Evaluation of Sodium Channel Inhibitors as Therapeutics for Chronic Muscle Disord

描述（由申请人提供）：一种天然毒素的合成修饰，gonyautoxin 2/3，使疼痛性神经肌肉疾病（如肛裂和慢性紧张性头痛）的新疗法得以发展。Gonyautoxins靶向电压门控Na+离子通道，这是一个完整的膜蛋白家族，负责沿导电细胞传递信号。gonyautoxin 2/3及其密切相关的化合物neosaxitoxin的初步人体临床试验表明，与现有的药物治疗方案相比，这些药物对肛裂、慢性紧张性头痛、术后疼痛等疾病具有优越的疗效和更少的副作用。尽管在300多名人类受试者中获得了令人信服的数据，但自然来源的有限可用性和低安全边际是两种物种临床发展的主要障碍。Site One拥有用廉价原料化学合成天然毒素类似物的技术。我们已经在核心结构周围的7个位置制备了约100种修饰化合物，并在体内模型中发现了具有提高安全性和延长作用时间的类似物，用于测量局部麻醉和肌肉收缩抑制。我们提案的总体目标是评估一小部分最有前途的化合物，并选择一种符合特定安全性和有效性标准的候选药物进行临床前开发。

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.