A novel calcium channel antagonist for neuroprotection in Parkinson???s disease

一种新型钙通道拮抗剂，用于帕金森病的神经保护

基本信息

批准号：
8401406
负责人：
DALTON JAMES SURMEIER
金额：
$ 19.31万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8401406
关键词：
Adult Alzheimer&apos s Disease Animal Model Biological Assay Biological Availability Biological Markers Brain Calcium Calcium Channel Clinical Clinical Trials Collaborations Communities Complement Contractor Development Dihydropyridines Disease Disease Progression Dose-Limiting Drug Kinetics Drug effect disorder Epidemiologic Studies Goals Health Human In Vitro Incidence Individual Lead Life Life Expectancy Link Metabolic stress Mitochondria Modeling Modification Motor Mus Neurodegenerative Disorders Neurons Optics Parkinson Disease Pathogenesis Performance Peripheral Pharmaceutical Chemistry Pharmaceutical Preparations Property Request for Proposals Risk Slice Structure Substantia nigra structure Symptoms System Testing Therapeutic Toxic effect United States National Institutes of Health Work age related dihydropyridine disability dopaminergic neuron drug development expectation experience high throughput screening improved in vivo in vivo Model meetings mouse model neuronal survival neuroprotection novel novel therapeutics oxidant stress pars compacta preclinical study prevent scaffold small molecule

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease is a widespread and debilitating aging-related neurodegenerative disorder. The incidence for Parkinson's disease is increasing in parallel with life expectancy. There is no cure or means of slowing the progression of this disease. Although current symptomatic therapies are initially effective, they are short-lived because disease progression cannot be arrested. Recent preclinical and epidemiological studies have implicated L-type Ca2+ channels with a CaV1.3 pore-forming subunit in disease pathogenesis. Although a clinical trial with a dihydropyridine (DHP) antagonist of these channels is underway, this trial could fail because off-target effects limit dosing. Thus, the development o a potent and selective CaV1.3 channel antagonist with good pharmacokinetics and low toxicity is an unmet need for the Parkinson's disease community. To meet this need, a high-throughput screening (HTS) effort was undertaken and two small molecules with low CaV1.3 selectivity were identified that had excellent pharmacological properties. A third scaffold has been identified using a computational approach informed by our HTS screen. Structure modification of one of the molecules led to an 833-fold increase in CaV1.3 selectivity (to 1000-fold). This proposal requests support to take the next steps toward developing these scaffolds into clinically useful drugs. Three specific aims are proposed: Specific Aim 1: To determine the ADMET liabilities of identified CaV1.3 channel antagonists; Specific Aim 2: To improve the potency, selectivity, stability, and brain bioavailability of identified CaV1.3 channel antagonists through medicinal chemistry; and Specific Aim 3: To determine the efficacy of the optimized lead compounds in models of Parkinson's disease. These studies will take full advantage of our early work with these scaffolds by our group and our expertise in assays of drug action in models of Parkinson's disease, complementing the drug development expertise of the NIH contractors. Achieving these aims will provide the first highly selective CaV1.3 channel antagonist suitable for human clinical trials in Parkinson's disease. Such a drug would have the potential to slow or stop the progression of Parkinson's disease, broadening the therapeutic window for symptomatic therapy. PUBLIC HEALTH RELEVANCE: Parkinson's disease is a major health problem in the U.S. Preclinical and epidemiological studies suggest that antagonizing a special class of calcium channel could slow or stop the progression of the disease. The studies proposed here are to develop a new selective antagonist of these channels for clinical use.

描述（由申请人提供）：帕金森氏病是一种普遍且使人衰弱的神经退行性疾病。帕金森氏病的发病率与预期寿命平行。没有治愈或减缓该疾病进展的手段。尽管目前的有症状疗法最初是有效的，但由于疾病进展无法逮捕，因此它们是短暂的。最近的临床前和流行病学研究暗示了L型Ca2+通道在疾病发病机理中具有CAV1.3孔形成亚基。尽管这些通道的二氢吡啶（DHP）拮抗剂的临床试验正在进行中，但该试验可能会失败，因为脱靶效应限制了限制给药。因此，具有良好药代动力学和低毒性的有效和选择性CAV1.3通道拮抗剂是对帕金森氏病社区的需求。为了满足这一需求，进行了高通量筛查（HTS）的工作，并确定了两个具有良好药理特性的选择性低的小分子。使用我们的HTS屏幕告知的计算方法已经确定了第三个脚手架。一个分子之一的结构修饰导致CAV1.3选择性增加了833倍（至1000倍）。该建议要求支持将这些脚手架开发为临床有用的药物的下一步。提出了三个具体目的：具体目标1：确定已识别的CAV1.3通道拮抗剂的管理责任；特定目的2：提高已鉴定的CAV1.3通道拮抗剂的效力，选择性，稳定性和脑生物利用度通过药物化学；和特定目的3：确定优化铅化合物在帕金森氏病模型中的功效。这些研究将充分利用我们小组与这些脚手架的早期工作以及我们在帕金森氏病模型中进行药物作用的专业知识，并补充了NIH承包商的药物开发专业知识。实现这些目标将提供第一个高度选择性的CAV1.3通道拮抗剂，适用于帕金森氏病的人类临床试验。这样的药物有可能减慢或阻止帕金森氏病的进展，从而扩大了有症状治疗的治疗窗口。公共卫生相关性：帕金森氏病是美国临床前和流行病学研究的主要健康问题，这表明对特殊类型的钙通道进行拮抗可能会减慢或阻止疾病的进展。这里提出的研究是为了临床使用开发新的选择性拮抗剂。