Effect of sepimostat mesilate on experimental venous thrombosis in rats.
Sepimostat mesilate (FUT-187: 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl) amino] benzoate dimethane sulfonate) is a newly synthesized serine protease inhibitor. In the present study, the oral administration of FUT-187 inhibited stasis-induced venous thrombosis in rats. We supposed that such effect of this compound was caused by its inhibitory effect on coagulation. However, the dose of FUT-187 that was effective at inhibiting thrombosis (10 and 30 mg/kg, po) had no effect on the plasma recalcification time (PRCT), activated partial thromboplastin time (APTT) and prothrombin time (PT) in rats. Therefore, we investigated the fibrinolytic activity of FUT-187 in rat plasma. The results revealed that rat plasma after FUT-187 administration exhibited increased amidolytic activity for a plasmin-, tissue-type plasminogen activator (t-PA)-, urokinase-type plasminogen activator (u-PA)-, factor Xa-, factor XIa- and factor XIIa-sensitive synthetic peptide substrate. On the other hand, the inhibitory effect of FUT-187 in the thrombosis model was not affected by additional treatment with epsilon-amino-n-caproic acid (EACA), a plasmin-mediated fibrinolysis inhibitor. These results suggest that even if FUT-187 enhanced fibrinolysis, it would be independent of a plasmin-mediated fibrinolytic pathway. To characterize the fibrinolytic activity, which might reduce the thrombus weight in the thrombosis model administered FUT-187, we carried out fibrinogen zymography, and clarified that FUT-187 enhanced the formation of a 20-kDa fibrinolytic fragment. Interestingly, this fragment was not affected by t-PA. Consequently, we consider that the inhibitory effect of FUT-187 on venous thrombosis model is caused by fibrinolysis, which is attributable to the 20-kDa fragment, rather than by inhibition of thrombus formation.
Research Laboratories, Torii Pharmaceutical Co., Ltd., 1-2-1 Ohnodai, Chiba 267-0056, Midori, Japan.
A
A
Tsuruda
S
S
Kanno
H
H
Ohtani
R
R
Suzuki
M
M
Nishioka
Y
Y
Koshiyama
M
M
Kurumi
D000818:Animals; D005342:Fibrinolysis / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D020246:Venous Thrombosis / Q000188:drug therapy*
D007093:Imidazoles; D011480:Protease Inhibitors; C058875:sepimostate mesilate