Preclinical Development of Novel Dual OXR/KOR Antagonists for Treatment of Substance Use Disorder

用于治疗药物滥用障碍的新型双 OXR/KOR 拮抗剂的临床前开发

• 批准号: 10400321
• 负责人: John A Butera
• 金额: $ 559.85万
• 依托单位: HAGER BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400321
• 关键词: ABCB1 gene; Acute; Address; Affect; Affinity; Animal Model; Anxiety; Arousal; Attenuated; Behavior; Behavioral Model; Binding; Binding Proteins; Biological; Biological Availability; Biological Sciences; Brain; Cessation of life; Chemicals; Clinical; Clinical Trials; Cocaine; Cocaine Abuse; Cocaine Dependence; Depressive disorder; Development; Disease; Dose; Dynorphins; Economic Burden; Emotional; FDA approved; Fentanyl; Funding; G-Protein-Coupled Receptors; Generations; Goals; Healthcare; Hepatocyte; Human; Illicit Drugs; In Vitro; Intake; Lead; Legal patent; Ligands; Medical; Mental Depression; Methamphetamine; Modality; Mood Disorders; Morbidity - disease rate; National Institute of Drug Abuse; Neuropeptides; New Agents; Non-Rodent Model; Oral; Outcome; Overdose; Performance; Permeability; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Plasma; Primates; Procedures; Process; Property; Psychological reinforcement; Public Health; Rattus; Receptor Signaling; Relapse; Reporting; Research; Rewards; Rodent; Rodent Model; Role; Safety; Self Administration; Series; Signal Pathway; Signal Transduction; Sleep; Sleep Disorders; Sleep Wake Cycle; Sleeplessness; Solubility; Stimulus; Stress; Structure; Substance Use Disorder; Substance Withdrawal Syndrome; Substance abuse problem; Therapeutic; Treatment Efficacy; addiction; attenuation; candidate selection; chemical property; circadian; clinical candidate; clinical development; cocaine use; comparative; cost; design; dopamine system; drug market; drug of abuse; drug seeking behavior; efficacy study; fentanyl abuse; global health; health economics; hypocretin; in vivo; in vivo Model; innovation; interest; kappa opioid receptors; lead optimization; methamphetamine abuse; mortality; motivated behavior; novel; novel therapeutics; opioid use disorder; orexin 1 receptor; pharmacokinetics and pharmacodynamics; physical property; pre-clinical; preclinical development; preclinical study; prescription opioid; productivity loss; psychostimulant; public health relevance; receptor; respiratory; response; risk mitigation; safety study; scaffold; scale up; small molecule; small molecule libraries; socioeconomics; stimulant abuse; substance use; substance use treatment; tool

ABSTRACT (Project Summary) Substance use disorder (SUD) characterized by the repeated use of an addictive substance leading to loss of intake control represents a serious public health and socio-economic burden with over 164 million people affected worldwide. SUD-related costs in the US surpass $750 billion USD annually, with over $272 billion of that attributed to the abuse of illicit drugs and prescription opioids. Of these, cocaine and related stimulants cause some of the most serious morbidity. More than 20% of fatal drug overdoses (2018) in the US involved cocaine, representing over 14,666 deaths. Mortality from cocaine use disorder (CUD) has tripled in the US from 2012 to 2018. Nonetheless, there are currently no approved drugs for the treatment of CUD, making it a serious global health threat and unmet medical need. Orexin neuropeptides (OX-A and OX-B) are endogenous ligands for two GPCRs, OX1R and OX2R. Their role in sleep/wake cycle and arousal has been studied, and the use of OXR antagonists for insomnia has been clinically validated with marketed drugs for sleep disorders (i.e.: Suvorexant). In addition to circadian cycle modulation, orexins also exert their effects through actions on the mesocorticolimbic dopamine (DA) system and thus are intricately involved with motivated behavior, arousal and reward-seeking, key components of addiction behavior. While both OX1R and OX2R signaling are implicated in the sleep/arousal effects, most or all the attenuation of stress-adaptive responses and addiction/reward-seeking behavior is attributed to OX1R signaling. First generation OXR antagonists (Suvorexant) are dual-acting (DORAs), inhibiting both OX1R and OX2R with similar potencies. Recently reported OX1R antagonist tool compounds tend to be modestly selective for OX1R (~50-fold) but possess poor physical properties. Designing ligands that can modulate two or more orthogonal signaling pathways simultaneously could provide a synergistic biological response in complicated disease states like stress-related mood disorders including depression, anxiety, and SUD. As such, the goal of this application is to develop a series of first-in-class, potent / highly selective OX1R antagonists (SORAs) as Dual-Targeted Ligands which also modulate other targets - that would provide an innovative treatment for CUD without the sleep-inducing liabilities seen with existing DORAs. We have already discovered, and patented potent multi-targeted preclinical small molecule leads with the following profiles: i) Highly Selective (>1000-fold) OX1R antagonists with dual mechanism of action and ii) OX1R-prefering antagonists which also modulate other targets. Thus, the 1st Specific Aim of this U01 application is to conduct in vitro pharm profiling studies of 6 selected OX1R- Dual Targeted leads including microsomal stability, solubility, Caco-2 permeability, MDR1-MDCK efflux ratio, and plasma & brain protein binding, initiate a med chem multi-parameter lead optimization campaign; select of up to 6 lead compounds that emerge with optimal overall profiles for in vivo PK/PD studies. The 2nd Specific Aim is Assess of up to 2-4 emerging compounds with optimal pharmacology and PK/PD profiles in 2 rodent behavioral models relevant for CUD/SUD. The 3rd Specific Aim is to identify up to 2 leads and a structurally distinct backup compound which meet pre-defined metrics and perform comprehensive preclinical studies including CYP Induction, Met ID, transporters Inhibition, CYP Phenotyping, PXR activation, and human hepatocyte stability, initiate non-GMP scale-ups (50 – 200 g) of up to 2 NCEs for dose range-finding studies to support rat PK/PD. The 4th Specific Aim: is to identify and select a lead with the best overall profile to be declared as a Clinical Development Candidate(s) and start all IND-enabling studies.

