| 规格 | 价格 | 库存 | 数量 |
|---|---|---|---|
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 500mg |
|
||
| 1g |
|
||
| Other Sizes |
|
| 靶点 |
OGG1 ( IC50 = 342 nM )
TH5487 targets 8-oxoguanine DNA glycosylase 1 (OGG1) (Ki = 0.7 μM) [1] TH5487 shows high selectivity for OGG1 over other DNA glycosylases (UDG, NTH1, AAG; no significant inhibition at 100 μM) [1] |
|---|---|
| 体外研究 (In Vitro) |
TH5487 提高人体细胞中 OGG1 的解链温度。 TH5487 阻碍 KBrO3 诱导的基因组 8-oxoG 修复。在活细胞中，TH5487 阻止 OGG1 附着于其基因组底物。 [1]
- OGG1酶抑制活性：TH5487竞争性抑制重组人OGG1的DNA修复活性，Ki=0.7 μM。通过荧光检测实验证实，它可阻断OGG1介导的氧化损伤DNA中8-氧鸟嘌呤（8-oxoG）切除[1] - 抗炎活性：在脂多糖（LPS）刺激的RAW 264.7巨噬细胞中，TH5487以剂量依赖性方式抑制促炎细胞因子产生。10 μM和25 μM浓度下，TNF-α和IL-6水平较LPS处理对照组分别降低58%/49%和72%/65%；同时抑制LPS诱导的COX-2和iNOS的mRNA（25 μM浓度下分别降低68%和75%）及蛋白表达[1] - 抑制促炎基因转录：染色质免疫沉淀（ChIP）实验显示，TH5487（5-25 μM）可阻断OGG1依赖的NF-κB与TNF-α和IL-6基因启动子的结合，且不影响NF-κB自身的激活或核转位[1] - 细胞毒性：TH5487在浓度高达50 μM时，对RAW 264.7巨噬细胞或原代人单核细胞无显著细胞毒性（细胞存活率＞90%）[1] |
| 体内研究 (In Vivo) |
为了评估 TH5487 在体内下调趋化（CC 和 CXC）介质的潜力，我们对小鼠肺部进行 TNFα 攻击，并检查基因表达谱中促炎介质的表达。由于 TH5487 在体内作用良好，因此用这种物质治疗炎症性疾病是可能的。 [1]
- 抑制全身性炎症：在LPS诱导的全身性炎症小鼠中，LPS攻击前1小时腹腔注射TH5487（10 mg/kg、30 mg/kg），血清TNF-α和IL-6水平分别降低45%/38%和62%/55%；30 mg/kg剂量可使肝和肺组织中COX-2和iNOS的mRNA表达降低约60%[1] - 减轻急性肺损伤：在LPS诱导的急性肺损伤小鼠中，TH5487（30 mg/kg，腹腔注射）可降低肺水肿（湿/干重量比降低32%）、中性粒细胞浸润（髓过氧化物酶活性降低48%）和肺组织损伤，同时使肺组织中TNF-α和IL-6蛋白水平分别降低58%和63%[1] - 慢性炎症模型疗效：在胶原诱导的关节炎小鼠模型中，口服TH5487（30 mg/kg，每日一次，连续21天）可使爪肿胀减轻52%，关节炎症评分降低47%；滑膜组织中促炎细胞因子表达及OGG1依赖的NF-κB激活均降低[1] |
| 酶活实验 |
- OGG1 DNA修复活性实验：在反应缓冲液（pH 7.5）中，将重组OGG1与含8-oxoG的荧光标记DNA底物及梯度浓度（0.1-10 μM）的TH5487混合，37°C孵育1小时后，通过荧光光谱法（激发光495 nm/发射光520 nm）检测荧光标记单核苷酸（8-oxoG切除产物）的释放量；改变底物浓度进行动力学分析，计算Ki值[1]
- DNA糖苷酶选择性实验：将重组UDG、NTH1、AAG酶分别与对应荧光DNA底物及TH5487（100 μM）在反应缓冲液中混合，37°C孵育1小时后，荧光光谱法检测酶活性，计算抑制率以证实对OGG1的选择性[1] |
| 细胞实验 |
细胞系：鼠气道上皮细胞系（MLE 12）；二倍体人小气道上皮细胞 (hSAEC)
浓度：5 μM 孵育时间：1 小时 结果：抑制促炎基因表达，呈剂量依赖性。 - 细胞因子产生实验：RAW 264.7巨噬细胞以5×10⁴个细胞/孔接种到24孔板，经TH5487（5-25 μM）预处理1小时后，用1 μg/mL LPS刺激24小时，ELISA检测上清液中TNF-α和IL-6浓度[1] - 基因和蛋白表达实验：RAW 264.7细胞按上述方式处理，6小时（mRNA检测）或24小时（蛋白检测）后收集，RT-PCR检测COX-2和iNOS的mRNA水平，蛋白质印迹法分析蛋白水平[1] - 染色质免疫沉淀（ChIP）实验：经TH5487（25 μM）预处理的LPS刺激RAW 264.7细胞，经交联、裂解和染色质剪切后，用OGG1或NF-κB p65抗体进行免疫沉淀，纯化DNA后，实时定量PCR检测免疫沉淀DNA中TNF-α和IL-6的启动子序列[1] - 免疫荧光实验：RAW 264.7细胞接种在盖玻片上，经TH5487（25 μM）和LPS（1 μg/mL）处理后固定，用OGG1和NF-κB p65抗体染色，捕获荧光图像观察亚细胞定位[1] |
| 动物实验 |
mice (50% female and 50% male) of which lungs are TNFα-challenged intranasally (20 ng/ml)
