Development of a Novel Medication for Alcohol Use Disorder with an Active IND Dual Inhibitor of T-Type Calcium Channel and Soluble Epoxide Hydrolase

使用 T 型钙通道和可溶性环氧化物水解酶的活性 IND 双重抑制剂开发治疗酒精使用障碍的新型药物

• 批准号: 10815882
• 负责人: Xinmin Simon Xie
• 金额: $ 48.39万
• 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: 2023-09-25 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10815882
• 关键词: Absence of pain sensation; Address; Alcohol consumption; Alcohols; Amendment; American; Analgesics; Animal Model; Anti-Inflammatory Agents; Anxiety; Area; Behavior; Biological Assay; Biological Availability; Brain; Canis familiaris; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cells; Chronic; Clinical; Clinical Trials; Collaborations; Darkness; Data; Depressed mood; Development; Disease; Disease model; Disulfiram; Drug Design; Drug Kinetics; Drug Targeting; Drug usage; Electrophysiology (science); Emergency department visit; Enzymes; Epoxide hydrolase; Ethanol; Evaluation; Exhibits; FDA approved; FOS gene; Fatty Acids; Future; Habenula; Half-Life; Health; Human; Hyperalgesia; Hypersensitivity; Inflammation; Inflammation Mediators; Investigation; Investigational Drugs; Investigational New Drug Application; Ion Channel; Lateral; Lead; Legal patent; Ligand Binding; Mechanics; Medical; Mental Depression; Microglia; Mood Disorders; Mus; Naltrexone; Neurons; Opiate Addiction; Oral; Organ; Pain; Pain Disorder; Penetration; Peripheral; Pharmaceutical Preparations; Pharmacology Study; Phase; Phase I Clinical Trials; Public Health; Rattus; Rewards; Rodent; Safety; Self Administration; Series; Small Business Innovation Research Grant; Substance Use Disorder; Sucrose; Surveys; Symptoms; T-Type Calcium Channels; Testing; Therapeutic; Toxic effect; Toxicology; Translating; Universities; Withdrawal; acamprosate; aged; alcohol seeking behavior; alcohol use disorder; animal pain; anxiety-like behavior; binge drinking; chronic alcohol ingestion; chronic neuropathic pain; chronic pain; clinical development; comorbidity; comparison control; density; deter alcohol use; evidence base; glial activation; healthy volunteer; inflammatory pain; inhibitor; innovation; lead optimization; negative affect; nerve injury; neural; neuroinflammation; non-opioid analgesic; novel; overdose death; pain model; painful neuropathy; patch clamp; pharmacokinetics and pharmacodynamics; pre-clinical; preference; receptor; response; reward circuitry; screening; side effect; spared nerve; success

7. SUMMARY Alcohol use disorder (AUD) is the most prevalent substance use disorder worldwide and often co-occurs with chronic pain, anxiety, depression, and opioid dependence. Unfortunately, currently available medications for AUD have limited efficacy with unwanted side effects. To address this unmet medical need, we propose an SBIR Phase I U43 project in response to PAR-22-102 "Investigational New Drug (IND)-enabling and Early-Stage Development of Medications to Treat Alcohol Use Disorder and Alcohol-Associated Organ Damage." Our project will focus on proof-of-concept studies of our active IND (157314), AFA-281, a novel dual inhibitor of T-type calcium channels (Cav3) and soluble epoxide hydrolase (sEH), for AUD treatment. These proof-of-concept studies would use well-established rodent AUD models and testing paradigms. AfaSci discovered AFA-281 from a series of patented dual modulators of Cav3 channels and sEH as a non- opioid analgesic. We completed lead identification through rational drug design and iterative screenings using patch-clamp recordings and enzymatic assays. Lead optimization was conducted, including selectivity screening on hERG and key cardiac ion channels, and CEREP proofing of 81 off-drug targets. These screenings together with studies using human cardiomyocytes ex vitro demonstrated that AFA-281 has no cardiac safety concerns. In pharmacokinetic and pharmacodynamic (PK/PD) studies, AFA-281 has shown excellent oral bioavailability, acceptable t1/2, CNS penetration, broad analgesic effects on neuropathic and inflammatory pain, and good safety margins. Recently, AFA-281's IND application was accepted by the FDA for a lead indication of neuropathic pain. Our preliminary studies on AUD have demonstrated that AFA-281 is capable of decreasing alcohol intake, binge drinking and preference, and suppressing alcohol-seeking behavior in rodents. In this proposed SBIR Phase I U43 project, we will conduct preclinical proof-of-concept studies to investigate AFA-281's effects on AUD, and its associated chronic pain and negative affective disorders, such as anxiety and depression in rats via three Specific Aims. Aim 1 will evaluate PK/PD of AFA-281 in reducing alcohol consuming and seeking behavior via operant self-administration. Aim 2 will investigate AFA-281's effects on hyperalgesia, anxiety, and depression in rats withdrawn from chronic alcohol consumption. Aim 3 will explore the mechanism of action of AFA-281 underlying its efficacy in AUD via assessing AFA-281’s modulation on alcohol-altered neural activity indicated by c-Fos expression and brain neuroinflammation, and evaluation of Cav3 channel activity, and cell excitability in the lateral habenula, a brain area implicated in AUD. Success in our Phase I project would demonstrate that AFA-281 can reduce alcohol consumption and seeking behavior, provide an evidence base to prepare for the transition to clinical proof-of-concept studies in the U44 SBIR project. Given the significant public health burden of AUD, developing a more effective and safe medication accessible for treatment and prevention of AUD would have a considerable positive impact on public health.

