Dysfunction of voltage-gated sodium channel Nav1.2 causes various epileptic disorders, and inhibition of the channel has emerged as an attractive therapeutic strategy. However, currently available Nav1.2 inhibitors exhibit low potency and limited structural diversity. In this study, a novel series of pyrimidine-based derivatives with Nav1.2 inhibitory activity were designed, synthesized, and evaluated. Compounds 14 and 35 exhibited potent activity against Nav1.2, boasting IC₅₀ values of 120 and 65 nM, respectively. Compound 14 displayed favorable pharmacokinetics (F = 43%) following intraperitoneal injection and excellent brain penetration potency (B/P = 3.6). Compounds 14 and 35 exhibited robust antiepileptic activities in the maximal electroshock test, with ED₅₀ values of 3.2 and 11.1 mg/kg, respectively. Compound 35 also demonstrated potent antiepileptic activity in a 6 Hz (32 mA) model, with an ED₅₀ value of 18.5 mg/kg. Overall, compounds 14 and 35 are promising leads for the development of new small-molecule therapeutics for epilepsy.

中文翻译：

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发现新型嘧啶衍生物作为 Nav1.2 抑制剂，对小鼠癫痫模型有效


电压门控钠通道 Nav1.2 的功能障碍会导致各种癫痫疾病，抑制该通道已成为一种有吸引力的治疗策略。然而，目前可用的 Nav1.2 抑制剂效力较低且结构多样性有限。在本研究中，设计、合成并评估了一系列具有 Nav1.2 抑制活性的新型嘧啶衍生物。化合物 14 和 35 对 Nav1.2 表现出有效的活性，IC ₅₀ 值分别为 120 和 65 nM。化合物14在腹腔注射后表现出良好的药代动力学(F = 43%)和优异的脑渗透效力(B/P = 3.6)。化合物14和35在最大电击试验中表现出强大的抗癫痫活性，ED ₅₀ 值分别为3.2和11.1 mg/kg。化合物 35 在 6 Hz (32 mA) 模型中也表现出有效的抗癫痫活性，ED ₅₀ 值为 18.5 mg/kg。总体而言，化合物 14 和 35 是开发新型癫痫小分子疗法的有希望的先导药物。