Development of RORbeta-selective modulators as in vivo probes

 描述（由申请人提供）：配体调节的转录因子的核受体（NR）超家族已被证明是开发多种人类疾病治疗剂的丰富靶点来源。视黄酸受体相关孤儿受体（RORα、RORβ和RORγ）调节多种生理过程，包括昼夜节律、糖和脂质代谢以及免疫功能。RORβ存在于中枢神经系统（CNS）的区域中，这些区域参与感觉信息的处理和哺乳动物计时系统（生物钟基因）的组成部分，包括视交叉上核（SCN）、视网膜、松果体和骨骼。RORβ-/-小鼠表型尚未完全表征。需要RORβ的选择性小分子调节剂来补充这些努力。缺乏与RORβ结合的易处理的小分子配体阻碍了对该受体在体内功能的研究。最近，已鉴定出双重RORβ/γ配体。由于我们的实验室之前已经合作鉴定和开发了泛ROR调节剂、RORα选择性激动剂和反向激动剂以及RORγ选择性反向激动剂，因此我们在鉴定、表征和开发RORβ选择性调节剂方面处于有利地位。鉴于RORβ受体的组织特异性分布和重要的生理功能，RORβ选择性小分子的鉴定将成为一种有价值的化学探针和药理学工具。我们的目标是将现有的PAN支架优化为具有适当药效学（PD）和药代动力学（PK）特性的RORβ选择性化合物，以提供RORβ探针来询问受体在体内的功能及其作用 疾病的病理生理学。为了实现这一目标，我们提出了以下具体目标：1）进一步开发和优化具有改进的效力、选择性和药代动力学性质的RORβ-选择性配体; 2）表征这些RORβ-选择性化合物的体外和体内药理学。这些目标的实现将提供选择性调节RORβ活性的新型一流配体。这些探针将是有用的受体功能的研究，在体内的动物模型的疾病，如昼夜节律和精神病，眼部疾病，以及在与年龄有关的骨丢失。

 DESCRIPTION (provided by applicant): The nuclear receptor (NR) superfamily of ligand regulated transcription factors has proven to be a rich source of targets for the development of therapeutics for a wide range of human diseases. The retinoic acid receptor-related orphan receptors (RORα, RORβ and RORγ) regulate several physiological processes, including the circadian rhythm, glucose and lipid metabolism, and immune functions. RORβ is found in regions of the central nervous system (CNS) that are involved in processing of sensory information and components of the mammalian timing system (circadian clock genes), including the suprachiasmatic nuclei (SCN), retina, pineal gland, and bone. The RORβ-/- mouse phenotype has not yet been completely characterized. Selective small molecule modulators of RORβ are needed to compliment these efforts. The lack of tractable small molecule ligands that bind RORβ has hindered interrogation of the function of this receptor in vivo. Recently, dual RORβ/γ ligands have been identified. Since, our labs have previously collaborated to identify and develop pan-ROR modulators, RORα-selective agonists and inverse agonists, and RORγ-selective inverse agonists, we are well positioned to identify, characterize and develop RORβ-selective modulators. Given the receptors specific tissue distribution and important physiological functions, the identification of RORβ-selective small molecules would be a valuable chemical probe and pharmacological tool. Our goal is to optimize current pan scaffolds into RORβ-selective compounds with the appropriate pharmacodynamic (PD) and pharmacokinetic (PK) properties to provide RORβ probes to interrogate the function of the receptor in vivo and its role in the pathophysiology of disease. In order to achieve this goal, we propose the following Specific Aims: 1) Further develop and optimize RORβ-selective ligands with improved potency, selectivity and pharmacokinetic properties; 2) Characterize the pharmacology of these RORβ-selective compounds in vitro and in vivo. Accomplishment of these Aims will provide novel, first-in-class ligands that selectively modulate RORβ activity. These probes will be useful for the study of the receptors function in vivo in animal models of disease such as circadian rhythm and psychosis, eye disorders, as well as in age-related bone loss.