TM5441
目录号 : GC18173
TM5441是一种具有口服生物利用度的纤溶酶原激活物抑制剂-1（PAI-1）抑制剂，其IC₅₀值介于13.9至51.1μM之间，并能在多种人类癌细胞系中诱导内源性凋亡。
Cas No.:1190221-43-2
Sample solution is provided at 25 µL, 10mM.
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TM5441 is an orally bioavailable inhibitor of plasminogen activator inhibitor-1 (PAI-1), has IC50 values between 13.9 and 51.1μM and induces intrinsic apoptosis in several human cancer cell lines[1]. TM5441 also exhibits anti-fibrotic and anti-tumor activities through suppression of PAI-1-mediated signaling pathways [2]. TM5441 attenuates Nω-nitro-l-arginine methyl ester-induced cardiac hypertension and vascular senescence[3].
In both HT1080 and HCT116 cells, treatment with TM5441 (25-100μM; 48h) increased Caspase 3/7 activity in a dose-dependent manner and enhanced apoptosis in both HT1080 and HCT116 cells [1].TM5441(20μM; 4h) inhibited downregulation of mitochondrial biogenesis-related genes, such as PGC-1α, mtDNA, TFAM, NRF1, and NRF2, and lipid accumulation in HepG2 cells [4]. In cardiomyocytes, TM5441(10μM; 24h) exerts its inhibitory effect on doxorubicin-induced cellular senescence by reducing the production of reactive oxygen species, inducing antioxidants such as catalase, and inhibiting stress-induced senescence [5]. In mouse proximal tubular epithelial cells, TM5441(10μM; 4h) inhibits PAI-1-induced mRNA expression of fibrosis and inflammation markers and also reverses PAI-1-induced inhibition of plasmin activity [6].
In an L-NAME-induced vascular aging model, TM5441 (20mg/kg; po; 8 weeks) prevented L-NAME-induced hypertension, cardiac hypertrophy, and periaortic fibrosis in rats. it reduced arterial p16Ink4a expression and maintained telomere length [3]. In a high-fat diet-induced nonalcoholic fatty liver disease model, early TM5441 (20mg/kg; po; 10 weeks) treatment prevented HFD-induced hepatic steatosis and reduced the expression of lipogenesis-related genes Acc1, Scd1, Cd36, and PPARγ [4]. In a mouse high-fat diet model, TM5441 (20mg/kg; po; 10 weeks) prevented high-fat diet (HFD)-induced weight gain and systemic insulin resistance. TM5441 normalized HFD-induced dysregulation of JNK and Akt phosphorylation, while also attenuating HFD-induced macrophage infiltration and increasing the expression of proinflammatory cytokines, such as inducible nitric oxide synthase[7]. In a high-fat diet model, TM5441 (15mg/kg; po; 35d) inhibited the activation of plasminogen activator-1 in mice, alleviated hypothalamic leptin resistance, and reduced high-fat diet-induced weight gain[8].
References:
[1]. Placencio V R, Ichimura A, Miyata T, et al. Small molecule inhibitors of plasminogen activator inhibitor-1 elicit anti-tumorigenic and anti-angiogenic activity[J]. PLoS One, 2015, 10(7): e0133786.
[2]. Abd Aziz Ibrahim T F, Uno T, Terada T, et al. Plasminogen activator inhibitor-1 promotes immune evasion in tumors by facilitating the expression of programmed cell death-ligand[J]. Frontiers in Immunology, 2024, 15.
[3]. Boe A E, Eren M, Murphy S B, et al. The PAI-1 antagonist TM5441 attenuates L-NAME-induced hypertension and vascular senescence[J]. Circulation, 2013, 128(21): 2318.
[4]. Lee S M, Dorotea D, Jung I, et al. TM5441, a plasminogen activator inhibitor-1 inhibitor, protects against high fat diet-induced non-alcoholic fatty liver disease[J]. Oncotarget, 2017, 8(52): 89746.
[5]. Ghosh A K, Rai R, Park K E, et al. A small molecule inhibitor of PAI-1 protects against doxorubicin-induced cellular senescence[J]. Oncotarget, 2016, 7(45): 72443.
[6]. Jeong B Y, Uddin M J, Park J H, et al. Novel plasminogen activator inhibitor-1 inhibitors prevent diabetic kidney injury in a mouse model[J]. PloS one, 2016, 11(6): e0157012. [2].
[7]. Piao L, Jung I, Huh J Y, et al. A novel plasminogen activator inhibitor‐1 inhibitor, TM5441, protects against high‐fat diet‐induced obesity and adipocyte injury in mice[J]. British journal of pharmacology, 2016, 173(17): 2622-2632.
[8]. Hosaka S, Yamada T, Takahashi K, et al. Inhibition of plasminogen activator inhibitor-1 activation suppresses high fat diet-induced weight gain via alleviation of hypothalamic leptin resistance[J]. Frontiers in Pharmacology, 2020, 11: 943.