7. 总结 酒精使用障碍 (AUD) 是全世界最普遍的物质使用障碍，并且经常与以下疾病同时发生： 不幸的是，目前可用的药物可以治疗慢性疼痛、焦虑、抑郁和阿片类药物依赖。 AUD 的疗效有限且有不良副作用。为了解决这一未满足的医疗需求，我们提出了 SBIR。 I期U43项目响应PAR-22-102“研究性新药（IND）启用和早期阶段 开发治疗酒精使用障碍和酒精相关器官损伤的药物。”我们的项目 将重点关注我们的活性 IND (157314)、AFA-281（一种新型 T 型双重抑制剂）的概念验证研究 钙通道 (Cav3) 和可溶性环氧化物水解酶 (sEH)，用于 AUD 治疗。 研究将使用完善的啮齿动物 AUD 模型和测试范例。 AfaSci 从一系列获得专利的 Cav3 通道和 sEH 双调制器中发现了 AFA-281，作为一种非 我们通过合理的药物设计和迭代筛选完成了阿片类镇痛药的先导物识别。 进行膜片钳记录和酶分析，包括选择性筛选。 hERG 和关键心脏离子通道，以及 81 个非药物靶标的 CEREP 验证。 使用人类心肌细胞进行的体外研究表明，AFA-281 不存在心脏安全问题。 在药代动力学和药效学 (PK/PD) 研究中，AFA-281 显示出优异的口服生物利用度， t1/2可接受，中枢神经系统渗透，对神经病理性疼痛和炎性疼痛有广泛的镇痛作用，安全性好 最近，AFA-281 的 IND 申请被 FDA 接受，作为神经病理性疼痛的主要适应症。 我们对 AUD 的初步研究表明，AFA-281 能够减少酒精摄入量、暴饮暴食 饮酒和偏好，以及抑制啮齿动物的饮酒行为。 在这个拟议的 SBIR I 期 U43 项目中，我们将进行临床前概念验证研究来调查 AFA-281 对 AUD 的影响及其相关的慢性疼痛和负面情感障碍，例如焦虑和 通过三个具体目标 1 将评估 AFA-281 在减少饮酒方面的 PK/PD。 目标 2 将研究 AFA-281 对痛觉过敏的影响， 目标 3 将探讨戒断长期饮酒的大鼠的焦虑和抑郁机制。 通过评估 AFA-281 对酒精改变神经的调节作用，了解 AFA-281 在 AUD 中的功效 c-Fos 表达和脑神经炎症指示的活性，以及​​ Cav3 通道活性的评估，以及 外侧缰核（与 AUD 相关的大脑区域）的细胞兴奋性。 我们第一阶段项目的成功将证明 AFA-281 可以减少酒精消耗并寻求 行为，为 U44 向临床概念验证研究的过渡提供证据基础 SBIR 项目。考虑到 AUD 带来的巨大公共卫生负担，开发一种更有效、更安全的药物。 AUD 的治疗和预防将对公众健康产生相当大的积极影响。