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

7.摘要 酒精使用障碍(AUD)是世界上最普遍的物质使用障碍，经常与 慢性疼痛、焦虑、抑郁和阿片类药物依赖。不幸的是，目前可供治疗的药物 AUD疗效有限，副作用大。为了解决这一未得到满足的医疗需求，我们提出了SBIR 响应PAR-22-102“研究性新药(IND)--支持和早期阶段”的第一阶段U43项目 开发治疗酒精使用障碍和酒精相关器官损伤的药物。 将集中于我们的活性IND(157314)的概念验证研究，AFA-281，一种新型的T-型双重抑制剂 钙通道(CaV3)和可溶性环氧化物水解酶(SEH)，用于AUD治疗。这些概念验证 研究将使用成熟的啮齿动物AUD模型和测试范式。 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 阿片类止痛药。我们通过合理的药物设计和迭代筛选完成了对铅的识别 膜片钳记录和酶分析。进行了铅的优化，包括选择性筛选 关于HERG和关键心脏离子通道，以及81个非药物靶点的CEREP验证。这些放映放在一起 利用体外培养的人心肌细胞进行的研究表明，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显示出极好的口服生物利用度， 可接受的T1/2，中枢神经系统渗透，对神经病理性和炎症性疼痛有广泛的止痛作用，安全性良好 利润率。最近，AFA281‘S IND申请被美国食品和药物管理局接受，作为神经病理性疼痛的先兆。 我们对AUD的初步研究表明，AFA-281能够减少酒精摄入量，酗酒 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第一阶段U43项目中，我们将进行临床前概念验证研究 S对自闭症及其相关的慢性疼痛和负性情感障碍如焦虑和抑郁的影响 通过三个特定的目标对大鼠进行抑郁。目标1将评估AFA-281在减少酒精消耗方面的PK/PD 以及通过可操作的自我管理寻求行为。目的研究AFA281‘S对痛觉过敏的影响。 停止长期饮酒的大鼠的焦虑和抑郁。目标3将探索这一机制 通过评估AFA-281‘S对酒精损伤神经的调节作用探讨其治疗酒精性痴呆的作用机制 通过c-Fos表达和脑神经炎症以及评估Cav3通道活性来指示活性，以及 外侧缰核的细胞兴奋性，这是一个与AUD有关的脑区。 我们第一阶段项目的成功将证明AFA-281可以减少酒精消耗和寻求 行为，为U44向临床概念验证研究过渡提供证据基础 SBIR项目。鉴于澳大利亚的重大公共卫生负担，开发一种更有效和更安全的药物 可用于治疗和预防非酒精性尿崩症，将对公众健康产生相当积极的影响。

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.