Soluble epoxide hydrolase (sEH) is related to arachidonic acid cascade and is over-expressed in a variety of diseases, making sEH an attractive target for the treatment of pain as well as inflammatory-related diseases. A new series of memantyl urea derivatives as potent sEH inhibitors was obtained using our previous reported compound 4 as lead compound. A preferential modification of piperidinyl to 3-carbamoyl piperidinyl was identified for this series via structure-based rational drug design. Compound A20 exhibited moderate percentage plasma protein binding (88.6%) and better metabolic stability in vitro. After oral administration, the bioavailability of A20 was 28.6%. Acute toxicity test showed that A20 was well tolerated and there was no adverse event encountered at dose of 6.0 g/kg. Inhibitor A20 also displayed robust analgesic effect in vivo and dose-dependently attenuated neuropathic pain in rat model induced by spared nerve injury, which was better than gabapentin and sEH inhibitor (±)-EC-5026. In one word, the oral administration of A20 significantly alleviated pain and improved the health status of the rats, demonstrating that A20 was a promising candidate to be further evaluated for the treatment of neuropathic pain.

可溶性环氧化物水解酶 (sEH) 与花生四烯酸级联相关，并在多种疾病中过度表达，这使得 sEH 成为治疗疼痛以及炎症相关疾病的有吸引力的靶点。使用我们之前报道的化合物4作为先导化合物，获得了一系列新的美金刚脲衍生物作为有效的 sEH 抑制剂。通过基于结构的合理药物设计，确定了该系列中哌啶基优先修饰为 3-氨基甲酰基哌啶基。化合物A20表现出中等百分比的血浆蛋白结合（88.6%）和更好的体外代谢稳定性。口服后，A20的生物利用度为28.6%。急性毒性试验显示A20耐受性良好，在6.0 g/kg剂量下未出现不良事件。抑制剂A20在体内也表现出强大的镇痛作用，并且在神经损伤引起的大鼠模型中呈剂量依赖性减轻神经病理性疼痛，优于加巴喷丁和 sEH 抑制剂 (±)-EC-5026。总之，口服A20显着缓解疼痛并改善大鼠的健康状况，表明A20是一种有希望的候选药物，有待进一步评估用于治疗神经性疼痛。