Tiplaxtinin(PAI-039),

Details:

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 inhibitor
in 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-1
mutant 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].