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

• 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
• 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' 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

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）：帕金森病是一种广泛存在且使人衰弱的与衰老相关的神经退行性疾病。帕金森病的发病率随着预期寿命的增加而增加。没有治愈方法或方法可以减缓这种疾病的进展。尽管目前的对症治疗最初是有效的，但由于无法阻止疾病进展，因此效果短暂。最近的临床前和流行病学研究表明 L 型 Ca2+ 通道与 CaV1.3 成孔亚基与疾病发病机制有关。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，但由于脱靶效应限制了剂量，该试验可能会失败。因此，开发一种具有良好药代动力学和低毒性的有效、选择性CaV1.3通道拮抗剂是帕金森病领域尚未满足的需求。为了满足这一需求，我们进行了高通量筛选 (HTS) 工作，并鉴定出两种具有低 CaV1.3 选择性的小分子，它们具有优异的药理学特性。第三种支架已通过我们的 HTS 屏幕的计算方法确定。其中一个分子的结构修饰使 CaV1.3 选择性提高了 833 倍（达到 1000 倍）。该提案请求支持采取下一步措施，将这些支架开发成临床有用的药物。提出了三个具体目标： 具体目标 1：确定已识别的 CaV1.3 通道拮抗剂的 ADMET 责任；具体目标 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；具体目标 3：确定优化的先导化合物在帕金森病模型中的功效。这些研究将充分利用我们小组对这些支架的早期工作以及我们在帕金森病模型中药物作用测定方面的专业知识，补充 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适合帕金森病人体临床试验的高度选择性 CaV1.3 通道拮抗剂。这种药物有可能减缓或阻止帕金森病的进展，扩大对症治疗的治疗窗口。 公共健康相关性：帕金森病是美国的一个主要健康问题。临床前和流行病学研究表明，拮抗一类特殊的钙通道可以减缓或阻止疾病的进展。这里提出的研究是为了开发一种新的选择性拮抗剂用于临床使用这些通道。