Developing a selective TRPC3 ion channel inhibitor for epilepsy treatment

开发用于癫痫治疗的选择性 TRPC3 离子通道抑制剂

• 批准号: 10819354
• 负责人: WEI LI
• 金额: $ 42.99万
• 依托单位: SEAK THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10819354
• 关键词: Acute; Adverse effects; Adverse event; Affect; Amides; Anticonvulsants; Antiepileptogenic; Behavioral; Benzodiazepines; Binding; Biological; Biological Availability; Brain; Brain Diseases; Brain-Derived Neurotrophic Factor; Cations; Cell Membrane Permeability; Clinical; Development; Diagnosis; Drug Kinetics; Drug Targeting; Electroencephalography; Epilepsy; Esters; Evaluation; FDA approved; Family; Flurothyl; Formulation; Foundations; Future; Hippocampus; Hydrolysis; Impairment; Industry Standard; Injections; Ion Channel; Kainic Acid; Legal patent; Licensing; Mediating; Medical; Metabolic; Modeling; Mus; Myoclonus; Names; Neocortex; Oral; Patients; Penetration; Persons; Pharmaceutical Preparations; Phase; Phenytoin; Phosphotransferases; Physiological; Pilocarpine; Plasma; Population; Property; Publishing; Quality of life; Rattus; Recurrence; Reporting; Risk; Role; Safety; Seizures; Severities; Signal Transduction; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Solid; Status Epilepticus; Testing; Therapeutic; Therapeutic Agents; Tonic - clonic seizures; Toxic effect; Toxicology; Tropomyosin; analog; clinical candidate; effective therapy; efficacy evaluation; head-to-head comparison; high risk; hippocampal pyramidal neuron; improved; in vivo; inhibitor; innovation; knock-down; knockout gene; member; mouse model; neocortical; nervous system disorder; new therapeutic target; novel; novel strategies; novel therapeutics; phase 1 study; prevent; receptor; scaffold; success; targeted treatment

Project Summary Epilepsy is one of the most common brain disorders. Current drugs have limited efficacy. Identifying new targeted drugs that can be used as safer, more effective therapies is in urgent unmet need. Selective inhibition of the transient receptor potential canonical 3 (TRPC3) emerges as a novel strategy to impede epilepsy. However, the currently best selective TRPC3 inhibitor, Pyr3, has poor metabolic stability and has significant safety liabilities. We recently published the discovery of a patented Pyr3 analog, JW-65, which has significantly improved metabolic stability and safety profiles. It has good brain penetration and retention, directly binds to TRPC3, and shows better efficacy than an existing drug phenytoin in a head-to-head comparison in an epilepsy mouse model. SEAK is licensing this patented scaffold and proposes in this Phase I STTR to thoroughly de-risk JW-65 as a potentially viable clinical candidate for targeted epilepsy therapy. Aim 1. Determine toxicological profiles, potential off-targets against a panel of physiologically important targets, major CYP inhibitions and inductions, membrane permeability, transporter effects, plasma binding and stability, and pharmacokinetic (PK) profiles to further de-risk JW-65. We have already confirmed the direct binding to and functional inhibition of TRPC3 by JW-65 and demonstrated its excellent drug- like properties. We have also showed that JW-65 has good PK properties with i.p. injection. In this aim, we will first perform large scale synthesis of JW-65 to support subsequent biological evaluations. We will then comprehensively evaluate its safety, off-targets, ADME properties, and industry standard rat PK (i.v. and oral) profiles to comprehensively de-risk JW-65 as a clinical candidate. Milestones: (1) three grams of JW-65 synthesized and rigorously characterized; (2) demonstrate the safety profiles and drug like properties of JW-65 as a viable candidate; (3) determine PK profiles and oral bioavailability of JW-65. Aim 2. Evaluate in vivo efficacy of JW-65 for its ability to suppress acute seizures in multiple models in both mice and rats. We will first assess the efficacy of JW-65 on acute seizures in rats induced by pilocarpine, using both Pyr3 and benzodiazepines (the first-line drugs for prolonged seizures) as references. To further increase the rigor and avoid any model- or species-specific findings, the anti-seizure effects of JW-65 will be validated in the mouse kainic acid model and flurothyl model. Milestones: (4) demonstrate efficacy against acute pilocarpine seizures in rats (~50% reduction in behavioral seizure scores or EEG spikes); (5) demonstrate efficacy against flurothyl-induced seizures in mice (~50% increase in latencies to the first myoclonic jerk and generalized tonic-clonic seizure); (6) demonstrate efficacy against 6 Hz-induced seizures in mice (~50% decrease in behavioral seizure scores); (7) demonstrate efficacy against spontaneous seizures (~50% decrease in total number of SRSs per day). Future directions: In Phase 2, SEAK will perform comprehensive IND-enabling studies for JW-65.