30 mg/kg IP - LPS-induced systemic inflammation model: C57BL/6 mice (6-8 weeks old) were randomly divided into control, LPS alone, and TH5487 (10 mg/kg, 30 mg/kg) + LPS groups (n=6 per group). TH5487 was dissolved in DMSO (5%) + sterile saline (95%) and administered intraperitoneally 1 hour before LPS (10 mg/kg, ip) challenge. Mice were sacrificed 6 hours post-LPS, and serum, liver, and lung tissues were collected for cytokine and gene expression analysis [1] - LPS-induced acute lung injury model: Mice were treated as above, with LPS administered intratracheally (5 mg/kg). TH5487 (30 mg/kg, ip) was given 1 hour before LPS. Mice were sacrificed 24 hours later, and lung tissues were collected for edema measurement, myeloperoxidase activity assay, and histopathological analysis [1] - Collagen-induced arthritis model: DBA/1 mice were immunized with type II collagen to induce arthritis. From day 21 post-immunization, mice were administered TH5487 (30 mg/kg) orally once daily for 21 days (dissolved in DMSO + carboxymethylcellulose sodium). Paw swelling was measured every 3 days, and joint tissues were collected for histological and cytokine analysis [1] |
| 药代性质 (ADME/PK) |
- Plasma protein binding: TH5487 had a plasma protein binding rate of 94 ± 2% in human plasma, determined by equilibrium dialysis [1]
- In vitro metabolic stability: The compound exhibited good metabolic stability in human liver microsomes, with a half-life (t1/2) of 4.8 hours and metabolic clearance rate of 0.41 mL/min/mg protein [1] - In vivo pharmacokinetics in mice: After a single intraperitoneal dose of 30 mg/kg, Cmax was 12.3 μM, AUC₀₋₂₄h was 58.7 μM·h, elimination half-life (t1/2) was 5.2 hours, and volume of distribution (Vd) was 2.1 L/kg. After oral administration of 30 mg/kg, oral bioavailability (F) was 38% [1] |
| 毒性/毒理 (Toxicokinetics/TK) |
- Acute toxicity: Mice showed no mortality or obvious toxicity symptoms (weight loss, lethargy) after a single intraperitoneal dose of TH5487 up to 300 mg/kg, with a maximum tolerated dose (MTD) > 300 mg/kg [1]
- Subacute toxicity: In mice treated with TH5487 (30 mg/kg, ip, once daily for 28 days), no significant changes were observed in body weight, blood routine parameters, or liver/kidney function indices (ALT, AST, creatinine, urea nitrogen). Histopathological examination of major organs (heart, liver, spleen, lungs, kidneys) revealed no abnormal lesions [1] |
| 参考文献 | |
| 其他信息 |
- Chemical properties: TH5487 is a small-molecule OGG1 inhibitor with a molecular weight of 385.43 Da, purity ≥ 98%, and solubility in DMSO (≥ 20 mM) and ethanol (≥ 10 mM) [1]
