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.

项目摘要 癫痫是最常见的脑部疾病之一。当前药物的功效有限。识别新的 可以用作更安全，更有效疗法的靶向药物紧急需要。选择性抑制 瞬态受体电位的规范3（TRPC3）是阻碍癫痫病的一种新型策略。 但是，目前最佳的选择性TRPC3抑制剂PYR3的代谢稳定性差，并且具有显着的 安全责任。我们最近发表了《发现专利的Pyr3模拟》 JW-65的发现 改善了代谢稳定性和安全性。它具有良好的大脑穿透和保留率，直接与 TRPC3，并且在癫痫的正对比较中表现出比现有的药物苯甲酸苯甲部的功效更好 鼠标模型。 Seak正在许可该专利的脚手架，并在此阶段提议彻底降级风险 JW-65是靶向癫痫疗法的潜在可行临床候选。 目标1。确定毒理学特征，潜在的靶向靶向靶向对生理学的面板 重要靶标，主要的CYP抑制和归纳，膜的渗透率，转运蛋白效应， 血浆结合和稳定性，以及药代动力学（PK）剖面，以进一步脱发JW-65。我们已经 证实了JW-65对TRPC3的直接结合和功能抑制，并证明了其优异的药物 喜欢属性。我们还表明，JW-65具有i.p.的良好PK特性。注射。在这个目标中，我们将 首先对JW-65进行大规模合成以支持随后的生物学评估。然后我们会 全面评估其安全性，靶标，ADME财产和行业标准RAT PK（i.v.和口头） 概况可全面脱离危险性JW-65作为临床候选者。里程碑：（1）JW-65的三克 合成并严格的特征； （2）演示了JW-65的安全性和药物的安全性和药物 作为可行的候选人； （3）确定JW-65的PK剖面和口服生物利用度。 AIM 2。评估JW-65的体内功效，以抑制多种模型的急性癫痫发作的能力 在小鼠和老鼠中。我们将首先评估JW-65对Pilocarpine诱导的大鼠急性癫痫发作的功效， 同时将pyr3和苯二氮卓类药物（长时间癫痫发作的一线药物）作为参考。进一步 增加严格并避免任何模型或物种特异性发现，JW-65的抗seizure效应将是 在小鼠海藻酸模型和氟乙酰基模型中进行了验证。里程碑：（4）证明了对急性的功效 大鼠的毛果石癫痫发作（行为癫痫发作评分降低约50％或EEG峰值）； （5）演示 针对氟噻硫基诱导的小鼠癫痫发作的功效（潜伏期增加了50％，到第一个肌阵挛性混蛋和 普遍的强直性持续癫痫发作）； （6）在小鼠中表现出对6 Hz诱导的癫痫发作的功效（〜50％ 行为癫痫发作得分的降低）； （7）证明对自发癫痫发作的功效（降低了约50％ 每天的SRSS总数）。 未来的方向：在第2阶段，SEAK将对JW-65进行全面的成分研究。