PAI-039

PAI-039, is a novel plasminogen activator inhibitor-1 (PAI-1) inhibitor. The pharmacokinetic profile of PAI-039 indicated an oral bioavailability of 43 +/- 15.3% and a plasma half-life of 6.2 +/- 1.3 h. PAI-039 is an orally active prothrombolytic drug that inhibits PAI-1 and accelerates fibrinolysis while maintaining normal coagulation in a model of coronary occlusion . PAI-039 exerts antithrombotic efficacy in rat models of arterial and venous vascular injury without effecting platelet aggregation. PAI-039 as a novel therapeutic may improve diabetic wound closure.

Product information

CAS Number: 393105-53-8

Molecular Weight: 439.38

Formula: C24H16F3NO4

Synonym:

Tiplaxtinin

PAI 039

PAI039

PAI-039

Chemical Name:  2-(1-benzyl-5-(4-(trifluoromethoxy)phenyl)-1H-indol-3-yl)-2-oxoacetic acid

Smiles: OC(=O)C(=O)C1=CN(CC2C=CC=CC=2)C2=CC=C(C=C21)C1C=CC(=CC=1)OC(F)(F)F

InChiKey: ODXQFEWQSHNQNI-UHFFFAOYSA-N

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)

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: Soluble in DMSO, not in water

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

How to use

In Vitro:

PAI-039 is 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 PAI-039 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 PAI-039 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 PAI-039 under attached condition.

In Vivo:

In the vena cava protocol, PAI-039 pretreatment significantly reduces thrombus weight at PAI-039 doses of 3, 10 and 30 mg/kg. When PAI-039 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 PAI-039 doses of 3, 10 and 30 mg/kg. 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 PAI-039 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 PAI-039 (P<0.0001) and 627±248 mm3 for T24 xenografts treated with 20 mg/kg (P<0.0001). PAI-039 (1, 3, and 10 mg/kg) is subjected to electrolytic injury of the coronary artery. PAI-039 causes 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).

References:

1. Rebalka IA, Raleigh MJ, D'Souza DM, Coleman SK, Rebalka AN, Hawke TJ. Inhibition of PAI-1 via PAI-039 improves dermal wound closure in diabetes mellitus. Diabetes. 2015 Mar 9. pii: db141174. [Epub ahead of print] PubMed PMID: 25754958.
2. Hennan JK, Morgan GA, Swillo RE, Antrilli TM, Mugford C, Vlasuk GP, Gardell SJ, Crandall DL. 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. doi: 10.1111/j.1538-7836.2008.03063.x. Epub 2008 Jul 4. PubMed PMID: 18624980.
3. Hennan JK, Elokdah H, Leal M, Ji A, Friedrichs GS, Morgan GA, Swillo RE, Antrilli TM, Hreha A, Crandall DL. 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):710-6. Epub 2005 Apr 28. PubMed PMID: 15860572.

Products are for research use only. Not for human use.