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，经济成本超过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， 目前的治疗无效，迫切需要新的药物。主要原因 复吸包括长期的戒酒症状，这些症状可以通过回到 喝酒酒精戒断也与依赖性相关的神经变性有关。 大量证据表明谷氨酸/NMDA受体（NMDAR）是酒精作用的分子靶点 NMDAR的抑制性调节剂作为抗复发剂具有潜在价值 药物治疗.靶标验证鉴定了多胺通过NR 2B增强NMDAR功能 亚基作为酒精戒断的特异性靶点，分子筛选确定了几个先导化合物。 JR 220是芳基亚氨基胍系列中活性最高的新化合物，其细胞效应 神经元培养物与通过该位点的NMDAR抑制一致。JR 220随后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 其他实验室。该药物在所有这些筛选中都具有高度活性，其效力为 阿坎酸，FDA批准用于预防复发。JR 220在较高的温度下引起轻度镇静 剂量，但没有明显的毒性，即使在重复给药。大鼠药代动力学研究 显示腹膜内、皮下和经口给药后血浆浓度呈剂量依赖性升高 给药（口服生物利用度>70%）。脑中获得的浓度比血浆高约10倍， 这表明在血/脑屏障处存在主动摄取系统。每日一次重复给药，持续7天， JR 220在血浆或脑中未蓄积，未观察到明显毒性。唯一的问题是， 口服给药后的血浆半衰期对于预防复发的每日一次给药来说可能太短。这 可以通过口服缓释制剂或透皮贴剂（ 还具有治疗酒精使用障碍的其它优点）。JR 220中的知识产权 酒精戒断方面的治疗和JR 220的透皮贴剂制剂， 向USPTO提出临时申请。初步数据表明，JR 220是一个很好的候选人， 一种抗复发药物，目前的建议是进一步开发这种药物用于这种用途。现在的目标是 在将药物提交给FDA考虑之前完成所需的研究， 研究性新药（IND）。因此，在拟议的研究中，我们将完成代谢的研究， 体外代谢物鉴别和体内吸收、分布、代谢和排泄。研究 还将包括对脱靶作用的筛选以及对两个物种（大鼠和 非人灵长类动物）。这些研究将包括急性剂量递增研究和亚慢性研究（以 反映患者维持抗复发药物治疗）。最佳制剂和给药方案将 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。JR 220将生产 在GMP条件下生产，并扩大生产规模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 这种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。目标是 开发JR 220用于预防复发和神经保护，以提供更有效的药物治疗 这些治疗靶点比其他目前可用的。