Developing a novel treatment of cocaine use disorder using an IND dual inhibitor of Cav3 channel and soluble epoxide hydrolase

使用 Cav3 通道和可溶性环氧化物水解酶的 IND 双重抑制剂开发可卡因使用障碍的新型治疗方法

• 批准号: 10786151
• 负责人: Xinmin Simon Xie
• 金额: $ 31.95万
• 依托单位: AFASCI, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10786151
• 关键词: Action Potentials; American; Analgesics; Animal Model; Animals; Anti-Inflammatory Agents; Behavior; Behavioral; Binding; Biological; Biological Assay; Biological Availability; Brain; Canis familiaris; Cardiac; Cardiac Myocytes; Cardiotoxicity; Clinical Trials; Cocaine; Cocaine use disorder; Cocaine withdrawal; Collaborations; Data; Databases; Depressed mood; Dose Limiting; Drug Design; Drug Interactions; Drug Kinetics; Drug Targeting; Electrocardiogram; Electrophysiology (science); Epoxide hydrolase; Fos-Related Antigens; Future; Genetic; Goals; Grant; Habenula; Half-Life; Home; Human; In Vitro; Intake; Intravenous; Intravenous infusion procedures; Investigational Drugs; Investigational New Drug Application; Ion Channel; Knockout Mice; Lateral; Lead; Legal patent; Ligand Binding; Locomotion; Measures; Methods; Mibefradil; Mus; Neurons; Nose; Oral; Overdose; Patients; Penetration; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Phenotype; Plasma; Play; Polypharmacy; Rattus; Relapse; Reporting; Research; Rewards; Role; Safety; Schedule; Self Administration; Series; Slice; Small Business Innovation Research Grant; Spinal Ganglia; Substance Use Disorder; Synapses; Testing; Thalamic structure; Therapeutic; Toxic effect; Training; Universities; Ventral Tegmental Area; addiction; aged; animal efficacy; capsule; clinical development; cocaine reward; cocaine seeking; cocaine self-administration; cocaine use; drug candidate; effective therapy; evidence base; experience; feasibility testing; genotoxicity; healthy volunteer; improved; inhibitor; innovation; lead optimization; manufacture; medical schools; medication nonadherence; neural; neuroinflammation; neuronal excitability; neurotransmission; new chemical entity; novel; painful neuropathy; patch clamp; pharmacokinetics and pharmacodynamics; phase I trial; pill; pre-clinical; psychostimulant; response; screening; sex; side effect; single molecule; small molecule; stability testing; stimulant use disorder; success; therapeutic target

7. PROJECT SUMMARY Our SBIR Phase I proposal focuses on preclinical proof of concept studies on our IND AFA-281 for treatment cocaine use disorder (CUD). AFA-281 is a new chemical entity discovered by AfaSci that inhibits both the T-type Cav3 channels and soluble epoxide hydrolase (sEH). T-type channels consist of Cav3.1, 3.2, and 3.3 subunits. Cocaine activates ion channels, including T-channels in the brain to increase neuronal excitability and alter synaptic neurotransmission. Mibefradil, an old T-channel inhibitor blocks cocaine-induced GABAergic abnormalities and hyperlocomotion in mice. Studies in Cav3.1 knockout mice revealed T-type channels play a major role in sustaining ventral tegmental area neuronal excitability, and Cav3.2-deficient mice display reduced psychostimulant sensitivity. Hence, two Cav3 subunits are biologically validated as CUD drug targets. Recent studies suggest an involvement of neuroinflammation in addiction. Single sEH inhibitors or sEH genetic deletion show a reduction in neuroinflammation. Although sEH involvement in CUD is unknown, we hypothesize our dual inhibitor of Cav3/sEH could suppress cocaine-induced hyperexcitability and neuroinflammation, and thereby be an effective treatment for CUD. The goal of this project is to test this feasibility. This project’s innovation lies in AfaSci’s discovery of a series of patented dual modulators of Cav3 channels and sEH with a favorable druggable profile. AfaSci completed lead identification through rational drug design, iterative screenings using patch-clamp recordings and enzymatic assays. Lead optimization was conducted through 81 off-drug target selectivity screening and demonstrated no cardiac safety concerns using human cardiomyocytes in vitro. Based on pharmacokinetic and pharmacodynamic (PK/PD) studies, AFA-281 has shown an excellent oral bioavailability (70% in rats and 92% in dogs), acceptable t1/2 (2.5-4.3 h), CNS penetration, broad analgesic effects and good safety margins. Upon completion of the IND-enabling studies, AFA-281’s IND application was recently accepted by the FDA for a primary indication in neuropathic pain. In Preliminary Studies, we have shown cocaine-enhanced neural excitability was blocked by AFA-281 in rat thalamocortical slices. Rat cocaine-seeking behavior indicated by self-administration (SA) of intravenous (IV) infusion of cocaine solution was suppressed by AFA-281, and cocaine-elicited hyperlocomotion in rats and mice were restored to control levels by AFA-281. Our Specific Aim 1 in this project is to rigorously investigate AFA-281’s effects on rat intentional drug seeking via SA of IV infusion of cocaine in acquisition training and compulsive reward seeking under progress ratio schedule and on reinstatement in relapse. Our Specific Aim 2 is to investigate PK/PD of AFA-281 for suppressing cocaine seeking behavior and cocaine-induced hyperlocomotion in rats. Success in SBIR Phase I project will demonstrate proof of concept, leading to clinical development of AFA-281 for a secondary indication in CUD with an SBIR Phase II project and/or with third party support. Ultimately, AFA-281 as a safe, effective, and accessible medication will mitigate CUD.

