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. 项目概要 我们的 SBIR 第一阶段提案侧重于我们的 IND AFA-281 治疗的临床前概念验证研究 可卡因使用障碍 (CUD) 是 AfaSci 发现的一种新化学实体，可抑制 T 型。 Cav3 通道和可溶性环氧化物水解酶 (sEH) 由 Cav3.1、3.2 和 3.3 亚基组成。 可卡因激活离子通道，包括大脑中的 T 通道，以增加神经元兴奋性并改变 米贝拉地尔（Mibefradil）是一种古老的 T 通道抑制剂，可阻断可卡因诱导的 GABA 能。 对 Cav3.1 敲除小鼠的异常和过度运动研究表明，T 型通道发挥着重要作用。 在维持腹侧被盖区神经元兴奋性中起主要作用，而 Cav3.2 缺陷小鼠表现出降低 因此，两个 Cav3 亚基被生物学验证为 CUD 药物靶点。 研究表明神经炎症与单一 sEH 抑制剂或 sEH 基因缺失有关。 尽管 sEH 参与 CUD 的情况尚不清楚，但我们采取了双重治疗。 Cav3/sEH 抑制剂可以抑制可卡因引起的过度兴奋和神经炎症，从而 该项目的目标是测试这种可行性。 该项目的创新点在于AfaSci发现了一系列获得专利的Cav3通道和 sEH 具有良好的成药特性，AfaSci 通过合理的药物设计和迭代完成了先导化合物的鉴定。 使用膜片钳记录和酶分析进行筛选 81。 使用人类心肌细胞进行非药物靶点选择性筛选并证明没有心脏安全问题 根据体外药代动力学和药效学 (PK/PD) 研究，AFA-281 显示出优异的效果。 口服生物利用度（大鼠为 70%，狗为 92%），可接受的 t1/2（2.5-4.3 小时），中枢神经系统渗透，广泛镇痛 IND 授权研究完成后，AFA-281 的 IND 申请已通过。 我们在初步研究中表明，最近被 FDA 接受为神经病理性疼痛的主要适应症。 大鼠丘脑皮质切片中可卡因增强的神经兴奋性被 AFA-281 阻断。 静脉（IV）输注可卡因溶液的自我给药（SA）所显示的行为受到抑制 AFA-281 可使可卡因引起的大鼠和小鼠过度运动恢复至 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 对大鼠故意寻毒的影响 在习得训练中通过静脉输注可卡因的SA和进度率下的强迫性奖励寻求 我们的具体目标 2 是研究 AFA-281 抑制复发的 PK/PD。 SBIR 第一阶段项目的成功将促进大鼠的可卡因寻求行为和可卡因诱导的过度运动。 展示概念验证，导致 AFA-281 用于 CUD 次要适应症的临床开发 SBIR 二期项目和/或第三方支持最终使 AFA-281 成为一种安全、有效且易于使用的药物。 药物可以减轻 CUD。