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: 9397465
• 负责人: JOHN M. LITTLETON
• 金额: $ 67.25万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9397465
• 关键词: Acute; Address; Adverse effects; 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 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; Treatment Efficacy; 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; subcutaneous; therapeutic target; 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. These studies will include escalating acute dose studies, and sub-chronic studies (to reflect the maintenance of patients on anti-relapse medication). 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一个主要的治疗靶点，但目前的治疗方法无效，迫切需要新药物。引起复发的主要因素包括从酒精中退出的旷日持久的症状，这可以通过返回饮酒来缓解。与依赖性相关的神经变性也与戒酒有关。有充分的证据表明，谷氨酸/NMDA受体（NMDAR）是戒酒的分子靶标，并且NMDAR的抑制性调节剂可能是抗透明化学药物治疗的潜在有价值的。目标验证通过NR2B亚基确定了NMDAR功能的多胺增强，是戒酒中的特定靶标，并且分子筛选确定了几种铅化合物。 JR220是芳基酰氨基氨酸系列中最活跃的新颖化合物，其细胞对神经元培养物的作用与通过该部位的NMDAR抑制一致。然后对JR220进行了与酒精依赖，戒断和神经毒性相关的各种啮齿动物筛选，包括其他实验室中的几个筛选。该药物在所有这些筛查中都高度活跃，其效力为5-200倍，Acamprosate的效力为5-200倍，该药物是FDA批准的，以预防复发。 JR220在较高剂量的情况下引起轻度镇静，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表明，腹膜内，皮下和口服给药后血浆浓度的剂量依赖性升高（口服生物利用度> 70％）。在大脑中获得的浓度比血浆高约10倍，这表明在血/脑屏障处有活跃的摄取系统。每天重复一次给药7天，JR220不会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，口服给药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制剂或透皮贴剂来解决（这也将具有治疗酒精饮用障碍的其他优势）。 JR220中的知识产权作为戒酒和JR220的透皮贴剂配方的一种治疗方法，由USPTO的临时申请涵盖。初步数据表明，JR220是抗雷神药物的出色候选者，目前的建议是进一步开发该药物以供此使用。现在，目的是在将药物提交给FDA之前完成所需的研究，以将其视为研究新药（IND）。因此，在拟议的研究中，我们将在体外对代谢和代谢物鉴定进行研究，并在体内吸收，分布，代谢和排泄。这些研究还将包括一个关闭两个物种安全性和毒理学研究的筛选。这些研究将包括急性剂量研究升级和少量研究（以反映抗释放药物的患者维持）。 JR220将在GMP条件下生产，生产规模缩小以满足未来人类试验的要求。如果获得了IND指定，则该目标将是与一家大型制药公司合作在人体安全试验中测试该药物，然后在酒精依赖志愿者的临床试验中与该药物合作。目的是开发用于预防复发和神经保护的JR220，以提供比目前可用的其他治疗靶标更有效的药物疗法。