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

描述(申请人提供)：帕金森氏病是一种广泛存在的与衰老有关的神经退行性疾病。帕金森氏症的发病率与预期寿命同步增加。没有治愈方法或手段来减缓这种疾病的发展。尽管目前的对症治疗最初是有效的，但它们是短暂的，因为疾病的发展无法阻止。最近的临床前和流行病学研究表明，具有CaV1.3孔形成亚单位的L型钙通道参与了疾病的发病机制。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，但这项试验可能会失败，因为非靶点效应限制了剂量。因此，开发一种有效的、选择性的CaV1.3通道拮抗剂，具有良好的药代动力学和低毒性，是帕金森病社区尚未满足的需求。为了满足这一需求，进行了高通量筛选(HTS)工作，并鉴定出两个具有良好药理特性的低CaV1.3选择性的小分子。第三个脚手架已经使用我们的HTS屏幕提供的计算方法进行了识别。其中一个分子的结构修饰导致CaV1.3的选择性增加了833倍(1000倍)。这项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：确定已识别的CaV1.3通道拮抗剂的顺应性；特定目标2：提高已识别的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；以及具体目标3：确定优化的先导化合物在帕金森病模型中的疗效。这些研究将充分利用我们团队在这些支架上的早期工作，以及我们在帕金森病模型药物作用分析方面的专业知识，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。这种药物有可能减缓或阻止帕金森氏症的发展，扩大对症治疗的治疗窗口。 公共卫生相关性：帕金森氏症是美国的一个主要健康问题。临床前和流行病学研究表明，拮抗一种特殊类型的钙通道可以减缓或阻止疾病的发展。本研究旨在开发一种新的选择性拮抗剂，用于临床应用。

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.