THERAPY FOR ALCOHOL USE DISORDER

摘要 酒精使用障碍(AUD)是一个重大的全球健康问题。在美国，澳元每年影响1400多万人。 18岁。虽然有三种药物被批准用于治疗AUD，但有资格接受药物治疗的患者不到4% 开了药--可能是由于目前批准的药物疗效有限。另外，复发率 因为澳元继续处于极高的水平。因此，AUD迫切需要新的治疗方法。两者都是临床前 临床证据表明，拮抗1型大麻素(CB1)受体是一种很有前途的策略 换成澳元。然而，第一代CB1阻滞剂在约6%的患者中产生了不良的精神影响 它们不适合长期使用。Artiam Bio正在开发第二代CB1阻滞剂，旨在 在不产生不良精神影响的情况下有效。阿塔姆·比奥的方法考虑到了 CB1受体的内在活性是情感幸福所必需的，而第一代完全相反 像SR141716A(利莫那班)这样的激动剂/拮抗剂完全取消了这一必要的有益过程。这个 由阿蒂坦开发的化合物，包括它的前导分子和载体，是高亲和力但低固有的 功效部分反向激动剂，保持CB1受体的基础活性-从而减少 潜在的不良神经精神事件。支持的证据来自于这篇文章中提出的啮齿动物研究 申请。对于这个第一阶段的STTR应用，Artiam的团队将与密歇根大学的研究人员合作 北卡罗来纳州鲍尔斯酒精研究中心对一只大鼠进行其先导化合物的药效研究 酒精消费和复发的模型。此外，还建议对易焦虑患者进行更多的行为研究。 小鼠使用长期给药方案，以进一步降低阿蒂坦的先导化合物用于临床开发的风险。 这些研究的成功完成将使阿蒂坦的先导化合物具有良好的药物性质， 用于临床开发治疗AUD。

Abstract Alcohol use disorder (AUD) is a major global health issue. In the US, AUD affects over 14 million people over the age of 18. While there are three approved drugs for AUD, less than 4% of patients eligible for pharmacotherapy are prescribed a medication – likely due to limited efficacy of currently approved agents. Also, the relapse rate for AUD continues to be exceedingly high. Thus, new therapies are urgently needed for AUD. Both preclinical and clinical evidence suggest that antagonism of the type 1 cannabinoid (CB1) receptor is a promising strategy for AUD. However, first generation CB1 blockers produced adverse psychiatric effects in ~6% of patients making them unsuitable for chronic use. Artiam Bio is developing second generation CB1 blockers that are designed to be efficacious without producing adverse psychiatric effects. Artiam Bio’s approach takes into consideration that intrinsic activity of the CB1 receptor is required for emotional welfare, and that first-generation full inverse agonists/antagonists like SR141716A (rimonabant) completely abrogated this necessary beneficial process. The compounds developed by Artiam, including its lead molecule and backup, are high affinity but low intrinsic efficacy partial inverse agonists that preserve basal activity of the CB1 receptor – thereby reducing the potential of adverse neuropsychiatric events. Supportive evidence comes from rodent studies presented in this application. For this Phase 1 STTR application, Artiam’s team will partner with investigators from University of North Carolina’s Bowles Alcohol Research Center to perform efficacy studies with its lead compound in a rat model of alcohol consumption and relapse. Further, additional behavioral studies are proposed in anxiety-prone mice using a chronic dosing regimen to further de-risk Artiam’s lead compound for clinical development. Successful completion of these studies will pose Artiam’s lead compound, which has good drug-like properties, for clinical development to treat AUD.