TM5441是一种具有口服生物利用度的纤溶酶原激活物抑制剂-1（PAI-1）抑制剂，其IC₅₀值介于13.9至51.1μM之间，并能在多种人类癌细胞系中诱导内源性凋亡[1]。TM5441还通过抑制PAI-1介导的信号通路发挥抗纤维化和抗肿瘤活性[2]。TM5441还能减轻Nω-硝基-L-精氨酸甲酯诱导的心脏高血压和血管衰老[3]。
在HT1080和HCT116细胞中，TM5441（25-100μM；48小时）以剂量依赖方式增强Caspase 3/7活性，并促进两种细胞的凋亡[1]。在HepG2细胞中，TM5441（20μM；4h）抑制了线粒体生物合成相关基因（如PGC-1α、mtDNA、TFAM、NRF1和NRF2）的下调及脂质积累[4]。在心肌细胞中，TM5441（10μM；24h）通过减少活性氧的产生、诱导过氧化氢酶等抗氧化剂以及抑制应激诱导的衰老，发挥对多柔比星诱导的细胞衰老的抑制作用[5]。在小鼠近端肾小管上皮细胞中，TM5441（10μM；4h）抑制PAI-1诱导的纤维化和炎症标志物mRNA表达，并逆转PAI-1诱导的纤溶酶活性抑制[6]。
在L-NAME诱导的血管衰老模型中，TM5441（20mg/kg；po；8周）可预防大鼠L-NAME诱导的高血压、心脏肥大和主动脉周围纤维化，同时降低动脉p16Ink4a表达并维持端粒长度[3]。在高脂饮食诱导的非酒精性脂肪肝模型中，早期TM5441干预（20 mg/kg；po；10周）可预防高脂饮食诱导的肝脏脂肪变性，并降低脂肪生成相关基因Acc1、Scd1、Cd36和PPARγ的表达[4]。在高脂饮食小鼠模型中，TM5441（20mg/kg；po；10周）阻止高脂饮食诱导的体重增加和全身性胰岛素抵抗，TM5441还能正常化高脂饮食引起的JNK和Akt磷酸化失调，同时减轻高脂饮食诱导的巨噬细胞浸润并降低诱导型一氧化氮合酶等促炎细胞因子的表达[7]。在另一高脂饮食模型中，TM5441（15mg/kg；po；35天）抑制小鼠纤溶酶原激活物抑制剂-1的激活，缓解下丘脑leptin抵抗，并减少高脂饮食引起的体重增加[8]。
| Cell experiment [1]: | |
Cell lines | HepG2 cells, human hepatoma cells |
Preparation Method | HepG2 cells, human hepatoma cells, were maintained in Dulbecco's Modified Eagle's Medium, supplemented with 10% fetal bovine serum, 100U/mL penicillin, 100μg/mL streptomycin, and 44mM NaHCO3 at 37°C in humidified 5% CO2. Growth arrested and synchronized cells were exposed with 50ng/mL tumor necrosis factor-α/TNF-α or 25 and 50nM mouse recombinant PAI-1 in the presence and absence of 20μM TM5441. TM5441 was added 4 hours prior to TNF-α or PAI-1 stimulation. |
Reaction Conditions | 20μM; 4h |
Applications | TM5441 inhibited downregulation of mitochondrial biogenesis-related genes ,such as PGC-1α, mtDNA, TFAM, NRF1, and NRF2, and lipid accumulation in HepG2 cells. |
| Animal experiment [1]: | |
Animal models | High fat diet (HFD)-induced NAFLD modle |
Preparation Method | 10-week-old C57BL/6J male mice were housed in a room maintained at 22±2°C with a 12h dark/12h light cycle, and fed either with normal diet (ND) or HFD. Control groups received 0.25% carboxymethyl cellulose by oral gavage; 20mg/kg TM5441 was daily administered by oral gavage on HFD mice. 10-week-treatment of TM5441 was started along with the initiation of HFD on 10-week-old mice. |
Dosage form | 20mg/kg; po; 10 weeks |
Applications | Early TM5441 treatment significantly downregulated lipogenesis-related genes (Acc1, Scd1, Cd36, and PPARγ) and upregulated lipolysis-related genes (PPARα). Hepatic steatosis was attenuated by TM5441 along with improvement of hepatic insulin sensitivity presented by decreased p-JNK along with increased p-Akt and p-GSK3β. |
References: | |
| Cas No. | 1190221-43-2 | SDF | |
| 化学名 | 5-chloro-2-[[2-[2-[[3-(3-furanyl)phenyl]amino]-2-oxoethoxy]acetyl]amino]-benzoic acid | ||
| Canonical SMILES | O=C(COCC(NC1=CC=C(Cl)C=C1C(O)=O)=O)NC2=CC(C3=COC=C3)=CC=C2 | ||
| 分子式 | C21H17ClN2O6 | 分子量 | 428.8 |
| 溶解度 | DMF: 33 m/ml,DMF:PBS(pH 7.2)(1:6): 0.14 mg/ml,DMSO: 20 mg/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 | 2.3321 mL | 11.6604 mL | 23.3209 mL |
| 5 mM | 466.4 μL | 2.3321 mL | 4.6642 mL |
| 10 mM | 233.2 μL | 1.166 mL | 2.3321 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。
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- Purity: >98.00%
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