Tiplaxtinin

• CAT Number: I003439
• CAS Number: 393105-53-8
• Molecular Formula: C₂₄H₁₆F₃NO₄
• Molecular Weight: 439.38
• Purity: ≥95%
• Synonyms: PAI-039;Tiplasinin
• Target: PAI-1 inhibitor
• Solubility: DMSO: ≥ 54 mg/mL
• Storage: -20°C
• IC50: 2.7 uM [1]
• 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)
• InChIKey: ODXQFEWQSHNQNI-UHFFFAOYSA-N
• 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

Tiplaxtinin(PAI-039) is a selective and orally efficacious inhibitor of plasminogen activator inhibitor-1 (PAI-1) with IC50 of 2.7 uM.IC50 value: 2.7 uM [1]Target: PAI-1 inhibitorin vitro: Tiplaxtinin was shown to be selective for PAI-1 as indicated by selectivity assays against a number of different proteins, including tPA and R1-antitrypsin, the serpin most closely related to PAI-1. Tiplaxtinin inhibited PAI-1 with an IC50 of 2.7 uM as determined by the antibody method. By use of fluorescent spectroscopy, Tiplaxtinin bound to the NBD-labeled S119C PAI-1mutant selectively with a Kd of 480 nM [1]. Silencing of PAI-1 in T24 and UM-UC-14 cells via shRNA or tiplaxtinin treatment was associated with a marked inhibition of cellular proliferation causing a cell cycle arrest in G1 to S phase. Treatment of all parental cells with tiplaxtinin resulted in a significant reduction in cellular proliferation, IC50 values for tiplaxtinin were determined for UROtsa cells (70.3 ± 0.1 μM), T24 cells (43.7 ± 6.3 μM), UM-UC-14 cells (52.8 ± 1.6 μM), and HeLa cells (29.9 ± 3.1 μM) [3].in vivo: In the rat carotid thrombosis model, 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 [1]. Dogs received by oral gavage either vehicle (control) or the PAI-1 inhibitor PAI-039 (1, 3, and 10 mg/kg) and were subjected to electrolytic injury of the coronary artery. PAI-039 caused prolongation in time to coronary occlusion (control, 31.7 +/- 6.3 min; 3 mg/kg PAI-039, 66.0 +/- 6.4 min; 10 mg/kg, 56.7 +/- 7.4 min; n = 5-6; p < 0.05) and a reduced thrombus weight (control, 7.6 +/- 1.5 mg; 10 mg/kg PAI-039, 3.6 +/- 1.0 mg; p < 0.05) [2]. Treatment of T24 xenografts with tiplaxtinin resulted in inhibition of angiogenesis and induction of apoptosis, leading to a significant reduction in tumor growth [4].

Reference

1:Effect of tiplaxtinin (PAI-039), an orally bioavailable PAI-1 antagonist, in a rat model of thrombosis. Hennan JK, Morgan GA, Swillo RE, Antrilli TM, Mugford C, Vlasuk GP, Gardell SJ, Crandall DL.J Thromb Haemost. 2008 Sep;6(9):1558-64. doi: 10.1111/j.1538-7836.2008.03063.x. Epub 2008 Jul 4. PMID: 18624980 Free Article2:Dose-dependent thrombus resolution due to oral plaminogen activator inhibitor (PAI)-1 inhibition with tiplaxtinin in a rat stenosis model of venous thrombosis. Baxi S, Crandall DL, Meier TR, Wrobleski S, Hawley A, Farris D, Elokdah H, Sigler R, Schaub RG, Wakefield T, Myers D.Thromb Haemost. 2008 Apr;99(4):749-58. doi: 10.1160/TH07-11-0669. PMID: 18392333 3:Tiplaxtinin impairs nutritionally induced obesity in mice. Lijnen HR, Alessi MC, Frederix L, Collen D, Juhan-Vague I.Thromb Haemost. 2006 Dec;96(6):731-7. PMID: 17139366 4:Tiplaxtinin, a novel, orally efficacious inhibitor of plasminogen activator inhibitor-1: design, synthesis, and preclinical characterization. Elokdah H, Abou-Gharbia M, Hennan JK, McFarlane G, Mugford CP, Krishnamurthy G, Crandall DL.J Med Chem. 2004 Jul 1;47(14):3491-4. PMID: 15214776