Novel Thioderivatives as Neuroprotective Anticonvulsants

作为神经保护抗惊厥药的新型硫代衍生物

• 批准号: 7745751
• 负责人: Douglas Eric Brenneman
• 金额: $ 29.6万
• 依托单位: ADVANCED NEURAL DYNAMICS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7745751
• 关键词: Achievement; Address; Aftercare; Animal Model; Animals; Anticonvulsants; Antiepileptic Agents; Antiepileptogenic; Area; Biological Assay; Brain; Businesses; Carbamates; Cardiovascular system; Chemicals; Chemistry; Disease; Drug Kinetics; Electroconvulsive Shock; Epilepsy; Epileptogenesis; Exhibits; Glutamates; Goals; Hippocampus (Brain); Human; Hydrogen Peroxide; In Vitro; Investigational New Drug Application; Lead; Libraries; Licensing; Marketing; Mediating; Medical; Metabolic; Mus; National Institute of Neurological Disorders and Stroke; Neurons; Oxidative Stress; Parents; Patients; Perception; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Principal Investigator; Property; Qualifying; Refractory; Safety; Screening procedure; Seizures; Series; Solubility; Structure; Sulfur; System; Testing; Therapeutic; Toxic effect; Work; abstracting; analog; base; chemical synthesis; design; effective therapy; efficacy evaluation; experience; felbamate; improved; in vitro testing; in vivo; innovation; interest; meetings; neuroprotection; novel; programs; public health relevance

DESCRIPTION (provided by applicant): Novel Thioderivatives as Neuroprotective Anticonvulsants Abstract: The aim is to discover novel lead compounds that provide a disease- modifying therapeutic for the treatment of epilepsy. The ideal candidate molecules generated by this program will exhibit both anti-seizure activity in animal models of epilepsy as well as neuroprotective properties from glutamate or hydrogen peroxide in cultures derived from an area of the brain that is vulnerable to seizures and resulting neuronal damage. The objective of the phase one studies is to generate "proof of concept" compounds that will exhibit the desired properties of neuroprotection and efficacy in an animal model of epilepsy. This objective directly coincides with the solicitation topic for new treatments for epilepsy as described by the NINDS. The chemistry will involve a highly directed synthesis of analogues of an existing experimental anticonvulsant. The proposed compounds will contain one or more of the following domains: sulfamide or a sulfur-containing heterocycle. The novel, sulfur- containing compounds will be designed and synthesized for a four-step qualifying sequence of testing: in vitro toxicity, in vitro neuroprotection, metabolic stability and in vivo anti-seizure consisting of the maximal electroshock seizure test in mice. The innovative aspects of this program are two-fold: 1) the novelty of the chemical series focused on the sulfur-containing derivatives with established anti-seizure activity; and 2) the use of hippocampal neurons as the primary screening system to detect both protective and toxic properties of the novel compounds. Devising compounds with greater metabolic stability and safety than the parent compound is a priority. While the emphasis of the first phase is to generate a library of promising neuroprotective, anti- seizure compounds, a limited number of tests will be conducted to assess solubility, drug permeability and potential cardiovascular liabilities (hERG channel interactions). Compounds emerging from the phase I portion of this program will be advanced to animal models of refractory epilepsy and for detailed studies of toxicological and pharmacokinetic properties that will comprise the phase II of discovery. The phase I project is critical to the long-term purpose of discovering new antiepileptic drugs that are both disease-modifying with neuroprotective properties and effective in treating patients that are refractory to current treatments. The long-term business strategy is to devise lead compounds that are ready for licensing in phase I clinical trials. PUBLIC HEALTH RELEVANCE: Current estimates indicate that 25% of people suffering from epilepsy receive no effective treatment for their seizures from today's available drugs. With the goal of meeting this unmet medical need and eventually to block epileptogenesis, we seek to discover novel compounds that are both neuroprotective and also possess anti-seizure properties.

描述（由申请人提供）：作为神经保护性抗惊厥剂的新型硫代衍生物摘要：目的是发现新型先导化合物，其提供用于治疗癫痫的疾病改善治疗剂.该计划产生的理想候选分子将在癫痫动物模型中表现出抗癫痫活性，以及在来自易受癫痫发作和导致神经元损伤的大脑区域的培养物中表现出谷氨酸或过氧化氢的神经保护特性。第一阶段研究的目的是产生“概念验证”化合物，其将在癫痫动物模型中表现出所需的神经保护和功效特性。这一目标与NINDS描述的癫痫新治疗方法的征集主题直接一致。化学反应将涉及现有实验性抗惊厥药类似物的高度定向合成。所提出的化合物将含有一个或多个以下结构域：磺酰胺或含硫杂环。将设计和合成新的含硫化合物用于四步合格测试序列：体外毒性、体外神经保护、代谢稳定性和体内抗癫痫发作，包括小鼠中的最大电休克癫痫发作测试。该计划的创新方面有两个方面：1）化学系列的新奇，重点是具有确定的抗癫痫活性的含硫衍生物; 2）使用海马神经元作为主要筛选系统，以检测新化合物的保护和毒性特性。设计比母体化合物具有更高代谢稳定性和安全性的化合物是一个优先事项。虽然第一阶段的重点是生成有前景的神经保护性、抗癫痫发作化合物的库，但将进行有限数量的测试以评估溶解度、药物渗透性和潜在的心血管责任（hERG通道相互作用）。该项目第一阶段的化合物将用于难治性癫痫的动物模型，并用于毒理学和药代动力学特性的详细研究，这些研究将包括第二阶段的发现。I期项目对于发现新的抗癫痫药物的长期目的至关重要，这些药物既具有神经保护特性，又能有效治疗目前治疗难治性患者。长期的商业战略是设计出可以在I期临床试验中获得许可的先导化合物。公共卫生关系：目前的估计表明，25%的癫痫患者没有从今天可用的药物中获得有效的治疗。为了满足这一未满足的医疗需求并最终阻断癫痫发生，我们寻求发现既具有神经保护作用又具有抗癫痫特性的新型化合物。