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

描述（由申请人提供）：帕金森氏病是一种广泛的、使人衰弱的衰老相关神经退行性疾病。帕金森病的发病率与预期寿命同步增加。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，因为疾病进展不能被阻止。最近的临床前和流行病学研究表明，具有CaV1.3孔形成亚基的L型Ca 2+通道在疾病发病机制中起作用。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，但该试验可能会失败，因为脱靶效应限制了剂量。因此，开发一种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）的努力，并确定了两个具有低CaV1.3选择性的小分子，具有优异的药理学特性。第三个支架已经使用由我们的HTS屏幕通知的计算方法确定。其中一个分子的结构修饰导致CaV1.3选择性增加833倍（至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：确定已鉴定的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 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高选择性的CaV1.3通道拮抗剂，适用于帕金森病的人体临床试验。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。

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.