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

项目概要： 帕金森病（Parkinson's disease，PD）是一种慢性进行性神经退行性疾病，以中枢运动障碍为特征 静止性震颤、运动功能减退、肌肉僵硬和运动迟缓的症状。到目前为止，多巴胺替代疗法， 多巴胺前体左旋多巴或L-DOPA仍然是PD中运动症状的金标准治疗。 然而，L-DOPA诱导的运动障碍（LID）的发展代表了与L-DOPA相关的主要剂量限制性不良反应。 长期使用左旋多巴治疗帕金森病例如，每年大约10%的PD患者发展为 L-DOPA治疗前7-8年内的LID。此外，没有有效的治疗方法来预防 在PD患者中发生LID或逆转已建立的LID。迄今为止，仍有一个关键的需求未得到满足， 开发新的治疗方法与慢性左旋多巴治疗PD的并发症。我们 最近发现了一系列多巴胺4受体拮抗剂，它们对D4受体具有强效和选择性 和广泛的选择性。此外，我们已经证明，一个原型化合物 能够在小鼠模型中产生抗运动障碍作用。随后我们发现 另外两种新的支架显示出作为D4拮抗剂的优异的效力和选择性。在本提案中，我们将 改善和优化我们的铅支架，以改善ADME性能（代谢稳定性），同时保持 效力和选择性。为了开发这些一流的化合物，我们将利用迭代药物 化学方法和综合DMPK研究，这将使我们能够评估效力和选择性，但也在 体外和体内DMPK性能的新的化合物及时。高级D4受体拮抗剂 然后在LID的体内动物模型中评价化合物。这些选择性的D4受体拮抗剂将提供一种 这是一个独特的机会，有助于将该领域推向一流的治疗药物。

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.