Development of JR-220 (4-Chlorobenzylidenamino-guanidine hydrochloride) as a medication for alcohol dependence

开发 JR-220（4-氯苯亚基氨基胍盐酸盐）作为酒精依赖药物

• 批准号: 10687845
• 负责人: Cindy Ann Burklow
• 金额: $ 99.33万
• 依托单位: NAPROGENIX, INC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-25 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687845
• 关键词: Acute; Address; Affect; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Autopsy; Binding; Biological Availability; Blood; Brain; Canis familiaris; Cardiovascular system; Chemicals; Chronic; Clinical; Clinical Trials; Complex; Data; Dependence; Development; Dose; Drug Kinetics; Enzymes; Equilibrium; Evaluation; Excretory function; FDA approved; Financial Hardship; Financial cost; Formulation; Future; Gastritis; Glutamates; Guanidines; Half-Life; Hepatic; Hepatocyte; Human; In Vitro; Incubated; Intellectual Property; Investigation; Investigational Drugs; Kilogram; Label; Laboratories; Lead; Liver Microsomes; Lung; Macaca fascicularis; Maintenance; Maximum Tolerated Dose; Medical; Metabolism; Methods; Modeling; Molecular; Molecular Target; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Nerve Degeneration; Neurons; Oral; Oral Administration; Pathologic; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Physiological; Plasma; Plasma Proteins; Play; Polyamines; Population; Rattus; Receptor Inhibition; Recovery; Relapse; Research; Rodent; Role; Route; Safety; Schedule; Sedation procedure; Series; Site; Symptoms; System; Testing; Therapeutic Uses; Toxic effect; Toxicokinetics; Toxicology; Up-Regulation; Validation; Withdrawal; Withdrawal Symptom; absorption; acamprosate; alcohol abuse therapy; alcohol exposure; alcohol use disorder; aminoguanidine; chemical synthesis; design; drinking; drug testing; genotoxicity; high throughput screening; human subject; in vivo; ineffective therapies; intraperitoneal; manufacturing scale-up; neuroprotection; neurotoxicity; nonhuman primate; novel; novel therapeutics; pharmacologic; phase 1 study; pre-Investigational New Drug meeting; preclinical development; preclinical study; receptor; receptor function; reduce symptoms; relapse prevention; scale up; screening; side effect; subcutaneous; therapeutic target; therapeutically effective; translational model; uptake; volunteer

Abstract Alcohol dependence affects at least 4% of the US population, with a financial cost in excess of $100Bn. Prevention of relapse in patients attempting to reduce alcohol consumption is a major therapeutic target, but current treatments are ineffective, and there is an urgent need for new medications. Major factors in causing relapse include the protracted symptoms of withdrawal from alcohol, which are relieved by returning to drinking. Alcohol withdrawal is also implicated in the neurodegeneration that is associated with dependence. There is abundant evidence that the glutamate/NMDA receptor (NMDAR) is a molecular target in alcohol withdrawal, and that inhibitory modulators of the NMDAR are potentially valuable as anti-relapse pharmacotherapy. Target validation identified polyamine enhancement of NMDAR function via the NR2B subunit as a specific target in alcohol withdrawal, and molecular screening identified several lead compounds. JR220 was the most active novel compound from an aryliminoguanidine series, and its cellular effects on neuronal cultures were consistent with NMDAR inhibition via this site. JR220 was then tested in a variety of rodent screens relevant to alcohol dependence, withdrawal and neurotoxicity, including several screens in other laboratories. The drug was highly active in all of these screens, with a potency 5-200x that of acamprosate, which is FDA-approved for the prevention of relapse. JR220 caused mild sedation at higher doses, but there was no overt toxicity even on repeated administration. Pharmacokinetic studies in the rat showed dose dependent elevations of concentrations in plasma after intraperitoneal, subcutaneous and oral administration (oral bioavailability >70%). Concentrations obtained in brain were ~10x higher than plasma, suggesting an active uptake system at the blood/brain barrier. On repeated once daily dosing for 7 days, JR220 did not accumulate in plasma or brain, and no overt toxicity was observed. The only concern is that the plasma half-life following oral administration may be too short for once-a-day dosing in relapse prevention. This can be addressed by formulation as an oral extended release formulation or by a transdermal patch (which would also have other advantages for treatment of alcohol use disorders). Intellectual property in JR220 as a treatment for aspects of alcohol withdrawal and the transdermal patch formulation of JR220 are covered by provisional applications to the USPTO. The preliminary data indicates that JR220 is an excellent candidate as an anti-relapse medication, and the current proposal is to develop the drug further for this use. The aim is now to complete the studies required prior to submission of the drug to the FDA for consideration as an investigational new drug (IND). Thus, in the proposed studies we will complete investigation of metabolism and metabolite identification in vitro, and Absorption, Distribution, Metabolism, and Excretion in vivo. The studies will also include a screen for off target actions and studies on safety and toxicology in two species (rats and non-human primates). These studies will include escalating acute dose studies, and sub-chronic studies (to reflect the maintenance of patients on anti-relapse medication). The best formulation and dosing schedule will then be tested in a translational model of alcohol dependence in non-human primates. JR220 will be produced under GMP conditions, and production scaled up to meet requirements for future human trials. If an IND designation is obtained, the objective will then be to partner with a major pharmaceutical company in testing the drug in a human safety trial, and then in clinical trials in alcohol dependent volunteers. The objective is to develop JR220 for relapse prevention and neuroprotection to provide a pharmacotherapy that is more effective for these therapeutic targets than others currently available.

