Pharmacological profile and efficiency in vivo of diflapolin, the first dual inhibitor of 5-lipoxygenase-activating protein and soluble epoxide hydrolase.
Pharmacological profile and efficiency in vivo of diflapolin, the first dual inhibitor of 5-lipoxygenase-activating protein and soluble epoxide hydrolase.
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Diflapolin的药理特征和效率，Difivo（5-脂氧合酶活性蛋白和可溶性环氧水解酶的第一个双重抑制剂）。
DOI：
10.1038/s41598-017-09795-w
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发表时间：
2017-08-24
影响因子：
4.6
通讯作者：
Werz O
中科院分区：
文献类型：
--
作者：
Garscha U;Romp E;Pace S;Rossi A;Temml V;Schuster D;König S;Gerstmeier J;Liening S;Werner M;Atze H;Wittmann S;Weinigel C;Rummler S;Scriba GK;Sautebin L;Werz O
花生四烯酸（AA）被代谢为多种生物活性脂质介质。5-脂氧合酶激活蛋白（FLAP）促进AA通过5-脂氧合酶（5-LOX）转化为促炎性白三烯（LT），而可溶性环氧化物水解酶（sEH）降解抗炎性环氧二十碳三烯酸（Epoxyeicosatrienoic Acids，ESTs）。因此，双重FLAP/sEH抑制可能是用于干预炎症的有利药物。我们介绍了双重靶向FLAP和sEH的N-[4-（苯并噻唑-2-基甲氧基）-2-甲基苯基]-N′-（3，4-二氯苯基）脲（diflapolin）的体内药理学特征和功效。Diflapolin抑制完整人单核细胞和中性粒细胞中5-LOX产物的形成，IC 50分别为30和170 nM，并抑制分离的sEH的活性（IC 50 = 20 nM）。作为FLAP抑制剂的特征，diflapolin（I）不能抑制分离的5-LOX，（II）仅当5-LOX/FLAP共表达时才阻断HEK细胞中5-LOX产物的形成，（III）当提供外源AA时在完整细胞中失去效力，以及（IV）阻止白细胞中5-LOX/FLAP复合物的组装。Diflapolin显示出靶特异性，因为与AA代谢相关的其他酶（即，COX 1/2、12/15-LOX、LTA 4 H、LTC 4S、mPGES 1和cPLA 2）未受到抑制。在酵母多糖诱导的小鼠腹膜炎模型中，diflapolin损害血管通透性，抑制半胱氨酰-LT和LTB 4形成，并抑制中性粒细胞浸润。Diflapolin是一种高活性的FLAP/sEH双重抑制剂，在体外和体内具有靶向特异性，可治疗炎症相关疾病。
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.
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影响因子：
4.4
作者：
Claveau, D;Sirinyan, M;Mancini, JA
通讯作者：
Mancini, JA
影响因子：
5.8
作者：
Garscha, Ulrike;Voelker, Susanna;Werz, Oliver
通讯作者：
Werz, Oliver
影响因子：
4.8
作者：
Gerstmeier, Jana;Weinigel, Christina;Garscha, Ulrike
通讯作者：
Garscha, Ulrike
影响因子：
2.1
作者：
GILLARD, J;FORDHUTCHINSON, AW;PACHOLOK, S
通讯作者：
PACHOLOK, S
影响因子：
--
作者：
Klingler, Franca-Maria;Wolf, Markus;Proschak, Ewgenij
通讯作者：
Proschak, Ewgenij