ABSTRACT
A novel series of prodrugs containing dabigatran and methyl (E)-3-(4-hydroxy-2-methoxyphenyl)propenoate (methyl ferulate) were synthesized. All of them reveal the effect of thrombin-induced anti-platelet aggregation in vitro. In addition, in vivo experiment shows that one of the target compounds, X-2 (ED50=3.7 ± 1.0 µmol/kg) possesses a more potent activity for inhibiting venous thrombosis than that of dabigatran etexilate (ED50=7.8 ± 1.5 µmol/kg).
Subject(s)
Drug Design , Fibrinolytic Agents/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Prodrugs/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Caffeic Acids/chemistry , Dabigatran , Dose-Response Relationship, Drug , Fibrinolytic Agents/chemical synthesis , Fibrinolytic Agents/chemistry , Humans , Molecular Structure , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/chemistry , Prodrugs/chemical synthesis , Prodrugs/chemistry , Pyridines/pharmacology , Thrombin/metabolism , Venous Thrombosis/drug therapy , beta-Alanine/analogs & derivatives , beta-Alanine/chemistryABSTRACT
A novel series of prodrugs consisting of dabigatran and 2-hydroxymethyl-3,5,6-trimethylpyrazine (HTMP) were synthesized. The pharmacological results show that all of them possess the effect of anti-platelet aggregation induced by thrombin in vitro. Moreover, one of those compounds, Y-2 (ED(50) = 2.1 ± 1.3 mg/kg) shows more potent activity for inhibiting thrombosis in vivo than that of dabigatran etexilate (ED(50) = 4.4 ± 2.2 mg/kg).
