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

选择性 D4R 拮抗剂的发现和表征及其在 PD-LID 临床前模型中的评估

• 批准号: 10642849
• 负责人: Corey R. Hopkins
• 金额: $ 56万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642849
• 关键词: Adrenergic Receptor; Adverse effects; Affect; Animal Model; Basal Ganglia; Behavior; Binding; Binding Proteins; Biological Assay; Bradykinesia; Brain; Brain region; Cell Nucleus; Cellular Assay; Characteristics; Chronic; Clinical; Clozapine; Complication; DRD4 gene; Development; Dopamine; Dopamine D2 Receptor; Dose; Dose Limiting; Drug Kinetics; Drug Targeting; Evaluation; Exclusion; Experimental Models; Ganglia; Globus Pallidus; Glutamate Receptor; Grant; Hypokinesia; In Vitro; L-DOPA induced dyskinesia; Lead; Levodopa; Ligands; MPTP Poisoning; Medical; Metabolic; Modeling; Motor; Mus; Muscle Rigidity; Neurodegenerative Disorders; Neurons; Output; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Patients; Penetration; Performance; Permeability; Pharmaceutical Chemistry; Pharmacological Treatment; Plasma; Plasma Proteins; Play; Pre-Clinical Model; Property; Protein Isoforms; Reaction; Rest Tremor; Rodent Model; Role; Series; Serotonin; Severities; Solubility; Stereotyping; Substantia nigra structure; Testing; Therapeutic; Therapeutic Agents; Toxicology; Treatment Efficacy; Work; analog; antagonist; chemical synthesis; design; dopamine replacement therapy; effective therapy; experimental study; improved; in vivo; in vivo evaluation; lead optimization; motor symptom; mouse model; negative affect; neuropsychiatry; nonhuman primate; novel; novel therapeutic intervention; prevent; psychotic; pyridine; receptor; scaffold; serotonin receptor; sigma-1 receptor; standard care; Adrenergic Receptor; Adverse effects; Affect; Animal Model; Basal Ganglia; Behavior; Binding; Binding Proteins; Biological Assay; Bradykinesia; Brain; Brain region; Cell Nucleus; Cellular Assay; Characteristics; Chronic; Clinical; Clozapine; Complication; DRD4 gene; Development; Dopamine; Dopamine D2 Receptor; Dose; Dose Limiting; Drug Kinetics; Drug Targeting; Evaluation; Exclusion; Experimental Models; Ganglia; Globus Pallidus; Glutamate Receptor; Grant; Hypokinesia; In Vitro; L-DOPA induced dyskinesia; Lead; Levodopa; Ligands; MPTP Poisoning; Medical; Metabolic; Modeling; Motor; Mus; Muscle Rigidity; Neurodegenerative Disorders; Neurons; Output; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Patients; Penetration; Performance; Permeability; Pharmaceutical Chemistry; Pharmacological Treatment; Plasma; Plasma Proteins; Play; Pre-Clinical Model; Property; Protein Isoforms; Reaction; Rest Tremor; Rodent Model; Role; Series; Serotonin; Severities; Solubility; Stereotyping; Substantia nigra structure; Testing; Therapeutic; Therapeutic Agents; Toxicology; Treatment Efficacy; Work; analog; antagonist; chemical synthesis; design; dopamine replacement therapy; effective therapy; experimental study; improved; in vivo; in vivo evaluation; lead optimization; motor symptom; mouse model; negative affect; neuropsychiatry; nonhuman primate; novel; novel therapeutic intervention; prevent; psychotic; pyridine; receptor; scaffold; serotonin receptor; sigma-1 receptor; standard care

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.

项目摘要： 帕金森氏病（PD）是一种慢性和进行性神经退行性疾病，其特征是基本电动机 静息树，高软化，肌肉僵硬和头肌动力的症状。迄今为止，使用多巴胺替代疗法 多巴胺前体左旋多巴或l-dopa仍然是PD运动症状的金标准治疗方法。 然而，L- dopa诱导的运动障碍（LID）的发展代表了相关的主要剂量限制不良效应 使用L-DOPA对PD进行长期处理。例如，每年约有10％的PD患者发展 在L-DOPA治疗的前7 - 8年内盖子。此外，没有有效的治疗方法可以防止 PD患者已经建立的盖子的盖子或逆转开发。迄今为止，仍然有关键的未满足需求 开发新的治疗方法，以解决与PD中慢性L-DOPA治疗相关的并发症。我们 最近发现了一系列多巴胺4受体拮抗剂，对D4受体具有潜力和选择性 在其他多巴胺同工型和广泛的选择性面板上。此外，我们已经表明了典型化合物 从这个脚手架中，能够在小鼠模型中产生抗动物基因作用。随后，我们发现了 另外两个新型的脚手架作为D4拮抗剂表现出极好的效能和选择性。在此提案中，我们将 改善和优化我们的铅脚手架，以提高ADME特性（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，我们将使用迭代药物 化学方法和综合DMPK研究将使我们能够评估效力和选择性，也可以 及时及时的化合物的体外和体内DMPK特性。晚期D4受体拮抗剂 然后，将在盖子的体内动物模型中评估化合物。这些选择性D4受体拮抗剂将提供 帮助该领域迈向第一类治疗剂的独特机会。