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。摘要 酒精使用障碍（AUD）是全球最普遍的药物使用障碍，并且经常与 慢性疼痛，焦虑，抑郁和阿片类药物依赖性。不幸的是，目前可用于 AUD的有效性有限，副作用不良。为了满足这种未满足的医疗需求，我们提出了一个SBIR I阶段U43项目响应PAR-22-102“研究性新药（IND） - 增强和早期阶段 开发用于治疗酒精使用障碍和与酒精相关的器官损害的药物。”我们的项目 将重点介绍我们主动IND（157314），AFA-281的概念验证研究，这是一种新型的T型双重抑制剂 钙通道（CAV3）和固体环氧水解酶（SEH），用于AUD处理。这些概念证明 研究将使用良好的啮齿动物AUD模型和测试范例。 Afasci从CAV3通道的一系列专利双调节符中发现了AFA-281，并将其视为非 - 阿片类镇痛药。我们通过合理的药物设计和迭代筛查完成了铅识别 贴片钳记录和酶试验。进行了铅优化，包括选择性筛选 在HERG和关键心脏离子通道上，以及对81个离职靶标的obep carep。这些放映在一起 通过使用人类心肌细胞的研究，体外表明AFA-281没有心脏安全问题。 在药代动力学和药效学（PK/PD）研究中，AFA-281显示出出色的口服生物利用度， 可接受的T1/2，CNS渗透，对神经性和炎症性疼痛的广泛镇痛作用以及良好的安全性 利润。最近，FDA接受了AFA-281的IND应用，以表明神经性疼痛的铅指示。 我们对AUD的初步研究表明，AFA-281能够减少酒精摄入量 饮酒和偏爱，并抑制啮齿动物中寻求酒精的行为。 在拟议的SBIR I期U43项目中，我们将进行临床前概念验证研究以研究 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 大鼠通过三个特定目标的抑郁症。 AIM 1将评估AFA-281的PK/PD，以减少饮酒量 并通过操作自我管理来寻求行为。 AIM 2将调查AFA-281对痛觉过敏的影响， 从长期饮酒中撤出的大鼠焦虑和抑郁症。 AIM 3将探索机制 通过评估AFA-281对饮酒神经的调节，AFA-281的作用在AUD中的有效性 C-FOS表达和脑神经炎症以及CAV3通道活性的评估和大脑神经炎症所指示的活性 细胞兴奋性在AUD中实现的大脑区域的外侧Habenula中的兴奋性。 在我们阶段I项目中的成功将证明AFA-281可以减少饮酒和寻求 行为，提供证据基础，以准备过渡到U44中的临床概念验证研究 SBIR项目。鉴于AUD的重要公共卫生伯恩伯恩（Burnen），开发了一种更有效，更安全的药物 可用于治疗和预防AUD将对公共卫生产生重大积极影响。