Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
Liaoning Key Laboratory of Targeting Drugs for Hematological Malignancies, Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China.
J Med Chem. 2024 Aug 8;67(15):12887-12911. doi: 10.1021/acs.jmedchem.4c00847. Epub 2024 Jul 21.
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 and showed the best inhibitory and selectivity of sEH and HDAC6. Compound had satisfactory pharmacokinetic characteristics in rats. Following administration at 30 mg/kg, compound exhibited more effective analgesic activity than either an sEH inhibitor () or an HDAC6 inhibitor () 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.
可溶性环氧化物水解酶 (sEH) 和 HDAC6 介导炎症反应中的 NF-κB 途径，其抑制剂在治疗炎症和疼痛方面表现出强大的抗炎和镇痛作用。因此，设计并合成了一系列含有脲或脒和偕胺肟基团的双靶抑制剂，并在福尔马林诱导的小鼠模型和二甲苯诱导的小鼠耳肿胀模型中评估了其作为新型 sEH/HDAC6 双靶抑制剂在炎症性疼痛中的作用。其中，化合物 和 对 sEH 和 HDAC6 表现出最好的抑制作用和选择性。化合物 在大鼠中具有令人满意的药代动力学特征。在 30mg/kg 给药后，化合物 的镇痛活性明显优于单独使用 sEH 抑制剂 () 或 HDAC6 抑制剂 ()，且与两种抑制剂联合使用的效果更好。因此，这些新型 sEH/HDAC6 双靶抑制剂在伤害性行为中表现出强大的镇痛活性，值得进一步开发。
