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的、使人衰弱的与衰老相关的神经退行性疾病。帕金森氏症的发病率随着预期寿命的增加而增加。目前还没有治愈或减缓这种疾病进展的方法。虽然目前的对症治疗最初是有效的，但它们是短暂的，因为疾病的进展不能被阻止。最近的临床前和流行病学研究表明，在疾病发病机制中，l型Ca2+通道与CaV1.3成孔亚基有关。虽然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，开发一种有效的、选择性的、具有良好药代动力学和低毒性的CaV1.3通道拮抗剂是帕金森病社区尚未满足的需求。为了满足这一需求，开展了高通量筛选（HTS）工作，并鉴定出两个具有低CaV1.3选择性的小分子，它们具有优异的药理特性。第三个支架已经确定使用计算方法告知我们的HTS屏幕。其中一个分子的结构修饰导致CaV1.3选择性增加833倍（达到1000倍）。该提案要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：确定已确定的CaV1.3通道拮抗剂的ADMET负荷；特异性目的2：提高已鉴定的CaV1.3通道拮抗剂的效价、选择性、稳定性和脑生物利用度