项目概要 癫痫是最常见的脑部疾病之一。目前的药物疗效有限。识别新 目前迫切需要可作为更安全、更有效的疗法的靶向药物。选择性抑制 瞬时受体电位规范 3 (TRPC3) 的研究成为一种阻止癫痫的新策略。 然而，目前选择性最好的TRPC3抑制剂Pyr3代谢稳定性较差，且具有显着的抑制作用。 安全责任。我们最近发表了专利 Pyr3 类似物 JW-65 的发现，它显着 改善代谢稳定性和安全性。具有良好的大脑渗透力和保留力，直接结合 TRPC3，在癫痫症的头对头比较中显示出比现有药物苯妥英钠更好的疗效 鼠标模型。 SEAK 正在授权该专利支架，并建议在第一阶段 STTR 中彻底降低风险 JW-65 作为靶向癫痫治疗的潜在可行的临床候选药物。 目标 1. 确定毒理学特征、针对一组生理学物质的潜在脱靶情况 重要靶标、主要 CYP 抑制和诱导、膜通透性、转运蛋白效应、 血浆结合和稳定性以及药代动力学 (PK) 特征，以进一步降低 JW-65 的风险。我们已经 证实了JW-65对TRPC3的直接结合和功能性抑制，并证明了其优异的药物- 喜欢属性。我们还表明，JW-65 具有良好的 PK 特性。注射。为了这个目标，我们将 首先进行JW-65的大规模合成以支持后续的生物学评价。我们随后将 综合评价其安全性、脱靶、ADME特性和行业标准大鼠PK（静脉注射和口服） 全面降低 JW-65 作为临床候选药物的风险。里程碑：(1) 三克 JW-65 合成并严格表征； (2) 展示JW-65的安全性和类药特性 作为可行的候选人； (3)确定JW-65的PK曲线和口服生物利用度。 目标 2. 评估 JW-65 在多种模型中抑制急性癫痫发作的体内功效 在小鼠和大鼠中。我们将首先评估 JW-65 对毛果芸香碱引起的大鼠急性癫痫发作的功效， 使用 Pyr3 和苯二氮卓类药物（治疗长时间癫痫发作的一线药物）作为参考。为了进一步 提高严谨性并避免任何模型或物种特异性的发现，JW-65 的抗癫痫作用将 在小鼠红藻氨酸模型和氟草酯模型中得到验证。里程碑：(4) 证明对急性发作有效 大鼠毛果芸香碱癫痫发作（行为癫痫评分或脑电图峰值减少约 50%）； (5) 演示 对氟洛酯诱发的小鼠癫痫发作有效（第一次肌阵挛性抽搐的潜伏期增加约 50%， 全身强直阵挛发作）； (6) 证明对小鼠中 6 Hz 诱发的癫痫发作有效（~50% 行为癫痫评分降低）； (7) 证明对自发性癫痫发作有效（减少约 50%） 每天的 SRS 总数）。 未来方向：在第二阶段，SEAK 将为 JW-65 进行全面的 IND 支持研究。