Development of CP-analogs as novel treatments for opioid use disorder.

开发 CP 类似物作为阿片类药物使用障碍的新疗法。

基本信息

批准号：
10255890
负责人：
Jeffrey Reich
金额：
$ 31.92万
依托单位：
SPARIAN BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10255890
关键词：
Absence of pain sensation Acute Adoption Agonist Attenuated Behavioral Assay Behavioral Model Biological Assay Biological Sciences Brain Buprenorphine Cardiac Cell Line Chemicals Chronic Chronic Disease Clinical Clinical Trials Consumption Country Data Development Discipline Disease remission Dose Drug Industry Drug Kinetics Epidemic GTP-Binding Proteins Goals In Vitro Incidence Ion Channel Lead Ligands Lung Maximum Tolerated Dose Medical Metabolic Methadone Mitragyna Morbidity - disease rate Morphine Morphine Dependence Mus Naloxone Names Natural Products Opioid Opioid Antagonist Opioid agonist Oral Pain Patients Penetration Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Physical Dependence Physicians Plants Plasma Prevalence Primary Care Physician Process Property Psychological Dependence Public Health Recovery Risk Safety Sampling Schedule Scientist Social Well-Being Specialist Structure Tail Testing Therapeutic Toxicology Translational Research Treatment Side Effects Ventilatory Depression Water Well in self Withdrawal Work addiction analog base chemical synthesis conditioned place preference delta opioid receptor design drug development effective therapy efficacy evaluation improved in vitro Model in vivo innovation lead candidate mortality mu opioid receptors mu receptors novel novel strategies novel therapeutics opioid misuse opioid overdose opioid therapy opioid use opioid use disorder opioid withdrawal prescription opioid receptor receptor binding scale up screening side effect small molecule standard of care

项目摘要

ABSTRACT Opioid use disorder (OUD) is a chronic disorder characterized by the repeated, compulsive use of opioid drugs with a detrimental impact to one's physical, social, and psychological wellbeing. The use of prescription opiates is often necessary to control moderate to severe levels of pain. However, about 10% of patients prescribed an opiate for a medical condition are at risk for developing OUD. Opiate Use Disorder is a global problem but is at crisis levels in the U.S with significant mortality. It is estimated in this country that about ~11M misuse opioids, ~2M people have OUD and close to 50K died from opioid related overdoses. At Sparian, we have assembled a comprehensive team of accomplished scientists, key clinical opinion leaders, and pharmaceutical industry experts across critical disciplines including translational research, medicinal chemistry, CMC, toxicology and clinical trials in an effort to develop an oral, potent, and selective small molecules for the treatment of OUD. Mitragyna speciosa, a plant commonly known as Kratom, is commonly used in the US as a self-remidy to treat opiate withdrawal and OUD. We have identified and synthesized a distinct new chemical entity based on Kratom named 9-methoxy corynantheidine pseudoindoxyl (9CP). 9CP has a different receptor binding profile and different pharmacology than mitragynine. 9CP is both a potent a MOR agonist and delta antagonist. In acute dosing studies it attenuates precipitated withdrawal, it is not rewarding, does not cause physical dependence, and has limited respiratory depression and tolerance. Our Fast Tract proposal aims to take an innovative pharmacological approach to develop orally active, highly potent and selective 9CP analogs, devoid of unwanted side effects, for the treatment of OUD with a better pharmacotherapeutic profile than either methadone or buprenorphine. It is organized into two coordinated phases that employ a succinct experimental plan and a focused drug development approach. In phase 1, we will use an in vitro and in vivo screening paradigm to select one lead molecule and 5-8 backup molecules with suitable drug-like properties. In phase 2, we will progress the selected lead and confirm our choice though exploratory safety and toxicology studies, while also characterizing our backup compounds to better understand our template mitigating risk. In summary, we propose a novel strategy to develop a new class of agents with potential to provide better therapy for OUD.

抽象的阿片类药物使用障碍 (OUD) 是一种慢性疾病，其特征是重复、强迫性使用阿片类药物对身体、社会和心理健康产生不利影响。通常需要使用处方阿片类药物来控制中度至重度疼痛。然而，大约 10% 因健康状况而服用阿片类药物的患者有患上阿片类药物的风险开发 OUD。阿片类药物使用障碍是一个全球性问题，但在美国已处于危机水平显着的死亡率。据估计，该国约有 1100 万人滥用阿片类药物，约 200 万人患有 OUD 的人，近 5 万人死于与阿片类药物相关的过量服用。在斯帕里安，我们有组建了一支由卓有成就的科学家、关键临床意见领袖和跨关键学科的制药行业专家，包括转化研究、药物化学、CMC、毒理学和临床试验，努力开发一种口服、有效、以及用于治疗 OUD 的选择性小分子。帽柱木，一种植物通常称为卡痛，在美国通常用作治疗阿片类药物的自我疗法提款和 OUD。我们已经鉴定并合成了一种独特的新化学实体 Kratom 命名为 9-甲氧基 corynantheidine 假吲哚酚 (9CP)。 9CP有不同的受体结合谱和药理学与帽柱木碱不同。 9CP 既是一种有效的 MOR 激动剂和 δ 拮抗剂。在急性剂量研究中，它可以减弱沉淀戒断后，没有奖励，不会造成身体依赖，呼吸受限抑郁和忍耐。我们的快速通道提案旨在采取创新的药理学开发口服活性、高效且选择性的 9CP 类似物的方法，不含不需要的副作用，用于 OUD 的治疗，其药物治疗效果优于任一药物美沙酮或丁丙诺啡。它分为两个协调的阶段，采用简洁的实验计划和有针对性的药物开发方法。在第一阶段，我们将使用用于选择一个先导分子和 5-8 个备用分子的体外和体内筛选范例具有合适的药物样特性的分子。在第二阶段，我们将推进选定的领先优势并通过探索性安全性和毒理学研究确认我们的选择，同时也表征我们的备用化合物可以更好地了解我们的模板，从而降低风险。综上所述，我们提出一种新颖的策略来开发一类新的代理，有可能提供更好的服务 OUD 疗法。