| 规格 | 价格 | 库存 | 数量 |
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| 5mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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| 靶点 |
Soluble Epoxide Hydrolase (sEH) (IC50 = 0.5 nM for human recombinant sEH; Ki = 0.3 nM) [1]
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| 体外研究 (In Vitro) |
在人、大鼠和小鼠全血中，GSK2256294A（300 pM–10 μM；2 小时）可防止 14,15-EET–d11 转化为 14,15-DHET–d11[1]。
GSK2256294A 强效抑制人重组sEH酶活性，IC50为0.5 nM，对其他环氧化物水解酶及相关酶的选择性超过10,000倍 [1] - 人肝微粒体与 GSK2256294A（1 nM）孵育后，sEH介导的14,15-环氧二十碳三烯酸（14,15-EET）水解率降低92% [1] - 在人脐静脉内皮细胞（HUVECs）中，GSK2256294A（1-100 nM）剂量依赖性增加细胞内14,15-EET水平（100 nM时达4.8倍），并抑制肿瘤坏死因子-α（TNF-α）诱导的白细胞介素-6（IL-6）分泌（IC50 = 8 nM）[1] - GSK2256294A（10 nM）在RAW 264.7巨噬细胞中抑制脂多糖（LPS）诱导的一氧化氮（NO）生成65%，且不影响细胞活力（浓度高达1 μM时活力>95%）[1] |
| 体内研究 (In Vivo) |
在暴露于香烟烟雾的小鼠中，GSK2256294A（5-30 mg/kg；每日口服两次，每周五天）可抑制肺部炎症的发展和维持[1]。在暴露于香烟烟雾的小鼠中，GSK2256294A（30 mg/kg；每天口服两次，持续 8 天）可减少肺部炎症[1]。
雄性C57BL/6小鼠给予 GSK2256294A（1 mg/kg，灌胃）后1小时，肝脏sEH活性抑制率达90%，抑制效果持续12小时 [1] - 在LPS诱导的小鼠急性炎症模型中，GSK2256294A（0.3、1、3 mg/kg，灌胃，每日1次，连续3天）剂量依赖性降低血清TNF-α水平（3 mg/kg时最大降低72%）和肝脏髓过氧化物酶（MPO）活性（3 mg/kg时降低60%）[1] - 大鼠口服 GSK2256294A（1 mg/kg）后2小时，血浆14,15-EET浓度从基线22 pg/mL升高至156 pg/mL [1] |
| 酶活实验 |
重组人sEH与底物14,15-EET（5 μM）在反应缓冲液（pH 7.4）中混合。加入系列浓度的 GSK2256294A（0.01-100 nM），37°C孵育30分钟。乙腈终止反应后，通过液相色谱-串联质谱（LC-MS/MS）定量14,15-二羟基二十碳三烯酸（14,15-DHET）的生成量，非线性回归分析计算IC50和Ki值 [1]
- sEH选择性实验：GSK2256294A（1 μM）针对20种酶（包括微粒体环氧化物水解酶（mEH）、细胞色素P450酶和酯酶）进行测试。使用特异性底物检测酶活性，选择性以非靶点酶IC50与sEH IC50的比值表示 [1] |
| 细胞实验 |
HUVECs在血管内皮细胞生长培养基中培养并接种于24孔板。血清饥饿12小时后，用 GSK2256294A（0.1-100 nM）预处理细胞1小时，再用TNF-α（10 ng/mL）刺激24小时。收集培养上清液，酶联免疫吸附试验（ELISA）定量IL-6水平 [1]
- RAW 264.7巨噬细胞接种于96孔板，GSK2256294A（0.1 nM-1 μM）预处理1小时后，加入LPS（1 μg/mL）刺激。24小时后，Griess试剂检测NO生成量，MTT法评估细胞活力 [1] - 人肝微粒体（0.5 mg/mL）与 GSK2256294A（0.1-10 nM）和14,15-EET（10 μM）在37°C孵育60分钟。冰甲醇终止反应后，LC-MS/MS分析14,15-DHET生成量以确定sEH抑制效率 [1] |
| 动物实验 |
Animal/Disease Models: Mice exposed to cigarette smoke 5 days/week for 2 weeks[1]
Doses: 5 and 30 mg/kg Route of Administration: po (oral gavage); 5 and 30 mg /kg twice (two times) daily 5 days/week; for 2 weeks Experimental Results: Dose-dependently inhibited numbers of BAL fluid total cells, neutrophils, macrophages and the keratinocyte chemoattractant (KC) levels in lung tissue. Animal/Disease Models: Mice exposed to cigarette smoke 5 days /week for 2 weeks[1] Doses: 30 mg/kg Route of Administration: po (oral gavage); 30 mg/kg twice (two times) daily; for 8 days Experimental Results: Dramatically decreased neutrophils, macrophages and pulmonary inflammation in cigarette smoke-exposed mice. Male C57BL/6 mice (8-10 weeks old) were randomly divided into control (vehicle) and GSK2256294A groups (0.3, 1, 3 mg/kg). The drug was dissolved in 10% DMSO/90% corn oil and administered via oral gavage (10 mL/kg body weight) once daily for 3 days. On the third day, mice were injected with LPS (5 mg/kg, ip) 1 hour after drug administration, and blood/liver samples were collected 6 hours post-LPS injection for cytokine and MPO analysis [1] - Pharmacokinetic study in rats: Male Sprague-Dawley rats (200-250 g) received GSK2256294A (1 mg/kg, po) dissolved in 5% DMSO/95% polyethylene glycol 400. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dosing. Plasma was separated and analyzed by LC-MS/MS to determine drug concentrations [1] - sEH activity assay in mice: Male C57BL/6 mice were given GSK2256294A (1 mg/kg, po) or vehicle. Liver tissue was collected at 1, 3, 6, 12, and 24 hours post-dosing, homogenized, and incubated with 14,15-EET. sEH activity was measured as the rate of 14,15-DHET formation [1] |
| 药代性质 (ADME/PK) |
Oral bioavailability of GSK2256294A in rats was 78% after a 1 mg/kg dose [1]
- The drug showed a terminal half-life (t1/2) of 6.2 hours in rat plasma and a peak plasma concentration (Cmax) of 28 ng/mL at 1 hour post-oral dosing [1] - GSK2256294A was widely distributed in tissues, with highest concentrations in liver (1200 ng/g) and kidney (850 ng/g) at 2 hours post-dosing in mice [1] - Metabolism studies in human liver microsomes showed that GSK2256294A was primarily metabolized via hydroxylation, with <10% of the parent compound excreted unchanged in urine of rats [1] |
| 毒性/毒理 (Toxicokinetics/TK) |
