Discovery and characterization of selective D4R antagonists and their evaluation in preclinical models of PD-LIDs

项目总结： 帕金森病(PD)是一种慢性进行性神经退行性疾病，以基本运动为特征 静止性震颤、运动减退、肌肉僵硬和运动迟缓的症状。到目前为止，多巴胺替代疗法使用 多巴胺前体左旋多巴，或L-多巴，仍然是治疗帕金森病运动症状的黄金标准。 然而，L-多巴诱发的运动障碍(LDS)的发展是一个主要的剂量限制性不良反应。 配合长期使用L多巴治疗帕金森病。例如，每年约有10%的帕金森病患者发生 眼睑在7-8年内接受L-多巴治疗。此外，目前还没有有效的治疗方法来预防 PD患者发生LIDs或逆转已建立的LIDs。迄今为止，仍有一个严重的需求未得到满足。 探讨L多巴治疗帕金森病慢性并发症的新方法。我们 最近发现了一系列对D4受体有效和选择性的多巴胺4受体拮抗剂 超过其他多巴胺异构体，以及广泛的选择性面板。此外，我们已经证明了一种典型的化合物 这种支架能够在小鼠模型中产生抗运动障碍的作用。随后，我们发现， 另外两种新型支架，显示出作为D4拮抗剂的出色效力和选择性。在这项提案中，我们将 改进和优化我们的铅支架，以便在保持ADME性能(代谢稳定性)的同时提高ADME性能 效力和选择性。为了开发这些最好的化合物，我们将使用一种迭代药物 化学方法和综合DMPK研究，将使我们能够评估效力和选择性，但也在 及时对新制备的化合物进行体外和体内DMPK性质研究。先进的D4受体拮抗剂 然后，化合物将在活体动物模型的眼睑中进行评估。这些选择性D4受体拮抗剂将提供一种 帮助该领域迈向一流治疗剂的独特机会。

PROJECT SUMMARY: Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder characterized by the cardinal motor symptoms of resting tremor, hypokinesia, muscle rigidity and bradykinesia. To date, dopamine replacement therapy using the dopamine precursor levodopa, or L-DOPA, remains the gold standard treatment for the motor symptoms in PD. However, development of L-DOPA-induced dyskinesias (LIDs) represents a major dose-limiting adverse effect associated with the long-term treatment of PD using L-DOPA. For example, approximately 10% of PD patients per year develop LIDs within the first 7-8 years of L-DOPA treatment. Moreover, there are no effective treatments for either preventing the development of LIDs or reversing already established LIDs in PD patients. To date, there remains a critical unmet need to develop novel therapeutic approaches for the complications associated with chronic L-DOPA treatment in PD. We have recently discovered a series of dopamine 4 receptor antagonists which are potent and selective for the D4 receptor over the other dopamine isoforms, and a wide selectivity panel. In addition, we have shown that a prototypical compound from this scaffold was capable of producing antidyskinetic action in a mouse model. Subsequently, we have discovered two additional novel scaffolds that show excellent potency and selectivity as D4 antagonists. In this proposal, we will improve and optimize our lead scaffolds in order to improve the ADME properties (metabolic stability) while maintaining the potency and selectivity. In order to develop these best-in-class compounds, we will utilize an iterative medicinal chemistry approach and integrated DMPK studies which will allow us to evaluate potency and selectivity, but also the in vitro and in vivo DMPK properties of newly made compound in a timely manner. The advanced D4 receptor antagonist compounds will then be evaluated in an in vivo animal model of LIDs. These selective D4 receptor antagonist will offer a unique opportunity to help advance the field toward a first-in-class therapeutic agent.