5-脂氧合酶和可溶性环氧化物水解酶双重抑制剂的设计、合成及细胞特性研究

Design, Synthesis and Cellular Characterization of a Dual Inhibitor of 5-Lipoxygenase and Soluble Epoxide Hydrolase.

作者信息

Meirer Karin, Glatzel Daniel, Kretschmer Simon, Wittmann Sandra K, Hartmann Markus, Blöcher René, Angioni Carlo, Geisslinger Gerd, Steinhilber Dieter, Hofmann Bettina, Fürst Robert, Proschak Ewgenij

机构信息

Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, Germany.

Institute of Pharmaceutical Biology, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60438 Frankfurt am Main, Germany.

出版信息

Molecules. 2016 Dec 29;22(1):45. doi: 10.3390/molecules22010045.

The arachidonic acid cascade is a key player in inflammation, and numerous well-established drugs interfere with this pathway. Previous studies have suggested that simultaneous inhibition of 5-lipoxygenase (5-LO) and soluble epoxide hydrolase (sEH) results in synergistic anti-inflammatory effects. In this study, a novel prototype of a dual 5-LO/sEH inhibitor was rationally designed and synthesized. was evaluated in enzyme activity assays with recombinant enzymes. Furthermore, activity of in human whole blood and endothelial cells was investigated. potently inhibited both enzymes in vitro and attenuated the formation of leukotrienes in human whole blood. was also tested in a cell function-based assay. The compound significantly inhibited the LPS-induced adhesion of leukocytes to endothelial cells by blocking leukocyte activation.

花生四烯酸级联反应在炎症中起关键作用，许多已被广泛认可的药物会干扰这一途径。先前的研究表明，同时抑制5-脂氧合酶（5-LO）和可溶性环氧化物水解酶（sEH）会产生协同抗炎作用。在本研究中，合理设计并合成了一种新型的双5-LO/sEH抑制剂原型。通过重组酶进行酶活性测定对其进行了评估。此外，还研究了其在人全血和内皮细胞中的活性。该抑制剂在体外能有效抑制这两种酶，并减弱人全血中白三烯的形成。还在基于细胞功能的试验中对该化合物进行了测试。该化合物通过阻断白细胞活化，显著抑制了脂多糖诱导的白细胞与内皮细胞的黏附。