Developing nonmuscle II inhibitors for substance use relapse

开发非肌肉 II 抑制剂治疗药物滥用复发

• 批准号: 9926588
• 负责人: Patrick Robert Griffin
• 金额: $ 18.03万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926588
• 关键词: ATP phosphohydrolase; Actins; Affect; Alcohol dependence; Alcohol or Other Drugs use; Amygdaloid structure; Animals; Area; Biochemical; Biochemistry; Biological; Biological Assay; Brain; Cardiac Myosins; Cell division; Cells; Cellular biology; Chronic; Clinical; Clinical Research; Clinical Trials; Cytokinesis; Cytoskeleton; Data; Development; Disease; Dose; Drug Kinetics; Drug usage; Emotional; Ethers; Florida; Goals; Guidelines; Health; Heart; Human; Investigational Drugs; Ion Channel; Lead; Long-Term Potentiation; Malignant neoplasm of brain; Memory; Metabolism; Methamphetamine; Methodology; Modeling; Molecular Motors; Motivation; Myosin ATPase; Myosin Type II; Neurobiology; Neuronal Plasticity; Nicotine Dependence; No-Observed-Adverse-Effect Level; Opiate Addiction; Penetrance; Penetration; Peripheral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Phase; Phosphotransferases; Plasma; Preclinical Drug Development; Process; Property; Protein Isoforms; Psychostimulant dependence; Rattus; Relapse; Replacement Therapy; Research; Rodent; Safety; Series; Solubility; Structure-Activity Relationship; Substance Use Disorder; Synapses; Therapeutic; Toxicology; Treatment Efficacy; United States Food and Drug Administration; analog; base; beta Actin; blebbistatin; cost; counterscreen; depolymerization; design; drug development; drug discovery; drug metabolism; drug seeking behavior; expectation; experience; genotoxicity; good laboratory practice; heart function; improved; in vivo; inhibitor/antagonist; non-drug; non-muscle myosin; novel therapeutics; polymerization; preclinical development; preclinical safety; prevent; programs; promoter; receptor; scaffold; selective expression; single molecule; small molecule; small molecule inhibitor; spinal cord and brain injury; stimulant abuse; success; therapeutic target

PROJECT SUMMARY Substance use disorder (SUD), a chronic, relapsing disorder with limited treatment options, costs the US ~$700 billion annually. A few, moderately effective replacement therapies exist for opiate, nicotine and alcohol dependence. However, no such options exist for stimulant dependence and, further, there are no pharmaco- therapies to prevent or even reduce relapse associated with any drug class. Associations that have formed during periods of drug use serve as powerful relapse factors by triggering motivation to seek the drug. Recently, the synaptic actin cytoskeleton, a critical regulator of memory, was identified as a biological target for the selective disruption of these associations. Indeed, intra-CNS actin depolymerization produces an immediate and persistent loss of well-established memories associated with the stimulant methamphetamine (METH), without affecting other types of memories. However, β-actin, the isoform implicated in neuronal plasticity, serves critical functions throughout the body. Therefore, efforts turned to an upstream regulator of the actin cytoskeleton, nonmuscle myosin II (NMII), a more selectively expressed molecular motor that promotes synaptic actin polymerization. All results with direct actin depolymerization have been recapitulated with Blebbistatin, a small molecule inhibitor of NMIIs. Importantly, a single treatment with Blebbistatin is sufficient to produce a seemingly permanent loss of METH-associated memories. In addition to its efficacy in animal relapse models, several properties make Blebbistatin an excellent scaffold for medicinal chemistry. Paramount among these are the molecule’s small size, selectivity for myosin IIs, high brain penetration, and rapid clearance from plasma and brain (short-acting is sufficient and reduces unwanted peripheral and central effects). Unfortunately, Blebbistatin’s activity at cardiac muscle myosin IIs is likely a liability. Optimization efforts have been limited because the therapeutic potentials of NMII inhibition have only been realized in the past few years. Thus, the central goal of this proposal is to develop a safe and selective NMII small molecule inhibitor with improved potency and solubility, that retains its existing, advantageous DMPK properties with minimized toxicological parameters. To accomplish the overall goal of developing an IND ready compound, an extensive pharmaceutical approach to drug discovery and development centered on Blebbistatin analogs will be employed, centered on a detailed structure activity relationship approach. A team has been assembled with many years of preclinical drug development experience that encompasses all of the methodologies employed in this project (medicinal chemistry, biochemistry, cell biology, neurobiology, in vivo pharmacology, drug metabolism and pharmacokinetics (DMPK), toxicology, and clinical research), making this team uniquely qualified to direct the program. By capitalizing on the unique therapeutic discovery and development capabilities at Scripps Florida, this proposal is expected to yield a safe, efficacious compound with sufficient preclinical safety data to support human clinical trials focused on SUD relapse.

项目摘要 物质使用障碍（SUD）是一种慢性复发性疾病，治疗选择有限，花费约700美元 每年十亿。目前存在一些对阿片类药物、尼古丁和酒精有一定疗效的替代疗法 依赖然而，没有这样的选择存在兴奋剂依赖，而且，没有药理学- 预防或甚至减少与任何药物类别相关的复发。已经形成的协会 吸毒期间的吸毒行为是诱发吸毒动机的强有力的复吸因素。最近， 突触肌动蛋白细胞骨架是记忆的关键调节器，被确定为神经元的生物学靶点。 有选择地破坏这些联系。事实上，中枢神经系统内肌动蛋白解聚产生了一个立即和 持续丧失与兴奋剂甲基苯丙胺（METH）相关的良好记忆， 影响其他类型的记忆。然而，β-肌动蛋白，涉及神经元可塑性的同种型， 在整个身体中发挥作用。因此，研究人员将目光转向了肌动蛋白细胞骨架的上游调节因子， 非肌肉肌球蛋白II（NMII），一种更有选择性表达的分子马达，促进突触肌动蛋白 聚合法所有直接肌动蛋白解聚的结果都被Blebbistatin所概括，Blebistatin是一种小分子的肌动蛋白。 NMIIs的分子抑制剂。重要的是，用Blebbistatin的单次治疗足以产生一种治疗效果。 似乎永久丧失了与冰毒有关的记忆除了对动物复发的疗效外， 模型，几个属性使Blebbistatin药物化学的一个很好的支架。最重要的是 这些是分子的小尺寸，对肌球蛋白II的选择性，高脑渗透性和快速清除。 血浆和大脑（短效是足够的，并减少不必要的外周和中枢效应）。不幸的是， Blebbistatin对心肌肌球蛋白II的活性可能是一种负担。优化工作受到限制 因为NMII抑制的治疗潜力仅在过去几年中才被认识到。因此 该建议的中心目标是开发一种安全和选择性的匪II小分子抑制剂， 效力和溶解度，保留其现有的、有利的DMPK特性，同时将毒理学降至最低 参数为了实现开发IND准备化合物的总体目标， 将采用以Blebbistatin类似物为中心的药物发现和开发方法， 详细的结构活性关系方法。一个团队已经组建了多年的临床前药物 开发经验，包括本项目中采用的所有方法（医学 化学、生物化学、细胞生物学、神经生物学、体内药理学、药物代谢和 药代动力学（DMPK），毒理学和临床研究），使这个团队唯一有资格指导 程序.通过利用斯克里普斯佛罗里达独特的治疗发现和开发能力， 该方案有望产生一种安全、有效的化合物，具有足够的临床前安全性数据， 人类临床试验集中于SUD复发。