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Tiplaxtinin(PAI-039)

Orally efficacious inhibitor of PAI-1 CAS# 393105-53-8

Tiplaxtinin(PAI-039)

Catalog No. BCC6439----Order now to get a substantial discount!

Product Name & Size Price Stock
Tiplaxtinin(PAI-039):5mg $67.00 In stock
Tiplaxtinin(PAI-039):10mg $114.00 In stock
Tiplaxtinin(PAI-039):25mg $268.00 In stock
Tiplaxtinin(PAI-039):50mg $469.00 In stock
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Chemical structure

Tiplaxtinin(PAI-039)

3D structure

Chemical Properties of Tiplaxtinin(PAI-039)

Cas No. 393105-53-8 SDF Download SDF
PubChem ID 6450819 Appearance Powder
Formula C24H16F3NO4 M.Wt 439.38
Type of Compound N/A Storage Desiccate at -20°C
Synonyms PAI 039, tiplasinin
Solubility DMSO : ≥ 54 mg/mL (122.90 mM)
H2O : < 0.1 mg/mL (insoluble)
*"≥" means soluble, but saturation unknown.
Chemical Name 2-[1-benzyl-5-[4-(trifluoromethoxy)phenyl]indol-3-yl]-2-oxoacetic acid
SMILES C1=CC=C(C=C1)CN2C=C(C3=C2C=CC(=C3)C4=CC=C(C=C4)OC(F)(F)F)C(=O)C(=O)O
Standard InChIKey ODXQFEWQSHNQNI-UHFFFAOYSA-N
Standard InChI InChI=1S/C24H16F3NO4/c25-24(26,27)32-18-9-6-16(7-10-18)17-8-11-21-19(12-17)20(22(29)23(30)31)14-28(21)13-15-4-2-1-3-5-15/h1-12,14H,13H2,(H,30,31)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Tiplaxtinin(PAI-039)

DescriptionPlasminogen activator inhibitor-1 (PAI-1) inhibitor (IC50 = 2.7 μM). Induces vascular smooth muscle cell apoptosis in vitro and reduces carotid artery neointimal formation in a rat vascular injury model. Promotes thrombolysis in rat and dog models of acute arterial thrombosis. Orally available.

Protocol

Cell Assay [2]
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].

Animal Administration [1][2]
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.

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. [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. [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):

Tiplaxtinin(PAI-039) Dilution Calculator

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Preparing Stock Solutions of Tiplaxtinin(PAI-039)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.2759 mL 11.3797 mL 22.7593 mL 45.5187 mL 56.8984 mL
5 mM 0.4552 mL 2.2759 mL 4.5519 mL 9.1037 mL 11.3797 mL
10 mM 0.2276 mL 1.138 mL 2.2759 mL 4.5519 mL 5.6898 mL
50 mM 0.0455 mL 0.2276 mL 0.4552 mL 0.9104 mL 1.138 mL
100 mM 0.0228 mL 0.1138 mL 0.2276 mL 0.4552 mL 0.569 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Tiplaxtinin(PAI-039)

Description:

IC50: 2.7 μM

Plasminogen activator inhibitor-1 (PAI-1) is the most important physiologic regulator of the plasminogen activation system through its inhibition of its target serine proteases, tissue plasminogen activator, and urokinase plasminogen activator. Significant elevations of PAI-1 lead to stabilization of arterial and venous thrombi, which contribute respectively to coronary arterial occlusion in postmyocardial infarction and venous thrombosis following postoperative recovery from orthopedic surgery. Tiplaxtinin (PAI-039) is a novel, orally efficacious inhibitor of PAI-1.

In vitro: Tiplaxtinin inhibited PAI-1 as determined by the antibody method. By use of fluorescent spectroscopy, tiplaxtinin bound to the PAI-1 mutant selectively with a Kd of 480 nM. This binding event was saturable and associated with inhibition of the protein [1].

In vivo: In the rat model of carotid thrombosis, oral administration of tiplaxtinin at 1 mg/kg increased time to occlusion and prevented the carotid blood flow reduction when compared to the vehicle group. All of the vehicle control rats exhibited thrombosis with an average time to occlusion of 11 min and a complete reduction of 100% carotid flow. Conversely, those rats receiving tiplaxtinin at 1 mg/kg po exhibited an average time to occlusion of >50 min and a carotid blood flow reduction of approximately 50% [1].

Clinical trial: Up to now, tiplaxtinin is still in the preclinical development stage.

Reference:
[1] Elokdah H, Abou-Gharbia M, Hennan JK, McFarlane G, Mugford CP, Krishnamurthy G, Crandall DL.  Tiplaxtinin, a novel, orally efficacious inhibitor of plasminogen activator inhibitor-1: design, synthesis, and preclinical characterization. J Med Chem. 2004 Jul 1;47(14):3491-4.

