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.

摘要 酒精依赖影响着至少 4% 的美国人口，造成的经济损失超过 1000 亿美元。试图减少饮酒的患者预防复发是主要的治疗目标，但目前的治疗方法无效，迫切需要新的药物。导致复发的主要因素包括长期戒酒症状，这些症状可以通过恢复饮酒来缓解。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) 是酒精戒断的分子靶标，并且 NMDAR 的抑制调节剂作为抗复发药物治疗具有潜在价值。目标验证确定多胺通过 NR2B 亚基增强 NMDAR 功能，作为酒精戒断的特定目标，分子筛选确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，其对神经元培养物的细胞作用与通过该位点的 NMDAR 抑制一致。随后，JR220 在与酒精依赖、戒断和神经毒性相关的各种啮齿动物筛查中进行了测试，包括在其他实验室进行的多次筛查。该药物在所有这些筛查中均表现出高度活性，其效力是阿坎酸的 5-200 倍，而阿坎酸已获得 FDA 批准用于预防复发。 JR220 在较高剂量下会引起轻度镇静，但即使重复给药也没有明显的毒性。大鼠药代动力学研究表明，腹膜内、皮下和口服给药后血浆浓度呈剂量依赖性升高（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/脑屏障处存在活跃的摄取系统。每日一次重复给药 7 天后，JR220 没有在血浆或脑中蓄积，也没有观察到明显的毒性。唯一的担忧是，口服给药后的血浆半衰期可能太短，不适合每日一次给药以预防复发。这可以通过口服缓释制剂或透皮贴剂（这对于治疗酒精使用障碍还有其他优点）来解决。 JR220 作为酒精戒断治疗方法的知识产权以及 JR220 的透皮贴剂配方均已向美国专利商标局 (USPTO) 提交临时申请。初步数据表明，JR220 是一种优秀的抗复发药物候选药物，目前的建议是进一步开发该药物用于此用途。现在的目标是完成向 FDA 提交该药物以考虑作为研究性新药 (IND) 之前所需的研究。因此，在拟议的研究中，我们将完成体外代谢和代谢物鉴定以及体内吸收、分布、代谢和排泄的研究。这些研究还将包括对两个物种的脱靶行为的筛查以及安全性和毒理学研究。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）。 JR220将在GMP条件下生产，并扩大生产以满足未来人体试验的要求。如果获得 IND 指定，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中进行临床试验。目标是开发用于预防复发和神经保护的 JR220，以提供一种比目前可用的其他药物更有效地针对这些治疗目标的药物疗法。