7。项目摘要 我们的SBIR I期建议重点介绍我们IND AFA-281的概念研究证明 可卡因使用障碍（CUD）。 AFA-281是AFASCI发现的新化学实体，它抑制了T型 CAV3通道和固体环氧水解酶（SEH）。 T型通道由CAV3.1、3.2和3.3个亚基组成。 可卡因激活离子通道，包括大脑中的T通道，以增加神经元令人兴奋并改变 突触神经传递。 Mibefradil，一种旧的T通道抑制剂可卡因诱导的Gabaergic 小鼠的异常和超代性。 Cav3.1敲除小鼠的研究表明，T型通道可以发挥 在维持腹侧换段区域神经元令人兴奋和Cav3.2缺陷小鼠中显示的主要作用减少 精神刺激敏感性。因此，两个CAV3亚基在生物学上被证实为CUD药物靶标。最近的 研究表明，神经炎症参与成瘾。单SEH抑制剂或SEH遗传缺失 显示神经炎症的减少。尽管SEH参与CUD是未知的，但我们假设我们的双重 CAV3/SEH的抑制剂可以抑制可卡因引起的过度兴奋性和神经炎症，从而抑制 有效的CUD治疗方法。该项目的目的是测试可行性。 该项目的创新在于Afasci发现了CAV3频道的一系列专利双调节器和 SEH具有有利的吸毒性。 Afasci通过理性药物设计完成了铅识别，迭代 使用贴片钳记录和酶试验进行筛选。通过81进行了铅优化 使用人类心肌细胞筛选筛选目标选择性筛查，并没有表现出心脏安全性问题 体外。基于药代动力学和药效学（PK/PD）研究，AFA-281显示出极好的 口服生物利用度（大鼠为70％，狗的92％），可接受的T1/2（2.5-4.3 h），CNS穿透，宽镇痛 效果和良好的安全边缘。完成研究后，AFA-281的IND申请是 最近，FDA接受了神经性疼痛的主要指示。在初步研究中，我们表明 大鼠丘脑皮层切片中AFA-281阻止了可卡因增强的神经兴奋性。老鼠可卡因寻求 通过静脉内（IV）输注可卡因溶液的自我管理（SA）表示的行为被抑制 到AFA-281，大鼠和小鼠的可卡因诱发的超替代恢复为AFA-281的对照水平。 我们在该项目中的具体目标1是严格研究AFA-281对RAT故意毒品寻求的影响 通过静脉输注可卡因的SA在收购培训和强迫性奖励中寻求进度比率 时间表和恢复退休时。我们的特定目的2是调查AFA-281的PK/PD以抑制 可卡因寻求行为和可卡因诱导的大鼠超替代性。 SBIR I阶段项目的成功将 展示概念证明，从而导致AFA-281的临床开发，以表明与 SBIR II期项目和/或在第三方支持下。最终，AFA-281是安全，有效且可访问的 药物将减轻cud。