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。导致复发的主要因素包括长期戒酒症状，恢复饮酒可以缓解这种症状。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)是酒精戒断的分子靶点，NMDAR的抑制性调节剂具有潜在的抗复发药物治疗价值。靶标验证确认多胺通过NR2B亚基增强NMDAR功能是酒精戒断的特异性靶标，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，其对神经细胞培养的细胞作用与通过该位点抑制NMDAR的作用一致。JR220随后在与酒精依赖、戒断和神经毒性相关的各种啮齿动物屏幕上进行了测试，包括其他实验室的几个屏幕。该药物在所有这些筛查中都非常活跃，效力是氨基己酸酯的5-200倍，后者是FDA批准的预防复发的药物。JR220在较高剂量时有轻度镇静作用，但重复给药也无明显毒性。在大鼠体内的药代动力学研究表明，在腹腔、皮下和口服给药(口服生物利用度为70%)后，血浆中的药物浓度随剂量的增加而升高。脑内药物浓度约为血浆的10倍，提示血/脑屏障存在主动摄取系统。连续给药7d，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。这可以通过口服缓释制剂或透皮贴剂(这在治疗酒精使用障碍方面也有其他优点)来解决。JR220中的知识产权作为酒精戒断方面的治疗和JR220的透皮贴剂配方，由美国专利商标局的临时申请涵盖。初步数据表明，JR220是一个很好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这一用途。现在的目标是在将药物提交给FDA作为研究新药(IND)考虑之前完成所需的研究。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非靶标行为的筛选，以及对两个物种的安全性和毒理学研究。这些研究将包括不断增加的急性剂量研究和亚慢性研究(以反映患者对抗复发药物的维持情况)。JR220将在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。如果获得IND称号，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身上进行临床试验。其目的是开发用于预防复发和神经保护的JR220，以提供一种对这些治疗靶点比现有其他药物更有效的药物疗法。