开发针对ROR的配体，可用于治疗与昼夜节律失调相关的疾病，例如双极性和睡眠障碍以及精神分裂症。最初的铅化合物（T0901317）用作靶向ROR的药物的最佳特性少，我们的初步数据表明我们可以显着改善其药物（如特性）。我们假设基于T0901317化学支架优化的ROR配体，具有改进的药效，药代动力学和受体选择性特性，将在调节昼夜节律的调节方面具有疗效。为了解决这一假设，我们将重点关注以下特定目的：1）开发和优化具有针对中枢神经系统的药代动力学和药物动力学特性的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配体，以调节ROR1活性，这些活性可能具有治疗睡眠障碍的潜在效用，以及与昼夜节律失调有关的其他疾病，包括生物极度疾病和精神分裂症。