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期提案重点关注IND AFA-281治疗的临床前概念验证研究 可卡因使用障碍（CUD）AFA-281是由AfaSci发现的一种新的化学实体，它抑制T-型 Cav 3通道和可溶性环氧化物水解酶（sEH）。T型通道由Cav3.1、3.2和3.3亚基组成。 辅酶A激活离子通道，包括大脑中的T通道，以增加神经元的兴奋性并改变神经元的功能。 突触神经传递Mibefradil，一种古老的T通道抑制剂，阻断可卡因诱导的GABA能 异常和过度运动。Cav3.1基因敲除小鼠的研究显示，T型通道发挥了重要作用。 在维持腹侧被盖区神经元兴奋性中起主要作用，Cav3.2缺陷小鼠显示减少 精神兴奋剂敏感性因此，两个Cav 3亚基被生物学验证为CUD药物靶标。最近 研究表明神经炎症与成瘾有关。单一sEH抑制剂或sEH基因缺失 显示神经炎症减少。虽然sEH参与CUD尚不清楚，但我们假设我们的双重 Cav 3/sEH抑制剂可抑制可卡因诱导的过度兴奋和神经炎症， 有效治疗CUD。这个项目的目的就是测试这种可行性。 该项目的创新在于AfaSci发现了一系列获得专利的Cav 3通道双调制器， sEH具有良好的药物特性。AfaSci通过合理的药物设计，迭代 使用膜片钳记录和酶测定进行筛选。通过81个电极导线进行了优化 使用人心肌细胞进行脱药靶点选择性筛选并证明没有心脏安全问题 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（大鼠中为70%，犬中为92%），可接受的t1/2（2.5-4.3 h），CNS渗透，广泛镇痛 效果好，安全系数高。在完成IND使能研究后，AFA-281的IND申请被批准。 最近被FDA接受用于神经性疼痛的主要适应症。在初步研究中，我们发现 可卡因增强的神经兴奋性被AFA-281阻断在大鼠丘脑皮层切片中。老鼠寻找可卡因 由静脉（IV）输注可卡因溶液的自我给药（SA）指示的行为受到抑制 AFA-281可使可卡因引起的大鼠和小鼠的过度运动恢复到对照水平。 本项目的具体目标1是严格研究AFA-281对大鼠有意药物寻求的影响 通过SA静脉输注可卡因在获得训练和强迫性奖励寻求中的作用 时间表和复发时的恢复。我们的具体目标2是研究AFA-281的PK/PD，用于抑制 可卡因寻求行为和可卡因诱导的大鼠过度运动。SBIR第一阶段项目的成功将 证明了概念验证，导致AFA-281用于CUD的次要适应症的临床开发， SBIR第二阶段项目和/或第三方支持。最终，AFA-281作为一种安全，有效， 药物可以缓解CUD。