Disease relevance of Tiplasinin

• To investigate the effect of tiplaxtinin, designed as a synthetic inhibitor of plasminogen activator inhibitor-1 (PAI-1), on obesity, male C57Bl/6 mice (13-14 weeks old) were kept on a high-fat diet (20.1 kJ/g) for four weeks without or with addition of tiplaxtinin (PAI-039) at a dose of 2 mg/g food [1].
• Although occlusive thrombosis was observed across all groups based upon the absence of measurable blood flow, a high incidence (>60%) of spontaneous reperfusion occurred only in those groups receiving PAI-039 [2].
• In conclusion, 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 [2].
• In a model of diet-induced obesity, pair-fed C57 Bl/6 mice administered PAI-039 in a high-fat diet exhibited a dose-dependent reduction in body weight, epididymal adipose tissue weight, adipocyte volume, and circulating plasma active PAI-1 [3].
• METHODS: Aged male wild-type (WT) or transgenic mice with adipose tissue overexpression of PAI-1 (45-55 weeks) in 50% C57Bl/6: 50% Friend Virus B-strain (FVB) genetic background, kept on normal chow, were used without or with administration of a synthetic low molecular weight PAI-1 inhibitor (PAI-039) to the food (1 mg g(-1)) for 4 weeks [4].

High impact information on Tiplasinin

• SDS-PAGE indicated that PAI-039 inactivated PAI-1 predominantly through induction of PAI-1 substrate behavior [5].
• This was confirmed by site-directed mutagenesis and molecular modeling studies, which suggest that the binding epitope for PAI-039 is localized adjacent to the previously identified interaction site for vitronectin [5].
• 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 [2].
• 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 [2].
• Plasma PAI-1 activity was reduced in all drug-treated groups (percentage of reduction in activity p < 0.05; 10 mg/kg PAI-039), whereas ADP-, 9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F(2alpha) (U46619)-, and collagen-induced platelet aggregation, as well as template bleeding and prothrombin time, remained unaffected by PAI-039 [2].

Biological context of Tiplasinin

• Addition of PAI-039 to the food did not significantly affect total body fat, weight of the isolated s.c. and gonadal fat territories or their adipocyte size and blood vessel composition in either genotype [4].

Anatomical context of Tiplasinin

• Dogs received by oral gavage either vehicle (control) or the PAI-1 inhibitor PAI-039 [{1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid] (1, 3, and 10 mg/kg) and were subjected to electrolytic injury of the coronary artery [2].
• In a tumor angiogenesis model, PAI-039 treatment of wild-type mice dose-dependently decreased hemoglobin concentration and endothelial cell staining within the Matrigel implant, indicating reduced angiogenesis, but exhibited no in vivo efficacy in PAI-1 null mice [6].
• Objectives: We hypothesized that an orally active small molecule inhibitor of PAI-1 (PAI-039; tiplaxtinin) could affect smooth muscle cell (SMC) attachment and migration in vitro on a vitronectin matrix, and exhibit antiangiogenic activity in vivo [6].

Associations of Tiplasinin with other chemical compounds

• Plasma glucose, triglycerides, and leptin were also significantly reduced in drug-treated mice, and concentrations of PAI-039 associated with these physiological effects were near the in vitro IC(50) for the inhibition of PAI-1 [3].

Gene context of Tiplasinin

• Differentiation of human preadipocytes to adipocytes was associated with leptin synthesis, which was significantly reduced in the presence of PAI-039, together with an atypical adipocyte morphology characterized by a reduction in the size and number of lipid containing vesicles [3].

Analytical, diagnostic and therapeutic context of Tiplasinin

• Previously PAI-039 has been shown to exhibit in vivo activity in various animal models, but the mechanism of inhibition is unknown [5].
• Spontaneous reperfusion in the 10 mg/kg PAI-039 group accounted for total blood flow (area under the curve of coronary blood flow) of 99.6 +/- 11.7 ml after initial thrombotic occlusion (p < 0.05 compared with control) [2].

References