Developing nonmuscle II inhibitors for substance use relapse

描述(由申请人提供)：物质使用障碍(SUD)是一种慢性、复发性障碍，治疗选择有限，每年花费美国约7000亿美元。对于鸦片、尼古丁和酒精依赖，存在一些中等有效的替代疗法。然而，对于兴奋剂依赖，没有这样的选择，而且，也没有预防或甚至减少与任何药物类别相关的复发的药物疗法。在药物使用期间形成的联系通过触发寻求药物的动机而成为强大的复发因素。最近，作为记忆的关键调节因子的突触肌动蛋白细胞骨架被确定为选择性破坏这些联系的生物靶点。事实上，中枢神经系统内肌动蛋白的解聚会立即和持久地丧失与兴奋剂甲基苯丙胺相关的已建立的记忆，而不会影响其他类型的记忆。然而，β-肌动蛋白，这一与神经元可塑性有关的异构体，在全身发挥着关键功能。因此，努力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)，这是一种更有选择性地表达的分子马达，可以促进突触肌动蛋白聚合。所有直接肌动蛋白解聚的结果都用NMIIs的小分子抑制剂Blebbistatin进行了总结。重要的是，单用博尔比星治疗就足以产生似乎永久性的冰毒相关记忆丧失。除了在动物复发模型中的疗效外，Blebbistatin的几个特性使其成为药物化学的优秀支架。其中最重要的是分子的小尺寸，对肌球蛋白II的选择性，高大脑渗透率，以及从血浆和大脑中快速清除(短效作用就足够了，并减少了不必要的外周和中枢影响)。不幸的是，Blebbistatin在心肌肌球蛋白II上的活性可能是一种易感性，因为NMII抑制的治疗潜力只是在过去几年才实现的，因此优化努力一直是有限的。因此，这项建议的中心目标是开发一种安全和选择性的NMII小分子抑制剂，具有更好的效力和溶解性，并以最小的毒理学参数保留其现有的、有利的DMPK特性。为了实现开发IND Ready化合物的总体目标，将采用以博莱比星类似物为中心的广泛的药物发现和开发方法，以详细的结构和活性关系方法为中心。一支拥有多年临床前药物开发经验的团队涵盖了该项目所采用的所有方法(药物化学、生物化学、细胞生物学、神经生物学、体内药理学、药物代谢和药物动力学(DMPK)、毒理学和临床研究)，使该团队成为唯一有资格指导该计划的团队。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，这项提议预计将产生一种安全、有效的化合物，具有足够的临床前安全数据，以支持专注于SUD复发的人类临床试验。

DESCRIPTION (provided by applicant): 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.