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Tiplaxtinin

MCE China：Tiplaxtinin

Brand：MedChemExpress (MCE)

Cat. No.HY-15253

CAS：393105-53-8

Synonyms：PAI-039; Tiplasinin

Purity：98.78%

Storage：Powder -20°C 3 years 4°C 2 years In solvent -80°C 2 years -20°C 1 year

Shipping：Room temperature in continental US; may vary elsewhere.

Description：Tiplaxtinin is a selective and orally efficacious inhibitor of plasminogen activator inhibitor-1 (PAI-1) with IC50 of 2.7 μM.

In Vitro：Tiplaxtinin (PAI-039), a small-molecule inhibitor of PAI-1 activity, on the urothelial cell lines. A significant inhibition in cellular proliferation is noted in T24 cells treated with Tiplaxtinin with the documentation of a favorable IC50 value of 43.7±6.3 μM and in UM-UC-14 cells 52.8±1.6 μM whereas the benign cell line, UROtsa, is noted to have a higher IC50 value of 70.3±0.1 μM. Notably, IC50 values of Tiplaxtinin in detached cells, 19.7±3.8 μM in T24, 44.5±6.5 μM in UM-UC-14, and 31.6±6.1 μM in UROtsa, are significantly lower than the IC50 values calculated for cells cultured in the presence of Tiplaxtinin under attached conditions[2].

In Vivo：In the vena cava protocol, Tiplaxtinin (PAI-039) pretreatment significantly reduces thrombus weight at Tiplaxtinin doses of 3, 10 and 30 mg/kg. When Tiplaxtinin is dosed in a treatment paradigm 4 h after stable arterial and venous thrombosis, a significant reduction in thrombus weight is observed 24 h later at Tiplaxtinin doses of 3, 10 and 30 mg/kg[1]. Tiplaxtinin (PAI-039) is administered by oral gavage to athymic mice bearing human bladder cancer cell line T24 xenografts and human cervical cancer HeLa cell xenografts. The subcutaneous tumor growth of both T24 and HeLa cell xenografts treated with Tiplaxtinin is markedly reduced compared with untreated controls. Specifically, at the end of the study, control T24 xenografts are noted to be 1,150±302 mm3 compared with 593±328 mm3 for T24 xenograft tumors treated with 5 mg/kg Tiplaxtinin (P3 for T24 xenografts treated with 20 mg/kg (P[2]. Tiplaxtinin (1, 3, and 10 mg/kg) is subjected to electrolytic injury of the coronary artery. Tiplaxtinin (PAI-039) causes prolongation in time to coronary occlusion (control, 31.7±6.3 min; 3 mg/kg Tiplaxtinin, 66.0±6.4 min; 10 mg/kg, 56.7±7.4 min; n=5-6; p[3].

Animal Administration：Rats[1] Male Sprague-Dawley rats (250-350 g) are dosed orally with either vehicle or Tiplaxtinin (0.3-3 mg/kg) on the morning of the experiment, then anesthetized with sodium-pentobarbital (50 mg/kg, i.p.). A midline incision is made along the neck, and the right and left carotid arteries and jugular veins are exposed. The left jugular vein is catheterized for tPA delivery and blood sampling. The right carotid artery is cannulated with PE-60 tubing filled with 3.8% sodium citrate solution, and interfaced to a saline-filled pressure transducer for monitoring of heart rate and blood pressure. The left carotid artery is used for vascular injury induction and thrombosis. An ultrasonic flow probe is placed on the left carotid artery, and baseline blood flow is recorded. A 3-mm section of PE-60 tubing is sectioned longitudinally, and a piece of filter paper saturated with 25% FeCl3 is inserted into the tubing. Flow is monitored in the damaged vessel during tPA infusion and for an additional 20 min afterwards. At the end of the experiment, the arterial thrombus is excised and weighed. Mice[2] Mice bearing bladder xenografts and mice bearing cervical xenografts are divided randomly into three groups (control, 5 mg/kg of Tiplaxtinin, and 20 mg/kg of Tiplaxtinin) and treatment is initiated. Each group is composed of at least 10 mice. No toxicity or weight loss is noted in any of the treatment groups. Tiplaxtinin (100 μL diluted in corn oil) is administered via oral gavage daily (Monday-Friday) for 5 weeks. Control mice received vehicle alone on the same schedule. Tumor volumes are measured weekly with digital calipers and calculated. After 5 weeks, the mice are sacrificed, tumors resected, and analyzed by immunohistochemical staining.

Cell Assay：T24, UM-UC-14, UROtsa, and HeLa cells are plated in 96-well dishes in triplicate at 1×103 cells per well and allowed to adhere for 24 hours. Subsequently, Tiplaxtinin is added to the wells and allowed to incubate at the indicated concentrations. Cellular proliferation is determined by CellTiter-Glo Luminescent Cell Viability Assay at 24 hours, and IC50 of Tiplaxtinin is determined in Graphpad Prism. Luminescence is measured using a FLUOstar OPTIMA Reader[2].

IC50 & Target：IC50: 2.7 μM (PAI-1)[1] In Vitro Tiplaxtinin (PAI-039), a small-molecule inhibitor of PAI-1 activity, on the urothelial cell lines. A significant inhibition in cellular proliferation is noted in T24 cells treated with Tiplaxtinin with the documentation of a favorable IC50 value of 43.7±6.3 μM and in UM-UC-14 cells 52.8±1.6 μM whereas the benign cell line, UROtsa, is noted to have a higher IC50 value of 70.3±0.1 μM. Notably, IC50 values of Tiplaxtinin in detached cells, 19.7±3.8 μM in T24, 44.5±6.5 μM in UM-UC-14, and 31.6±6.1 μM in UROtsa, are significantly lower than the IC50 values calculated for cells cultured in the presence of Tiplaxtinin under attached conditions[2]. MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. 0 --> Tiplaxtinin Related Antibodies

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References：

[1]. Hennan JK, et al. Effect of Tiplaxtinin (PAI-039), an orally bioavailable PAI-1 antagonist, in a rat model of thrombosis. J Thromb Haemost. 2008 Sep;6(9):1558-64.  [Content Brief]

[2]. Gomes-Giacoia E, et al. Targeting plasminogen activator inhibitor-1 inhibits angiogenesis and tumor growth in a human cancer xenograft model. Mol Cancer Ther. 2013 Dec;12(12):2697-708.  [Content Brief]

[3]. Hennan JK, et al. Evaluation of PAI-039 [{1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid], a novel plasminogen activator inhibitor-1 inhibitor, in a canine model of coronary artery thrombosis. J Pharmacol Exp Ther. 2005 Aug;314(2):  [Content Brief]