Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9 D-60438 Frankfurt a.M., Germany.
Institute of General Pharmacology and Toxicology, Pharmazentrum Frankfurt, ZAFES, Theodor-Stern-Kai 7, D-60590 Frankfurt a.M., Germany.
J Med Chem. 2020 Oct 22;63(20):11498-11521. doi: 10.1021/acs.jmedchem.0c00561. Epub 2020 Oct 12.
Inhibition of multiple enzymes of the arachidonic acid cascade leads to synergistic anti-inflammatory effects. Merging of 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH) pharmacophores led to the discovery of a dual 5-LOX/sEH inhibitor, which was subsequently optimized in terms of potency toward both targets and metabolic stability. The optimized lead structure displayed cellular activity in human polymorphonuclear leukocytes, oral bioavailability, and target engagement in vivo and demonstrated profound anti-inflammatory and anti-fibrotic efficiency in a kidney injury model caused by unilateral ureteral obstruction in mice. These results pave the way for investigating the therapeutic potential of dual 5-LOX/sEH inhibitors in other inflammation- and fibrosis-related disease models.
抑制花生四烯酸级联的多种酶可产生协同的抗炎作用。将 5-脂氧合酶（5-LOX）和可溶性环氧化物水解酶（sEH）的药效团融合，发现了一种双重 5-LOX/sEH 抑制剂，随后针对这两个靶点的活性和代谢稳定性对其进行了优化。优化后的先导结构在人多形核白细胞中具有细胞活性，口服生物利用度，并在体内与靶标结合，在单侧输尿管梗阻引起的小鼠肾脏损伤模型中表现出显著的抗炎和抗纤维化作用。这些结果为在其他炎症和纤维化相关疾病模型中研究双重 5-LOX/sEH 抑制剂的治疗潜力铺平了道路。
