Mu Opioid Receptor Modulator Development to Treat Opioid Use Disorder

Mu 阿片受体调节剂开发用于治疗阿片类药物使用障碍

基本信息

批准号：
10671268
负责人：
YAN ZHANG
金额：
$ 143.16万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10671268
关键词：
Mu Opioid Receptor Modulator Development

项目摘要

Project Summary The United States is currently in an opioid crisis, and NIDA is committed to research on the mechanisms and treatment of opioid use disorder. Current Food and Drug Administration-approved pharmacotherapies for opioid use disorder include the MOR agonist methadone, the MOR partial agonist buprenorphine, and the MOR antagonist naltrexone. However, the clinical utility of all three compounds is limited for various reasons. Therefore, it is imperative to develop novel and effective drug candidates with enhanced therapeutic effects and reduced undesirable effects. Recently, we have identified several highly selective and potent MOR modulators as novel leads for opioid use disorder treatment. They all showed more promising pharmacological profiles compared to other known drugs in this category. The current proposal will focus on further development of these leads for preclinical IND-enabling studies, and dynamic drug discovery and development pipeline construct. Four integrated specific aims will be pursued in this project in two phases. In the UG3 phase, we will 1) further Validate therapeutic profiles of the current leads with self-administration and PK studies, and 2) expand the small molecule library to build a dynamic drug discovery and development pipeline. In the UH3 phase, we will 1) conduct preclinical IND-enabling studies on the lead(s) identified from UG3 phase, and 2) compare in vivo pharmacokinetics and pharmacodynamics profiles of the new hits from UG3 phase with current leads to define our next generation of lead compound(s).

项目摘要美国目前正处于阿片类药物危机中，NIDA致力于研究机制和治疗阿片类药物使用障碍。目前的食品和药物管理局批准的药物治疗阿片类药物使用障碍包括MOR激动剂美沙酮，MOR部分激动剂丁丙诺啡和 MOR拮抗剂Naltrexone。但是，由于各种原因，所有三种化合物的临床实用性都受到限制。因此，必须开发具有增强治疗作用的新颖有效的候选药物并降低了不良影响。最近，我们确定了几种高度选择性和有效的MOR 调节剂作为阿片类药物使用障碍治疗的新型铅。他们都表现出更有希望的药理学与此类别中的其他已知药物相比，轮廓。当前的提议将集中在进一步上这些铅的开发用于临床前辅助研究以及动态药物发现和开发管道结构。该项目将在两个阶段中追求四个集成的特定目标。在UG3中阶段，我们将1）进一步验证具有自我管理和PK的当前潜在客户的治疗特征研究，以及2）扩展小分子文库以建立动态的药物发现和发育管道。在UH3阶段，我们将1）对从UG3阶段确定的铅进行临床前的指定研究， 2）比较UG3阶段的新热门单体的体内药代动力学和药效学概况当前导致定义我们的下一代铅化合物。