Development of JR-220 (4-Chlorobenzylidenamino-guanidine hydrochloride) as a medication for alcohol dependence

酒精依赖影响了至少4%的美国人口，其经济成本超过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，但目前的治疗是无效的，迫切需要新的药物。导致复发的主要因素包括长期戒酒的症状，这些症状可以通过重新饮酒来缓解。酒精戒断也与依赖相关的神经变性有关。大量证据表明，谷氨酸/NMDA受体（NMDAR）是酒精戒断的分子靶点，NMDAR的抑制性调节剂在抗复发药物治疗中具有潜在的价值。靶标验证确定了多胺通过NR2B亚基增强NMDAR功能作为酒精戒断的特定靶标，分子筛选确定了几个先导化合物。JR220是芳基氨基胍系列中活性最高的新化合物，其对神经元培养的细胞作用与通过该位点抑制NMDAR一致。然后在与酒精依赖、戒断和神经毒性有关的各种啮齿动物筛选中对JR220进行了测试，包括在其他实验室进行的若干筛选。该药物在所有这些筛选中都非常活跃，效力是阿坎普罗酸的5-200倍，阿坎普罗酸是fda批准用于预防复发的药物。JR220在高剂量下有轻微镇静作用，但即使重复给药也没有明显的毒性。大鼠药代动力学研究显示，经腹腔、皮下和口服给药后，血浆中浓度呈剂量依赖性升高（口服生物利用度为70%）。脑内浓度比血浆高约10倍，提示血脑屏障处存在活跃的摄取系统。JR220每天给药一次，连续7天，没有在血浆或大脑中积累，也没有观察到明显的毒性。唯一值得关注的是，口服后的血浆半衰期可能太短，不适合每天服用一次预防复发。这可以通过口服缓释制剂或透皮贴剂来解决（这对治疗酒精使用障碍也有其他好处）。JR220作为酒精戒断治疗方面的知识产权和JR220的透皮贴剂配方在向美国专利商标局提交的临时申请中予以涵盖。初步数据表明，JR220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作为试验性新药（IND）提交给FDA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两种物种的脱靶作用和安全性及毒理学研究的筛选。这些研究将包括逐步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）。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。目的是开发用于预防复发和神经保护的JR220，为这些治疗靶点提供比现有药物更有效的药物治疗。

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.