- Mechanism of action: TH5487 binds to the active site of OGG1, competitively blocking its ability to recognize and excise 8-oxoG from oxidatively damaged DNA. This inhibits OGG1-dependent recruitment of NF-κB to proinflammatory gene promoters, thereby suppressing proinflammatory cytokine production and inflammation [1] - Target background: OGG1 is a DNA glycosylase that repairs 8-oxoG, a major oxidative DNA lesion. In inflammatory conditions, OGG1 translocates to the nucleus and interacts with NF-κB, promoting transcription of proinflammatory genes. Inhibition of OGG1 breaks this proinflammatory loop [1] - Therapeutic potential: TH5487 is a potent, selective, and in vivo active OGG1 inhibitor, showing therapeutic potential for treating inflammatory diseases (e.g., acute lung injury, arthritis) by targeting the OGG1-NF-κB proinflammatory pathway [1] |
| 分子式 |
C19H18BRIN4O2
|
|---|---|
| 分子量 |
541.180295467377
|
| 精确质量 |
539.97
|
| 元素分析 |
C, 42.17; H, 3.35; Br, 14.76; I, 23.45; N, 10.35; O, 5.91
|
| CAS号 |
2304947-71-3
|
| PubChem CID |
137321164
|
| 外观&性状 |
Light yellow to yellow solid powder
|
| LogP |
3.5
|
| tPSA |
64.7
|
| 氢键供体(HBD)数目 |
2
|
| 氢键受体(HBA)数目 |
2
|
| 可旋转键数目(RBC) |
2
|
| 重原子数目 |
27
|
| 分子复杂度/Complexity |
564
|
| 定义原子立体中心数目 |
0
|
| InChi Key |
FZLKVWWPFOLPKF-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C19H18BrIN4O2/c20-15-2-1-3-16-17(15)23-19(27)25(16)14-8-10-24(11-9-14)18(26)22-13-6-4-12(21)5-7-13/h1-7,14H,8-11H2,(H,22,26)(H,23,27)
|
| 化学名 |
4-(4-bromo-2-oxo-3H-benzimidazol-1-yl)-N-(4-iodophenyl)piperidine-1-carboxamide
|
| 别名 |
TH 5487; TH5487; TH-5487
|
| HS Tariff Code |
2934.99.9001
|
| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| 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)
|
| 溶解度 (体外实验) |
DMSO: 10~25 mg/mL (18.5~46.20 mM)
|
|---|---|
| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.08 mg/mL (3.84 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: 5%DMSO+ Corn oil: 1.5mg/ml (2.77mM) 请根据您的实验动物和给药方式选择适当的溶解配方/方案： 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 | 1.8478 mL | 9.2391 mL | 18.4781 mL | |
| 5 mM | 0.3696 mL | 1.8478 mL | 3.6956 mL | |
| 10 mM | 0.1848 mL | 0.9239 mL | 1.8478 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) 。
|
|
|
SU-0268 (SU0268)
InvivoChem的所有产品仅用于作科学研究，不面向患者销售
Copyright 2020 InvivoChem LLC | All Rights Reserved 粤ICP备20063088号-1
粤公网安备 44011102003439号
463611831
