Soluble epoxide hydrolase (sEH) and HDAC6 mediate the NF-κB pathway in inflammatory responses, and their inhibitors exhibit powerful anti-inflammatory and analgesic activities in treating both inflammation and pain. Therefore, a series of dual-targeting inhibitors containing urea or squaramide and hydroxamic acid moieties were designed and synthesized, and their role as a new sEH/HDAC6 dual-targeting inhibitor in inflammatory pain was evaluated in a formalin-induced mice model and a xylene-induced mouse ear swelling model. Among them, compounds 28g and 28j showed the best inhibitory and selectivity of sEH and HDAC6. Compound 28g had satisfactory pharmacokinetic characteristics in rats. Following administration at 30 mg/kg, compound 28g exhibited more effective analgesic activity than either an sEH inhibitor (GL-B437) or an HDAC6 inhibitor (Rocilinostat) alone and coadministration of both inhibitors. Thus, these novel sEH/HDAC6 dual-targeting inhibitors exhibited powerful analgesic activity in nociceptive behavior and are worthy of further development.

中文翻译：

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用于治疗炎性疼痛的 sEH/HDAC6 双靶向抑制剂的设计与合成


可溶性环氧化物水解酶 (sEH) 和 HDAC6 介导炎症反应中的 NF-κB 通路，它们的抑制剂在治疗炎症和疼痛方面表现出强大的抗炎和镇痛活性。因此，设计并合成了一系列含有尿素或方酰胺和异羟肟酸部分的双靶向抑制剂，并在福尔马林诱导的小鼠模型和二甲苯中评估了它们作为新型sEH/HDAC6双靶向抑制剂在炎性疼痛中的作用。诱导的小鼠耳肿胀模型。其中，化合物28g和28j对sEH和HDAC6表现出最好的抑制性和选择性。化合物28g在大鼠中具有令人满意的药代动力学特征。以30 mg/kg给药后，化合物28g表现出比单独的sEH抑制剂(GL-B437)或HDAC6抑制剂(罗西林司他)以及两种抑制剂的共同给药更有效的镇痛活性。因此，这些新型 sEH/HDAC6 双靶向抑制剂在伤害感受行为中表现出强大的镇痛活性，值得进一步开发。