Arachidonic acid (AA) is metabolized to diverse bioactive lipid mediators. Whereas the 5-lipoxygenase-activating protein (FLAP) facilitates AA conversion by 5-lipoxygenase (5-LOX) to pro-inflammatory leukotrienes (LTs), the soluble epoxide hydrolase (sEH) degrades anti-inflammatory epoxyeicosatrienoic acids (EETs). Accordingly, dual FLAP/sEH inhibition might be advantageous drugs for intervention of inflammation. We present the in vivo pharmacological profile and efficiency of N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N'-(3,4-dichlorophenyl)urea (diflapolin) that dually targets FLAP and sEH. Diflapolin inhibited 5-LOX product formation in intact human monocytes and neutrophils with IC₅₀ = 30 and 170 nM, respectively, and suppressed the activity of isolated sEH (IC₅₀ = 20 nM). Characteristic for FLAP inhibitors, diflapolin (I) failed to inhibit isolated 5-LOX, (II) blocked 5-LOX product formation in HEK cells only when 5-LOX/FLAP was co-expressed, (III) lost potency in intact cells when exogenous AA was supplied, and (IV) prevented 5-LOX/FLAP complex assembly in leukocytes. Diflapolin showed target specificity, as other enzymes related to AA metabolism (i.e., COX1/2, 12/15-LOX, LTA₄H, LTC₄S, mPGES₁, and cPLA₂) were not inhibited. In the zymosan-induced mouse peritonitis model, diflapolin impaired vascular permeability, inhibited cysteinyl-LTs and LTB₄ formation, and suppressed neutrophil infiltration. Diflapolin is a highly active dual FLAP/sEH inhibitor in vitro and in vivo with target specificity to treat inflammation-related diseases.

中文翻译：

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Diflapolin（5-脂氧合酶激活蛋白和可溶性环氧化物水解酶的第一个双重抑制剂）的体内药理特性和效率。

花生四烯酸（AA）被代谢为多种生物活性脂质介体。5-脂氧合酶激活蛋白（FLAP）促进5-脂氧合酶（5-LOX）将AA转化为促炎性白三烯（LTs），而可溶性环氧化物水解酶（sEH）则可降解抗炎性环氧二十碳三烯酸（EET）。因此，双重FLAP / sEH抑制可能是用于炎症干预的有利药物。我们目前的体内药理学概况和N- [4-（苯并噻唑-2-基甲氧基）-2-甲基苯基] -N'-（3,4-二氯苯基）脲（地夫拉普林）的双重功效是双重靶向FLAP和sEH。Diflapolin 分别通过IC ₅₀ = 30和170 nM抑制完整人类单核细胞和嗜中性粒细胞中5-LOX产物的形成，并抑制了分离的sEH的活性（IC ₅₀ = 20 nM）。对于FLAP抑制剂，双黄素（I）不能抑制分离的5-LOX，（II）仅在5-LOX / FLAP共表达时才阻止HEK细胞中5-LOX产物的形成，（III）当完整细胞中的能力丧失时提供了外源AA，（IV）阻止了白细胞中5-LOX / FLAP复合物的组装。由于未抑制与AA代谢相关的其他酶（例如，COX1 / 2、12 / 15-LOX，LTA ₄ H，LTC ₄ S，mPGES ₁和cPLA ₂），地黄精显示了靶标特异性。在酵母聚糖诱导的小鼠腹膜炎模型中，双黄素破坏了血管通透性，抑制了半胱氨酸-LTs和LTB ₄形成，并抑制中性粒细胞浸润。Diflapolin是一种高活性的双重FLAP / sEH抑制剂，在体外和体内均具有治疗炎症相关疾病的靶标特异性。