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References on Tiplaxtinin(PAI-039)

Effect of tiplaxtinin (PAI-039), an orally bioavailable PAI-1 antagonist, in a rat model of thrombosis.[Pubmed:18624980]

J Thromb Haemost. 2008 Sep;6(9):1558-64.

OBJECTIVE: To assess the antithrombotic and profibrinolytic effects of tiplaxtinin (PAI-039), an orally bioavailable antagonist of PAI-1, in rat models of thrombosis. METHODS AND RESULTS: Carotid artery and vena cava vascular injury was produced by application of FeCl3 and blood flow was monitored using ultrasonic technology. To assess efficacy in a thrombosis prevention paradigm, PAI-039 was administered orally 90 min before injury (1-30 mg kg(-1)). To assess efficacy in a thrombosis treatment paradigm, vascular injury and stable thrombus formation were followed 4 h later by recovery and PAI-039 administration. PAI-039 prevented carotid artery occlusion in 20, 68 and 60% of animals pretreated with 0.3, 1.0 and 3.0 mg kg(-1), respectively. Time to occlusive thrombosis was increased from 18.2 +/- 4.6 min in controls to 32.5 +/- 8.7 (P = ns), 46.1 +/- 7.0 (P < 0.05), and 41.6 +/- 11.3 min (P < 0.05) in the respective PAI-039 treatment groups. In the vena cava protocol, PAI-039 pretreatment significantly reduced thrombus weight at PAI-039 doses of 3, 10 and 30 mg kg(-1). When PAI-039 was dosed in a treatment paradigm 4 h after stable arterial and venous thrombosis, a significant reduction in thrombus weight was observed 24 h later at PAI-039 doses of 3, 10 and 30 mg kg(-1). PAI-039 (10, 30 and 100 mg kg(-1)) had no effect on platelet aggregation in response to ADP or collagen and was not associated with increased bleeding or prolonged prothrombin time. In animals bearing no vascular injury, PAI-039 had no effect on circulating, low-levels of PAI-1 activity. In contrast, circulating PAI-1 activity increased 5-fold following the induction of vascular injury, which was completely neutralized by PAI-039. CONCLUSIONS: PAI-039 exerts antithrombotic efficacy in rat models of arterial and venous vascular injury without effecting platelet aggregation.

A small molecule PAI-1 functional inhibitor attenuates neointimal hyperplasia and vascular smooth muscle cell survival by promoting PAI-1 cleavage.[Pubmed:25617690]

Cell Signal. 2015 May;27(5):923-33.

Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of urokinase-and tissue-type plasminogen activators (uPA and tPA), is an injury-response gene implicated in the development of tissue fibrosis and cardiovascular disease. PAI-1 mRNA and protein levels were elevated in the balloon catheter-injured carotid and in the vascular smooth muscle cell (VSMC)-enriched neointima of ligated arteries. PAI-1/uPA complex formation and PAI-1 antiproteolytic activity can be inhibited, via proteolytic cleavage, by the small molecule antagonist tiplaxtinin which effectively increased the VSMC apoptotic index in vitro and attenuated carotid artery neointimal formation in vivo. In contrast to the active full-length serine protease inhibitor (SERPIN), elastase-cleaved PAI-1 (similar to tiplaxtinin) also promoted VSMC apoptosis in vitro and similarly reduced neointimal formation in vivo. The mechanism through which cleaved PAI-1 (CL-PAI-1) stimulates apoptosis appears to involve the TNF-alpha family member TWEAK (TNF-alpha weak inducer of apoptosis) and it's cognate receptor, fibroblast growth factor (FGF)-inducible 14 (FN14). CL-PAI-1 sensitizes cells to TWEAK-stimulated apoptosis while full-length PAI-1 did not, presumably due to its ability to down-regulate FN14 in a low density lipoprotein receptor-related protein 1 (LRP1)-dependent mechanism. It appears that prolonged exposure of VSMCs to CL-PAI-1 induces apoptosis by augmenting TWEAK/FN14 pro-apoptotic signaling. This work identifies a critical, anti-stenotic, role for a functionally-inactive (at least with regard to its protease inhibitory function) cleaved SERPIN. Therapies that promote the conversion of full-length to cleaved PAI-1 may have translational implications.

Tiplaxtinin, a novel, orally efficacious inhibitor of plasminogen activator inhibitor-1: design, synthesis, and preclinical characterization.[Pubmed:15214776]

J Med Chem. 2004 Jul 1;47(14):3491-4.

Indole oxoacetic acid derivatives were prepared and evaluated for in vitro binding to and inactivation of human plasminogen activator inhibitor-1 (PAI-1). SAR based on biochemical, physiological, and pharmacokinetic attributes led to identification of tiplaxtinin as the optimal selective PAI-1 inhibitor. Tiplaxtinin exhibited in vivo oral efficacy in two different models of acute arterial thrombosis. The remarkable preclinical safety and metabolic stability profiles of tiplaxtinin led to advancing the compound to clinical trials.

Description

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

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