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: 10478126
• 负责人: Cindy Ann Burklow
• 金额: $ 140.5万
• 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/10478126
• 关键词: Acute; Address; Affect; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Autopsy; Binding; Biological Availability; Blood - brain barrier anatomy; 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; 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; Pharmacology; Pharmacotherapy; Phase; Physiological; Plasma; Plasma Proteins; Play; Polyamines; Population; Production; 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; disorder later incidence prevention; drinking; drug testing; genotoxicity; high throughput screening; human subject; in vivo; ineffective therapies; intraperitoneal; meetings; neuroprotection; neurotoxicity; nonhuman primate; novel; novel therapeutics; phase 1 study; preclinical development; preclinical study; receptor; receptor function; reduce symptoms; 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 酒精依赖影响至少4％的美国人口，其财务成本超过100亿美元。 试图减少饮酒的患者预防复发是主要的治疗靶点，但 目前的治疗方法无效，迫切需要新药物。引起的主要因素 复发包括从酒精中戒断的旷日持久的症状，这可以通过返回到 喝。与依赖性相关的神经变性也与戒酒有关。 有很多证据表明谷氨酸/NMDA受体（NMDAR）是酒精的分子靶标 撤回，NMDAR的抑制调节剂可能具有抗释放的价值 药物治疗。目标验证通过NR2B确定了NMDAR功能的多胺增强 亚基作为戒断酒精的特定靶标，分子筛选确定了几种铅化合物。 JR220是芳基酰氨基烷类系列中最活跃的新颖化合物，其细胞对 神经元培养与通过该部位的NMDAR抑制一致。然后对JR220进行了多种测试 与酒精依赖，戒断和神经毒性相关的啮齿动物筛选，包括几个筛选 其他实验室。该药物在所有这些筛查中都高度活跃，效力为5-200x Acamprosate，该抗酸盐已被FDA批准用于预防复发。 JR220在较高的 剂量，但即使反复给药也没有明显的毒性。大鼠的药代动力学研究 在腹膜内，皮下和口服后血浆中浓度的剂量依赖性升高 管理（口服生物利用度> 70％）。在大脑中获得的浓度比血浆高约10倍， 建议在血/脑屏障处有主动摄取系统。每天重复一次服用7天， JR220没有在血浆或大脑中积聚，也没有观察到明显的毒性。唯一关心的是 口服治疗后的血浆半衰期可能太短了，对于预防复发的每日剂量一次。这 可以通过公式作为口服扩展释放公式或透皮贴片来解决 治疗酒精饮用障碍的其他优势也将具有其他优势）。 JR220的知识产权作为 戒酒方面的治疗和JR220的透皮贴剂配方的处理 向USPTO的临时申请。初步数据表明JR220是一个极好的候选人 一种抗释放药物，当前的建议是进一步开发用于此用途的药物。目的是 要在将药物提交给FDA之前完成所需的研究，以考虑 研究新药（IND）。因此，在拟议的研究中，我们将完成对代谢和 体外的代谢物鉴定，吸收，分布，代谢和体内排泄。研究 还将包括一个屏幕，以关闭两个物种（大鼠和 非人类灵长类动物）。这些研究将包括不断升级的急性剂量研究和亚基次研究（TO TO 反映患者在抗雷神药物方面的维持）。最好的配方和给药时间表将 然后在非人类灵长类动物的酒精依赖性转化模型中进行测试。 JR220将产生 在GMP条件下，生产规模缩小以满足未来人类试验的要求。如果是印第安人 获得了名称，目标将是与一家大型制药公司合作进行测试 该药物在人类安全试验中，然后在依赖酒精志愿者的临床试验中进行。目的是 开发用于预防复发和神经保护的JR220，以提供更有效的药物治疗 对于这些治疗靶标而不是目前可用的目标。