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.

摘要 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的复发是一个主要的治疗目标，但 目前的治疗方法无效，迫切需要新的药物。主要致病因素 复发包括长期戒酒的症状，通过重新戒酒可以缓解这些症状 喝酒。戒酒也与与依赖相关的神经退化有关。 大量证据表明谷氨酸/NMDA受体(NMDAR)是酒精的分子靶标 戒断，以及NMDAR的抑制调节剂在抗复发方面具有潜在的价值 药物疗法。靶向验证确认多胺通过NR2B增强NMDAR功能 亚基作为酒精戒断的特定靶点，分子筛选确定了几种先导化合物。 JR220是芳亚胺类化合物中活性最强的一种新化合物，它对细胞的作用 神经元培养与NMDAR抑制一致，通过这个位置。然后，JR220在各种不同的 与酒精依赖、戒断和神经毒性有关的啮齿动物筛选，包括在 其他实验室。这种药物在所有这些筛查中都非常活跃，效力是5-200倍 氨基己酸酯，这是FDA批准的预防复发的药物。JR220在较高的温度下引起轻度镇静 剂量，但即使重复给药也没有明显的毒性。大鼠体内药代动力学研究 经腹膜、皮下和口服后血药浓度呈剂量依赖性升高 给药(口服生物利用度&GT；70%)。在大脑中获得的浓度是血浆的10倍左右， 说明血/脑屏障存在主动摄取系统。每天重复给药一次，连续7天， JR220未在血浆和脑内蓄积，未见明显毒性。唯一令人担忧的是 口服给药后的血浆半衰期可能太短，不适合一天一次的剂量来预防复发。这 可通过口服缓释制剂或透皮贴剂(其 在治疗酒精使用障碍方面也有其他优势)。JR220中的知识产权作为 有关酒精戒断的治疗和JR220的透皮贴剂配方，请参阅 向USPTO提出的临时申请。初步数据表明，JR220是一个很好的候选者 一种抗复发药物，目前的建议是进一步开发这种药物以用于这种用途。现在的目标是 在将药物提交给FDA审议之前完成所需的研究 研究用新药(IND)。因此，在拟议的研究中，我们将完成对新陈代谢和 体外代谢物鉴定，体内吸收、分布、代谢和排泄。这些研究 还将包括对两个物种(大鼠和大鼠)的偏离目标行动和安全和毒理学研究的筛查 非人灵长类)。这些研究将包括不断增加的急性剂量研究和亚慢性研究(至 反映患者对抗复发药物的维持性)。最佳配方和剂量计划为 然后在非人类灵长类动物的酒精依赖的翻译模型中进行测试。将生产JR220 在GMP条件下，生产规模扩大，以满足未来人体试验的要求。如果是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 该药物在人体安全性试验中，然后在酒精依赖志愿者的临床试验中。我们的目标是 开发JR220预防复发和神经保护，提供更有效的药物治疗 对于这些治疗靶点，比目前可用的其他治疗靶点更多。