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

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：
10928929
负责人：
Alexandros Makriyannis
金额：
$ 79.75万
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 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10928929
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 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 Reporting Research Residual state Rewards Rodent Safety Self Administration Societies Solvents Specific qualifier value 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 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 manufacture micronucleus neurochemistry nonhuman primate novel patient population pharmacologic pre-Investigational New Drug meeting pre-clinical preclinical safety preclinical study product development prototype relapse prevention respiratory response rimonabant safety study scale up side effect socioeconomics verification and validation

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.

摘要