CB1 Neutral Antagonists for Alcohol Use Disorder

摘要 响应RFA-AA-20-007，其中呼吁开发治疗酒精使用障碍的药物 (AUD)，这份U01申请建议研究将CB1中性拮抗剂AM6527推向IND- 使治疗澳门氏症的研究成为可能。目前治疗AUD的方法要么是行为疗法，要么仅限于药物治疗。 如双硫兰、氨基己酸酯和纳曲酮，在以下方面仅限于特定患者群体 它们的治疗效果。鉴于这些与澳元相关的流行病和经济问题，有一种 迫切需要更易接受和更有选择性地治疗的新药理学干预措施 澳元。CB1拮抗剂利莫那班已被证明具有不可接受的不良反应，可能导致 通过其CB1反向激动剂作用。相反，AM6527是一种新型的选择性CB1大麻素受体 缺乏反向激动剂活性的中性拮抗剂。AM6527在啮齿动物体内的临床前药理作用 非人灵长类动物体内这类化合物的其他原型有力地支持了它们的潜力 作为治疗澳门氏症的有效方法。AM6527具有良好的安全性，没有不良副作用的证据 (例如，恶心、抑郁)，已报道使用CB1受体反向激动剂，如利莫那班 以及临床前和临床研究中的达那班。基于这些积极的临床前数据表明 作为CB1拮抗剂的有效性，我们计划将AM6527转向启用IND的研究，以准备 首例用于治疗澳门氏症的人研究。具体地说，我们在U01提案中的工作旨在满足以下要求 目标：药物的化学、制造和控制，非GLP临床前安全性研究，包括 两个物种的HERG、遗传毒性、ADME和剂量递增研究。后续步骤将包括： 药品的化学、制造和控制，包括配方开发、cGMP放大、 稳定性和分析方法；单次和重复28天给药的毒代动力学安全药理学， 随后就产品开发规划、IND准备和临床前监管战略提供建议。

ABSTRACT In response to RFA-AA-20-007, which calls for the development of medications to treat Alcohol Use Disorders (AUD), this U01 application proposes research to advance the CB1 neutral antagonist AM6527 towards IND- enabling studies for treating AUD. The current therapies for AUD are either behavioral or is limited to drugs such as disulfiram, acamprosate and naltrexone, which are restricted to specific patient populations in terms of their therapeutic effects. Given these epidemiological, and economic issues related with AUD, there is an urgent need for novel pharmacological interventions that are more acceptable and selective towards treating AUD. Rimonabant, a CB1 antagonist, has proven to have unacceptable adverse effects, possibly resulting from its CB1 inverse agonist actions. In contrast, AM6527 is a novel, selective, CB1 cannabinoid-receptor neutral antagonist that is devoid of inverse agonist activity. The preclinical pharmacology of AM6527 in rodents and other prototypes within this class of compounds in nonhuman primates strongly supports their potential utility as therapy for AUD. AM6527 has a favorable safety profile, without evidence of adverse side effects (e.g., nausea, depression) that have been reported with CB1-receptor inverse agonists such as rimonabant and taranabant in preclinical and clinical studies. Based upon these positive preclinical data indicating its effectiveness as a CB1 antagonist, we plan to move AM6527 toward IND-enabling studies in preparation for first-in-man studies to treat AUD. Specifically, our work in this U01 proposal is designed to meet the following aims: Chemistry, manufacturing, and controls of drug substance, non-GLP preclinical safety studies including hERG, genotoxicity, ADME and dose escalation studies in two species. The subsequent steps will comprise: Chemistry, manufacturing, and controls of drug product including formulation development, cGMP scale-up, stability, and analytical methods; toxicokinetics with single and repeat 28-day dosing safety pharmacology, followed by advisement on product development planning, IND preparation and preclinical regulatory strategy.