Diflapolin
(Synonyms: 双黄素) 目录号 : GC43453
A dual FLAP/sEH inhibitor
Cas No.:724453-98-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Diflapolin is a dual inhibitor of 5-lipoxygenase-activating protein (FLAP) and soluble epoxide hydrolase (sEH). It inhibits formation of the 5-lipoxygenase (5-LO) products leukotriene B4 and 5-HpETE in isolated human monocytes and neutrophils (IC50s = 30 and 170 nM, respectively) and inhibits the epoxide hydrolase activity of sEH with an IC50 value of 20 nM in a cell-free assay. It is selective for FLAP and sEH over other arachidonic acid metabolism enzymes, including 5-LO, LTC4 synthase, mPGES-1, COX-1, or COX-2 in cell-free assays, as well as 12- and 15-LO in neutrophils. Diflapolin (1, 3, and 10 mg/kg) decreases inflammation in a mouse model of peritonitis induced by zymosan, reducing the production of LTB4 and LTC4 and inhibiting leukocyte recruitment.
| Cas No. | 724453-98-9 | SDF | |
| 别名 | 双黄素 | ||
| Canonical SMILES | CC1=C(NC(NC2=CC(Cl)=C(Cl)C=C2)=O)C=CC(OCC3=NC4=C(C=CC=C4)S3)=C1 | ||
| 分子式 | C22H17Cl2N3O2S | 分子量 | 458.4 |
| 溶解度 | DMF: 2.5mg/mL,DMSO: 1.6mg/mL | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1815 mL | 10.9075 mL | 21.815 mL |
| 5 mM | 0.4363 mL | 2.1815 mL | 4.363 mL |
| 10 mM | 0.2182 mL | 1.0908 mL | 2.1815 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Synthesis and structure-activity relationships for some novel Diflapolin derivatives with benzimidazole subunit
J Enzyme Inhib Med Chem 2022 Dec;37(1):1752-1764.PMID:36124840DOI:10.1080/14756366.2022.2087645.
A series of derivatives of the potent dual soluble epoxide hydrolase (sEH)/5-lipoxygenase-activating protein (FLAP) inhibitor Diflapolin was designed, synthesised, and characterised. These novel compounds, which contain a benzimidazole subunit were evaluated for their inhibitory activity against sEH and FLAP. Molecular modelling tools were applied to analyse structure-activity relationships (SAR) on both targets and to predict solubility and gastrointestinal (GI) absorption. The most promising dual inhibitors of these series are 5a, 6b, and 6c.
Encapsulation of the Anti-inflammatory Dual FLAP/sEH Inhibitor Diflapolin Improves the Efficiency in Human Whole Blood
J Pharm Sci 2022 Jun;111(6):1843-1850.PMID:34756868DOI:10.1016/j.xphs.2021.10.030.
Diflapolin is a dual FLAP/sEH inhibitor with potent anti-inflammatory efficiency in cellular assays and experimental in vivo studies. Despite these outstanding characteristics, its high lipophilicity and plasma protein binding hamper the bioactivity in blood. To overcome these limitations, Diflapolin was encapsulated in poly(lactic-co-glycolic acid) nanoparticles to develop an efficient and biocompatible drug delivery system. Two different cosolvent approaches were tested showing the possibility to exchange dimethyl sulfoxide in the organic phase by the sustainable 400 g/mol poly(ethylene glycol). A particle size of 220 nm and the amorphous encapsulation of Diflapolin in high amounts rendered the nanoparticles appropriate for the intended application. Excellent biocompatibility of the nanoparticles was demonstrated in an ex ovo hen's egg model. The potent suppression of FLAP-dependent 5-lipoxygenase product formation by the nanoparticles in human whole blood, superior to the free drug, makes them to a promising drug delivery system to improve the bioactivity of Diflapolin.
Synthesis, Biological Evaluation and Structure-Activity Relationships of Diflapolin Analogues as Dual sEH/FLAP Inhibitors
ACS Med Chem Lett 2018 Nov 29;10(1):62-66.PMID:30655948DOI:10.1021/acsmedchemlett.8b00415.
A series of derivatives of the potent dual soluble epoxide hydrolase (sEH)/5-lipoxygenase-activating protein (FLAP) inhibitor Diflapolin was designed, synthesized, and characterized by 1H NMR, 13C NMR, and elemental analysis. These novel compounds were biologically evaluated for their inhibitory activity against sEH and FLAP. Molecular modeling tools were applied to analyze structure-activity relationships (SAR) on both targets. Results show that even small modifications on the lead compound Diflapolin markedly influence the inhibitory potential, especially on FLAP, suggesting very narrow SAR.
Pharmacological profile and efficiency in vivo of Diflapolin, the first dual inhibitor of 5-lipoxygenase-activating protein and soluble epoxide hydrolase
Sci Rep 2017 Aug 24;7(1):9398.PMID:28839250DOI:10.1038/s41598-017-09795-w.
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.