pai-039 and Thrombosis

Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of fibrinolysis and regulates cell migration and fibrosis. Preclinical studies using genetically altered mice and biological or small molecule inhibitors have elucidated a role for PAI-1 in the pathogenesis of thrombosis, vascular remodeling, renal injury, and initiation of diabetes. Inhibition of PAI-1 is a potential therapeutic strategy in these diseases.

Topics: Animals; Atherosclerosis; Fibrinolysis; Humans; Indoleacetic Acids; Kidney Diseases; Plasminogen Activator Inhibitor 1; Pulmonary Fibrosis; Thrombosis

Two novel series of 5-nitro-2-phenoxybenzoic acid derivatives are designed as potent PAI-1 inhibitors using hybridization and conformational restriction strategy in the tiplaxtinin and piperazine chemo types. The lead compounds 5a, 6c, and 6e exhibited potent PAI-1 inhibitory activity and favorable oral bioavailability in the rodents.

Topics: Administration, Oral; Animals; Benzoates; Biological Availability; Disease Models, Animal; Drug Design; Drug Discovery; Drug Evaluation, Preclinical; Indoleacetic Acids; Male; Molecular Structure; Phenyl Ethers; Piperazine; Piperazines; Plasminogen Activator Inhibitor 1; Rats; Rats, Wistar; Structure-Activity Relationship; Thrombosis

To assess the antithrombotic and profibrinolytic effects of tiplaxtinin (PAI-039), an orally bioavailable antagonist of PAI-1, in rat models of thrombosis.. 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.. PAI-039 exerts antithrombotic efficacy in rat models of arterial and venous vascular injury without effecting platelet aggregation.

Topics: Administration, Oral; Animals; Biological Availability; Disease Models, Animal; Indoleacetic Acids; Male; Plasminogen Activator Inhibitor 1; Platelet Aggregation; Prothrombin Time; Rats; Rats, Sprague-Dawley; Thrombosis

The increased risk of thrombotic events associated with disease states such as diabetes and hypertension has been correlated with elevated circulating levels of Plasminogen Activator Inhibitor type-1 (PAI-1). In the present study we evaluate the benzothiophene derivative S35225 in comparison with two recently described inhibitors of PAI-1 activity Tiplaxtinin and WAY140312 on a panel of PAI-1 activity assays in vitro and in vivo. In a direct chromogenic assay, S35225 has an IC50 value of 44+/-0.9 microM similar to that of Tiplaxtinin (34+/-7 microM) and of WAY140312 (39+/-1 microM). In a clot lysis assay however, S35225 has a significantly lower IC50 value than Tiplaxtinin and WAY140312 (0.6+/-0.3 versus 22+/-5 and 16+/-2 microM respectively). Using a tPA capture assay to quantify active PAI-1 in rat or human plasma, neither WAY140312, nor Tiplaxtinin attained 50% inhibition of PAI-1 activity at the highest concentration tested (1 mM); S35225 has an IC50 value of 194+/-30 microM against active rat PAI-1 and 260+/-41 microM against active human PAI-1. The ability of the compounds to inhibit endogenous active PAI-1 in the rat following intravenous administration was also tested using the tPA capture assay. Only S35225 reduced circulating active PAI-1 levels in vivo (maximum inhibition of 76+/-5% at 10 mg/kg and 53+/-5% at 3 mg/kg). In contrast to Tiplaxtinin and WAY140312, S35225 is a direct inhibitor of PAI-1 activity in vitro in rat and human plasmas where vitronectin is constitutively present as well as in vivo in the blood after an intravenous administration in the rat.

Topics: Animals; Biphenyl Compounds; Dose-Response Relationship, Drug; Humans; Indoleacetic Acids; Infusions, Intravenous; Inhibitory Concentration 50; Models, Chemical; Plasminogen Activator Inhibitor 1; Rats; Recombinant Proteins; Risk; Thiophenes; Thrombosis; Time Factors; Tissue Plasminogen Activator; Vitronectin