Evaluation of Sodium Channel Inhibitors as Therapeutics for Chronic Muscle Disord

描述（由申请人提供）：天然毒素gonyautoxin 2/3的合成修饰使得能够开发用于疼痛性神经肌肉疾病（如肛裂和慢性紧张型头痛）的新疗法。膝关节藻毒素靶向电压门控Na+离子通道，这是一个负责沿着导电细胞传递信号的完整膜蛋白家族。用gonyautoxin 2/3和一种密切相关的化合物新蛤蚌毒素进行的初步人体临床试验表明，这些物种对肛裂、慢性紧张型头痛、术后疼痛和其他医疗状况的疗效优于现有的药物治疗选择，副作用更少。尽管在>300名人类受试者中获得了令人信服的数据，但天然来源的有限可用性和低安全边际是两个物种临床开发的主要障碍。一号站点拥有利用廉价原料通过化学合成制备天然毒素类似物的技术。我们已经在核心结构周围的七个位置制备了约100种修饰的化合物，并且已经鉴定了在测量局部麻醉和肌肉收缩抑制的体内模型中显示出改善的安全范围和延长的作用持续时间的类似物。我们提案的总体目标是评估我们最有前途的化合物的一小部分，并选择符合特定安全性和有效性标准的单一候选药物，以推进临床前开发。

DESCRIPTION (provided by applicant): Synthetic modification of a natural toxin, gonyautoxin 2/3, is enabling the development of new therapies for painful neuromuscular disorders, such as anal fissure and chronic tension-type headache. Gonyautoxins target voltage-gated Na+ ion channels, a family of integral membrane proteins responsible for the transmission of signals along electrically conducting cells. Preliminary human clinical trials conducted with gonyautoxin 2/3 and a closely related compound, neosaxitoxin, indicate that these species have superior efficacy and fewer side effects than existing pharmacological treatment options for anal fissure, chronic tension-type headache, postoperative pain, and other medical conditions. Despite compelling data in >300 human subjects, limited availability from natural sources and a low margin of safety are major obstacles to the clinical development of either species. Site One has technology in place to prepare analogues of the natural toxins by chemical synthesis from inexpensive starting materials. We have prepared ~100 modified compounds at seven position around the core structure, and have identified analogues showing an improved margin of safety and extended duration of action in in vivo models measuring local anesthesia and inhibition of muscle contraction. The overarching aim of our proposal is to evaluate a small collection of our most promising compounds, and to select a single drug candidate meeting specific safety and efficacy criteria for advancement to pre-clinical development.