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.

项目概要 药物滥用障碍 (SUD) 是一种治疗选择有限的慢性复发性疾病，费用约为 700 美元 每年亿。对于阿片类药物、尼古丁和酒精，存在一些中等有效的替代疗法 依赖性。然而，对于兴奋剂依赖，不存在这样的选择，而且，也没有药物- 预防甚至减少与任何药物类别相关的复发的疗法。已成立的协会 吸毒期间通过触发寻求药物的动机，成为强大的复发因素。最近， 突触肌动蛋白细胞骨架是记忆的关键调节因子，被确定为 选择性破坏这些关联。事实上，中枢神经系统内肌动蛋白解聚会立即产生 与兴奋剂甲基苯丙胺（METH）相关的已建立的记忆持续丧失，而没有 影响其他类型的记忆。然而，β-肌动蛋白（与神经元可塑性有关的亚型）发挥着关键作用 作用遍及全身。因此，人们的努力转向了肌动蛋白细胞骨架的上游调节剂， 非肌肉肌球蛋白 II (NMII)，一种更具选择性表达的分子马达，可促进突触肌动蛋白 聚合。直接肌动蛋白解聚的所有结果均已用布雷他汀（一种小分子）重现。 NMII 分子抑制剂。重要的是，单次使用布雷他汀治疗就足以产生 与冰毒相关的记忆似乎永久丧失。除了对动物复发具有功效外 模型、多种特性使布雷他汀成为药物化学的优秀支架。其中最重要的是 这些是分子尺寸小、对肌球蛋白 II 的选择性、高脑渗透性以及快速清除 血浆和大脑（短效就足够了，可以减少不必要的外周和中枢影响）。很遗憾， 布雷他汀对心肌肌球蛋白 II 的活性可能是一种不利因素。优化努力有限 因为 NMII 抑制的治疗潜力直到最近几年才被认识到。因此， 该提案的中心目标是开发一种安全、选择性的 NMII 小分子抑制剂，并具有改进的 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。实现开发 IND 就绪化合物（一种广泛的药物）的总体目标 将采用以布雷他汀类似物为中心的药物发现和开发方法，以 详细的结构活动关系方法。集结了多年临床前药物研发团队 涵盖该项目中使用的所有方法的开发经验（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），使该团队具有独特的资格来指导 程序。通过利用佛罗里达州斯克里普斯独特的治疗发现和开发能力， 该提案预计将产生一种安全、有效的化合物，并有足够的临床前安全数据来支持 人体临床试验的重点是 SUD 复发。