Treatment for cannabis use disorder

摘要 我们的目标是开发一种治疗大麻使用障碍(Cud)的创新药物疗法，影响超过400万人。 美国人。我们建议开发一种新的第二代大麻素1部分反向激动剂 受体(CB1)，对CUD具有良性行为特征。大麻素是滥用第二多的一类 世界上最大的药物，而且没有FDA批准的治疗CUD的药物--使这一领域成为一个迫切需要的领域。这个 大麻和合成大麻素的精神活性效应源于中枢CB1受体的激活。 阻止滥用药物的回报和渴求特性是一种得到充分验证和接受的策略 物质使用障碍(SUD)，没有强烈的不良身体戒断成分。利莫那班是一种有效的 CB1受体的完全反向激动剂，在欧洲被批准作为抗肥胖剂。不幸的是， 利莫那班在约6%的使用者中产生了不良的烦躁反应--这种影响可能是由于持续的大脑高度兴奋所致 暴露和强烈的反向激动感，导致它最终停止使用。在人体研究中，利莫那班 在治疗CUD的多个方面都有效。Artiam Bio正在开发下一代CB1拮抗剂 与利莫那班和以前的临床试验相比，这些药物具有更好的不良反应 候选人。阿蒂坦生物公司的先导化合物是一种口服活性、有效和选择性的CB1部分反向激动剂，具有 大脑渗透率有限。这种化合物在功能上与利莫那班一样有效，但不会产生 啮齿动物研究中的烦躁不安/快感缺乏。从三个方面提出了该化合物的进一步发展方向。 通过AIM 1，将使用现有的化学路线合成约500克的化合物，利用 阿塔姆和一个同类人的经历。通过AIMS 2和AIMS 3，剂量范围毒理学研究将 在两个物种中进行试验，将建立毒物动力学参数。成功完成此阶段1 SBIR申请将为GLP监管研究和Artiam的Lead的其他支持IND的活动铺平道路 CUD的候选人。

Abstract Our goal is to develop an innovative pharmacotherapy for cannabis use disorder (CUD) that affects over 4 million Americans. We propose to develop a novel second generation PARTIAL inverse agonist of the cannabinoid 1 receptor (CB1) that has a benign behavioral profile for CUD. Cannabinoids are the second most abused class of drug in the world and there is no FDA approved medication for CUD -- making this an area of urgent need. The psychoactive effects of cannabis and synthetic cannabinoids result from activation of central CB1 receptors. Blocking the rewarding and craving properties of drugs of abuse is a well-validated and accepted strategy for substance use disorders (SUD) without a strong adverse physical withdrawal component. Rimonabant is a potent FULL inverse agonist of the CB1 receptor that was approved in Europe as an anti-obesity agent. Unfortunately, rimonabant produced adverse dysphoric effects in ~6% of users -- effects likely due to sustained high brain exposure and potent inverse agonism, which led to its eventual discontinuation. In human studies, rimonabant was efficacious in treating many aspects of CUD. Artiam Bio is developing the next generation of CB1 antagonists that are expected to have a superior adverse effect profile compared to rimonabant and previous clinical candidates. Artiam Bio’s lead compound is an orally active, potent, and selective CB1 partial inverse agonist with limited brain penetration. This compound is functionally as efficacious as rimonabant but produces no dysphoria/anhedonia in rodent studies. Further development of this compound is proposed through three aims. Through aim 1, ~500 g of the compound will be synthesized using an established chemical route leveraging upon Artiam’s experience with a congener. Through aims 2 and 3, dose range finding toxicological studies will be performed in two species and toxicokinetic parameters will be established. Successful completion of this phase 1 SBIR application will pave the way for GLP regulatory studies and other IND-enabling activities of Artiam’s lead candidate for CUD.