摘要（项目概要） 物质使用障碍（SUD），其特征是重复使用成瘾物质导致摄入量减少 控制带来了严重的公共卫生和社会经济负担，全世界有超过 1.64 亿人受到影响。 美国与 SUD 相关的成本每年超过 7500 亿美元，其中超过 2720 亿美元归因于滥用 非法药物和处方阿片类药物。其中，可卡因和相关兴奋剂导致一些最严重的 发病率。在美国，超过 20% 的致命药物过量（2018 年）涉及可卡因，导致超过 14,666 人死亡。 从 2012 年到 2018 年，美国因可卡因使用障碍 (CUD) 造成的死亡率增加了两倍。尽管如此，目前 目前还没有批准治疗 CUD 的药物，使其成为严重的全球健康威胁和未得到满足的医疗需求。食欲素 神经肽（OX-A 和 OX-B）是两种 GPCR OX1R 和 OX2R 的内源性配体。他们在睡眠/觉醒中的作用 已经研究了周期和觉醒，并且 OXR 拮抗剂治疗失眠的用途已得到临床验证 已上市的治疗睡眠障碍的药物（即：Suvorexant）。除了昼夜节律周期调节之外，食欲素还发挥作用 它们通过对中皮质边缘多巴胺（DA）系统的作用产生影响，因此与 动机行为、唤醒和寻求奖励，是成瘾行为的关键组成部分。虽然 OX1R 和 OX2R 信号传导与睡眠/唤醒效应、压力适应性反应的大部分或全部衰减以及 成瘾/寻求奖励行为归因于 OX1R 信号传导。第一代 OXR 拮抗剂 (Suvorexant) 是 双重作用 (DORA)，以相似的效力抑制 OX1R 和 OX2R。最近报道的OX1R拮抗剂工具 化合物往往对 OX1R 具有适度的选择性（约 50 倍），但物理性质较差。设计配体 可以同时调节两个或多个正交信号通路，可以提供协同的生物效应 对复杂疾病状态的反应，如与压力相关的情绪障碍，包括抑郁、焦虑和 SUD。 因此，本申请的目标是开发一系列一流的、强效/高选择性的 OX1R 拮抗剂 （SORA）作为双靶点配体，还可以调节其他靶点——这将提供创新的治疗方法 对于 CUD，没有现有 DORA 中出现的导致睡眠的问题。我们已经发现并申请了专利 具有以下特征的有效多靶点临床前小分子先导化合物： i) 高选择性（>1000 倍）OX1R 具有双重作用机制的拮抗剂和 ii) OX1R 偏好的拮抗剂，它也调节其他靶点。 因此，该 U01 申请的第一个具体目标是对 6 种选定的 OX1R-进行体外药物分析研究 双靶向先导化合物，包括微粒体稳定性、溶解度、Caco-2 渗透性、MDR1-MDCK 外排比、 以及血浆和脑蛋白结合，启动医学化学多参数先导物优化活动；选择的 多达 6 种先导化合物具有体内 PK/PD 研究的最佳总体特征。第二个具体目标 在 2 种啮齿动物行为中评估多达 2-4 种具有最佳药理学和 PK/PD 特征的新兴化合物 与 CUD/SUD 相关的模型。第三个具体目标是确定最多 2 个线索和一个结构不同的备用线索 满足预先定义的指标并进行全面的临床前研究（包括 CYP）的化合物 诱导、Met ID、转运蛋白抑制、CYP 表型分析、PXR 激活和人肝细胞稳定性， 启动最多 2 个 NCE 的非 GMP 放大（50 – 200 g），用于剂量范围探索研究，以支持大鼠 PK/PD。 第四个具体目标：确定并选择具有最佳整体概况的领导者，以宣布为临床 开发候选药物并开始所有支持 IND 的研究。