CB1 Neutral Antagonists for Alcohol Use Disorder

CB1 中性拮抗剂治疗酒精使用障碍

基本信息

批准号：
10475285
负责人：
Alexandros Makriyannis
金额：
$ 121.88万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-20 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10475285
关键词：
3-Dimensional ADME Study Adverse effects Affect Agonist Alcohol consumption Alcohols Anhedonia Animal Model Behavioral Biological Sciences CNR1 gene Canis familiaris Cardiovascular system Chemistry Chromosome abnormality Chronic Clinical Protocols Clinical Research Complement Conduct Clinical Trials Consent Forms Cyclic GMP Data Development Development Plans Disease Disulfiram Dose Drug Controls Economics Effectiveness Epidemiology FDA approved Feeling suicidal Formulation Goals Heavy Drinking High Pressure Liquid Chromatography In Vitro Intervention Investigation Letters Measurement Mediation Mental Depression Methods Modeling Mus Naltrexone Nausea Oral Persons Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pharmacology and Toxicology Population Preparation Public Health Published Comment Rattus Reference Standards Relapse Reporting Research Residual state Rewards Rodent Safety Self Administration Societies Solvents Stress Tablets Therapeutic Therapeutic Effect Toxicokinetics United States Validation Work acamprosate alcohol abuse therapy alcohol effect alcohol intervention alcohol reward alcohol use disorder analytical method antagonist base behavioral pharmacology capsule clinical development clinical research site design drug of abuse economic impact effective therapy endogenous cannabinoid system first-in-human genotoxicity in vitro Assay meetings micronucleus neurochemistry nonhuman primate novel patient population pre-clinical preclinical safety preclinical study prevent product development prototype respiratory response rimonabant safety study scale up side effect socioeconomics

项目摘要

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.

抽象的响应 RFA-AA-20-007，其中呼吁开发治疗酒精使用障碍的药物（澳元），该 U01 申请提出了将 CB1 中性拮抗剂 AM6527 推向 IND-的研究开展治疗 AUD 的研究。目前 AUD 的治疗方法要么是行为疗法，要么仅限于药物疗法例如双硫仑、阿坎酸和纳曲酮，这些药物仅限于特定的患者人群他们的治疗效果。鉴于这些与澳元相关的流行病学和经济问题，有一个迫切需要新的药物干预措施，这些干预措施对治疗更容易接受和选择性澳元。利莫那班 (Rimonabant) 是一种 CB1 拮抗剂，已被证明具有不可接受的副作用，可能导致来自其 CB1 反向激动剂作用。相比之下，AM6527 是一种新型、选择性 CB1 大麻素受体没有反向激动剂活性的中性拮抗剂。 AM6527 在啮齿动物中的临床前药理学和非人类灵长类动物中此类化合物的其他原型强烈支持其潜力作为 AUD 治疗的实用性。 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）已报告与利莫那班等 CB1 受体反向激动剂有关和 taranabant 的临床前和临床研究。基于这些积极的临床前数据表明其作为 CB1 拮抗剂的有效性，我们计划将 AM6527 转向 IND 启用研究，为治疗 AUD 的首次人体研究。具体来说，我们在 U01 提案中的工作旨在满足以下要求目标：原料药的化学、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 天给药安全药理学的毒代动力学，其次是关于产品开发规划、IND 准备和临床前监管策略的建议。