权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Treatment for cannabis use disorder

大麻使用障碍的治疗

基本信息

批准号：
10546566
负责人：
HERBERT H SELTZMAN
金额：
$ 31.99万
依托单位：
ARTIAM BIO INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10546566
关键词：
Adverse effects Affect Agonist American Anhedonia Animals Anti-Obesity Agents Area Award Behavioral Benign Brain CNR1 gene CNR2 gene Canis familiaris Cannabinoids Cannabis Cells Chemicals Clinical Data Cognitive Therapy Development Dose Emergency department visit Emotional Europe FDA approved Failure G-Protein-Coupled Receptors Generations Goals Human Immune Lead Legal patent Marijuana Maximum Tolerated Dose Oral Organ Outcome Penetration Peripheral Pharmaceutical Preparations Pharmacotherapy Phase Physiological Plasma Production Property Rattus Receptor Signaling Research Design Rewards Rodent Route Self Stimulation Signal Transduction Small Business Innovation Research Grant Substance Use Disorder Tetrahydrocannabinol Therapeutic Toxic effect Toxicokinetics Toxicology Withdrawal addiction antagonist base behavioral study chemical synthesis clinical candidate cohort craving design drug discrimination drug of abuse dysphoria experience imaging study innovation interest lead candidate marijuana legalization marijuana use marijuana use disorder next generation novel novel therapeutics preclinical study psychologic receptor rimonabant scale up small molecule social synthetic cannabinoid welfare

项目摘要

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.

抽象的我们的目标是开发一种针对影响超过 400 万人的大麻使用障碍 (CUD) 的创新药物疗法美国人。我们建议开发一种新型第二代大麻素 1 的部分反向激动剂受体 (CB1) 对 CUD 具有良性行为特征。大麻素是第二大滥用类别世界上尚无 FDA 批准的治疗 CUD 的药物，这使得该领域成为一个迫切需要的领域。这大麻和合成大麻素的精神作用是由中枢 CB1 受体激活引起的。阻止滥用药物的奖励和渴望特性是一种经过充分验证和接受的策略物质使用障碍（SUD），不具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。很遗憾，利莫那班对大约 6% 的使用者产生不良的烦躁反应——这种影响可能是由于持续的高脑力造成的暴露和有效的反向激动作用，导致其最终停产。在人体研究中，利莫那班在治疗 CUD 的许多方面都有效。 Artiam Bio 正在开发下一代 CB1 拮抗剂与利莫那班和之前的临床研究相比，预计具有更好的不良反应候选人。 Artiam Bio 的先导化合物是一种口服活性、强效、选择性 CB1 部分反向激动剂，具有大脑渗透力有限。该化合物在功能上与利莫那班一样有效，但不产生啮齿动物研究中的烦躁/快感缺失。该化合物的进一步开发提出了三个目标。通过目标 1，将利用已建立的化学路线合成约 500 克化合物阿蒂亚姆与同类的经历。通过目标 2 和 3，毒理学研究的剂量范围将在两个物种中进行，并将确定毒代动力学参数。顺利完成第一阶段 SBIR 申请将为 Artiam 主导的 GLP 监管研究和其他 IND 支持活动铺平道路 CUD 候选人。