Multitarget anti-inflammatory drugs interfering with the arachidonic acid cascade exhibit superior efficacy. In this study, a prototype dual inhibitor of soluble epoxide hydrolase (sEH) and LTA₄ hydrolase (LTA₄H) with submicromolar activity toward both targets has been designed and synthesized. Preliminary structure–activity relationship studies were performed to identify optimal substitution patterns. X-ray structure analysis of a promising dual inhibitor in complex with sEH, as well as molecular docking with LTA₄H provided a rationale for further optimization. Hereby, scaffold extension was successfully applied to yield potent dual sEH/LTA₄H inhibitors. The spectrum of pro- and anti-inflammatory lipid mediators was evaluated in M1 and M2 macrophages, stimulated with LPS, and incubated with the most promising compound 14. The effect of 14 on the inflammatory lipid mediator profile characterizes dual sEH/LTA₄H inhibitors as an interesting option for future anti-inflammatory agent investigations.

中文翻译：

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可溶性环氧水解酶和LTA ₄水解酶双重抑制剂的设计

干扰花生四烯酸级联反应的多靶点抗炎药显示出优异的功效。在这项研究中，设计并合成了对两个目标都具有亚微摩尔活性的可溶性环氧化物水解酶（sEH）和LTA ₄水解酶（LTA ₄ H）的双重抑制剂原型。进行了初步的结构-活性关系研究，以确定最佳的取代方式。与sEH结合的有前景的双重抑制剂的X射线结构分析，以及与LTA ₄ H的分子对接为进一步优化提供了理论依据。从而，支架扩展成功地应用于产生有效的双重sEH / LTA ₄H抑制剂。在M1和M2巨噬细胞中评估促炎和抗炎脂质介体的光谱，用LPS刺激，并与最有希望的化合物14孵育。效果14对炎症脂质介质简档表征的双的sEH / LTA ₄ H抑制剂作为未来抗炎剂调查一个有趣的选择。