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（项目摘要） 物质使用障碍（SUD），以重复使用成瘾物质导致摄入量减少为特征 控制是一个严重的公共卫生和社会经济负担，全世界有1.64亿多人受到影响。 美国每年与SUD相关的成本超过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，代表超过14，666人死亡。 从2012年到2018年，美国可卡因使用障碍（CUD）的死亡率增加了两倍。尽管如此，目前 没有批准的药物用于治疗CUD，使其成为严重的全球健康威胁和未满足的医疗需求。食欲素 神经肽（OX-A和OX-B）是两种GPCR（OX 1 R和OX 2 R）的内源性配体。在睡眠/觉醒中的作用 已经研究了睡眠周期和觉醒，并且使用OXR拮抗剂治疗失眠已经在临床上得到验证， 用于治疗睡眠障碍的上市药物（即：苏沃雷生）。除了昼夜节律周期调节外，食欲素还发挥作用 它们通过对中皮质边缘多巴胺（DA）系统的作用而发挥作用，因此与 动机性行为，唤醒和奖励寻求，成瘾行为的关键组成部分。虽然OX 1 R和OX 2 R 信号传导与睡眠/觉醒效应有关，大多数或所有压力适应性反应的衰减， 成瘾/奖励寻求行为归因于OX 1 R信号传导。第一代OXR拮抗剂（苏沃雷生）是 双作用（DORA），以相似的效力抑制OX 1 R和OX 2 R。最近报道的OX 1 R拮抗剂工具 这些化合物倾向于对OX 1 R具有适度的选择性（~50倍），但具有较差的物理性质。设计配体 可以同时调节两个或多个正交信号传导途径， 在复杂的疾病状态，如压力相关的情绪障碍，包括抑郁症，焦虑症和SUD的反应。 因此，本申请的目标是开发一系列一流的、有效/高选择性的OX 1 R拮抗剂 （SORA）作为双靶向配体，也可以调节其他靶点-这将提供一种创新的治疗方法 对于CUD，没有现有DORA所见的睡眠诱导责任。我们已经发现并申请了专利 具有以下特征的有效多靶向临床前小分子先导物：i）高选择性（>1000倍）OX 1 R 具有双重作用机制的拮抗剂和ii）也调节其它靶点的OX 1 R-优选拮抗剂。 因此，该U 01申请的第一个具体目的是对6种选定的OX 1 R-1进行体外药物谱研究。 双靶向电极导线，包括微粒体稳定性、溶解度、Caco-2渗透性、MDR 1-MDCK外排率， 和血浆和脑蛋白结合，启动医学化学多参数铅优化活动;选择 最多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种啮齿动物行为模型中评估了多达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。第三个具体目标是识别最多2个电极导线和一个结构上不同的备份 满足预定义指标并进行全面临床前研究的化合物，包括 诱导、Met ID、转运蛋白抑制、CYP表型分析、PXR活化和人肝细胞稳定性， 启动最多2个NCE的非GMP规模扩大（50 - 200 g），用于剂量范围探索研究，以支持大鼠PK/PD。 第4个具体目标：识别并选择具有最佳总体特征的电极导线，宣布为临床 开发候选人，并开始所有IND使能研究。