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: 10459072
• 负责人: JOHN M. LITTLETON
• 金额: $ 101.67万
• 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/10459072
• 关键词: Development; JR; 220; Chlorobenzylidenamino; guanidine

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.

酒精依赖影响至少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，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的戒酒症状，这些症状通过重新饮酒而得到缓解。酒精戒断也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）是酒精戒断中的分子靶标，并且NMDAR的抑制性调节剂作为抗复发药物疗法具有潜在价值。靶点验证确定了多胺通过NR 2B亚基增强NMDAR功能作为酒精戒断的特异性靶点，分子筛选确定了几种先导化合物。JR 220是芳基亚氨基胍系列中活性最高的新型化合物，其对神经元培养物的细胞效应与通过该位点的NMDAR抑制一致。然后在与酒精依赖、戒断和神经毒性相关的各种啮齿动物筛选中测试JR 220，包括其他实验室的几个筛选。该药物在所有这些筛选中都具有高度活性，其效力是FDA批准用于预防复发的阿坎酸的5- 200倍。JR 220在较高剂量下引起轻度镇静，但即使重复给药也没有明显的毒性。对大鼠的药代动力学研究表明，腹膜内、皮下和口服给药后，血浆中的浓度呈剂量依赖性升高（口服生物利用度>70%）。在脑中获得的浓度比血浆高约10倍，表明血/脑屏障处存在主动摄取系统。在每天一次重复给药7天后，JR 220未在血浆或脑中蓄积，也未观察到明显的毒性。唯一的问题是，口服给药后的血浆半衰期可能太短，无法用于预防复发的每日一次给药。这可以通过口服缓释制剂或透皮贴剂（其对于治疗酒精使用障碍也具有其他优势）来解决。JR 220作为酒精戒断治疗方面的知识产权和JR 220的透皮贴剂制剂由USPTO的临时申请涵盖。初步数据表明，JR 220是一种很好的抗复发药物，目前的建议是进一步开发这种药物。现在的目标是在将药物提交给FDA考虑作为研究性新药（IND）之前完成所需的研究。因此，在拟定研究中，我们将完成体外代谢和代谢物鉴别研究以及体内吸收、分布、代谢和排泄研究。这些研究还将包括对脱靶作用的筛选以及对两个物种的安全性和毒理学研究。这些研究将包括急性剂量递增研究和亚慢性研究（以反映患者持续使用抗复发药物）。JR 220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指定，目标将是与一家大型制药公司合作，在人体安全性试验中测试该药物，然后在酒精依赖志愿者中进行临床试验。我们的目标是开发用于复发预防和神经保护的JR 220，以提供比目前可用的其他治疗靶点更有效的药物治疗。