抽象的 酒精依赖影响了至少 4% 的美国人口，造成的经济损失超过 1000 亿美元。 预防试图减少饮酒的患者复发是一个主要的治疗目标，但是 目前的治疗方法无效，迫切需要新的药物。造成的主要因素 复发包括长期戒酒症状，这些症状可以通过恢复饮酒来缓解 喝。酒精戒断还与与依赖性相关的神经变性有关。 有大量证据表明谷氨酸/NMDA 受体 (NMDAR) 是酒精中的分子靶标 NMDAR 的抑制性调节剂具有抗复发的潜在价值 药物治疗。目标验证确定多胺通过 NR2B 增强 NMDAR 功能 亚基作为酒精戒断的特定靶标，分子筛选鉴定了几种先导化合物。 JR220 是芳基亚氨基胍系列中最活跃的新型化合物，其细胞效应 神经元培养物与通过该位点的 NMDAR 抑制一致。随后 JR220 在各种环境中进行了测试 与酒精依赖、戒断和神经毒性相关的啮齿动物筛查，包括在 其他实验室。该药物在所有这些筛选中均表现出高度活性，其效力是 5-200 倍 阿坎酸，经 FDA 批准用于预防复发。 JR220 在较高浓度下引起轻度镇静 剂量，但即使重复给药也没有明显的毒性。大鼠药代动力学研究 腹膜内、皮下和口服后血浆浓度呈剂量依赖性升高 给药（口服生物利用度>70%）。大脑中获得的浓度比血浆高约 10 倍， 表明血/脑屏障有一个活跃的摄取系统。每日一次重复给药 7 天， JR220 不会在血浆或脑中蓄积，也没有观察到明显的毒性。唯一令人担忧的是 口服给药后的血浆半衰期对于预防复发而言每日一次给药可能太短。这 可以通过口服缓释制剂或透皮贴剂（其 对于治疗酒精使用障碍也有其他优点）。 JR220的知识产权作为 酒精戒断方面的治疗和 JR220 的透皮贴剂配方涵盖在 向美国专利商标局提出临时申请。初步数据表明，JR220 是一个优秀的候选者 一种抗复发药物，目前的建议是进一步开发该药物用于此用途。现在的目标是 在将药物提交给 FDA 考虑作为药物之前完成所需的研究 研究性新药（IND）。因此，在拟议的研究中，我们将完成代谢和 体外代谢物鉴定，以及体内吸收、分布、代谢和排泄。研究 还将包括对两个物种（大鼠和大鼠）的脱靶行为筛查和安全性和毒理学研究 非人类灵长类动物）。这些研究将包括逐步升级的急性剂量研究和亚慢性研究（以 反映患者抗复发药物的维持情况）。最佳的配方和给药方案将 然后在非人类灵长类动物的酒精依赖转化模型中进行测试。 JR220即将量产 在 GMP 条件下，并扩大生产以满足未来人体试验的要求。如果 IND 获得指定后，目标将是与一家大型制药公司合作进行测试 该药物进行了人体安全试验，然后在酒精依赖志愿者中进行了临床试验。目标是 开发JR220用于预防复发和神经保护，提供更有效的药物治疗 对于这些治疗目标，比目前可用的其他目标更有效。