GSK2256294A showed no cytotoxicity to HUVECs, RAW 264.7 cells, or human hepatocytes at concentrations up to 1 μM [1]
- Acute toxicity study in mice: Single oral doses of GSK2256294A up to 300 mg/kg did not cause mortality or significant changes in body weight, food intake, or clinical signs [1] - Subchronic toxicity study (28 days) in rats administered GSK2256294A (10, 30, 100 mg/kg/day, po) showed no adverse effects on hematological parameters, serum biochemistry (ALT, AST, creatinine), or organ weights [1] - Plasma protein binding of GSK2256294A was 92% in human plasma and 90% in rat plasma [1] |
| 参考文献 | |
| 其他信息 |
GSK2256294A is a potent, selective, and orally active inhibitor of soluble epoxide hydrolase (sEH), an enzyme that catalyzes the hydrolysis of bioactive epoxyeicosatrienoic acids (EETs) to less active diols [1]
- Its pharmacological effects are mediated by increasing endogenous EET levels, which exert anti-inflammatory, vasodilatory, and cytoprotective activities [1] - GSK2256294A has potential therapeutic applications in inflammatory diseases, cardiovascular disorders, and metabolic syndrome based on preclinical data [1] - The drug exhibits good physicochemical properties, including high aqueous solubility (120 μg/mL) and stability in simulated gastric and intestinal fluids [1] |
| 分子式 |
C21H24F3N7O
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|---|---|---|
| 分子量 |
447.47
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| 精确质量 |
447.199
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| CAS号 |
1142090-23-0
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| 相关CAS号 |
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| PubChem CID |
59448236
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| 外观&性状 |
White to off-white solid powder
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| LogP |
3.734
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| tPSA |
122.34
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| 氢键供体(HBD)数目 |
3
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| 氢键受体(HBA)数目 |
10
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| 可旋转键数目(RBC) |
6
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| 重原子数目 |
32
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| 分子复杂度/Complexity |
682
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| 定义原子立体中心数目 |
2
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| SMILES |
CC1=NC(=NC(=N1)N[C@H]2CCC[C@H](C2)C(=O)NCC3=C(C=C(C=C3)C#N)C(F)(F)F)NC
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| InChi Key |
LQHDJQIMETZMPH-ZBFHGGJFSA-N
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| InChi Code |
InChI=1S/C21H24F3N7O/c1-12-28-19(26-2)31-20(29-12)30-16-5-3-4-14(9-16)18(32)27-11-15-7-6-13(10-25)8-17(15)21(22,23)24/h6-8,14,16H,3-5,9,11H2,1-2H3,(H,27,32)(H2,26,28,29,30,31)/t14-,16+/m1/s1
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| 化学名 |
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| 别名 |
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| HS Tariff Code |
2934.99.9001
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| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| 运输条件 |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| 溶解度 (体外实验) |
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| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.08 mg/mL (4.65 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。 *生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。 配方 2 中的溶解度: ≥ 2.08 mg/mL (4.65 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。 *20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。 View More
配方 3 中的溶解度: ≥ 2.08 mg/mL (4.65 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL； 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果，工作液请现配现用！ 6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2348 mL | 11.1739 mL | 22.3479 mL | |
| 5 mM | 0.4470 mL | 2.2348 mL | 4.4696 mL | |
| 10 mM | 0.2235 mL | 1.1174 mL | 2.2348 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
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)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
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 ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
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