Design, synthesis and antithrombotic evaluation of novel dabigatran prodrugs containing methyl ferulate

• Published in: Bioorganic & medicinal chemistry letters 2013-04, Vol.23 (7), p.2089-2092
• Main Authors: Yang, Xiao-Zhi, Diao, Xiao-Juan, Yang, Wen-Hui, Li, Feng, He, Guang-Wei, Gong, Guo-Qing, Xu, Yun-Gen
• Format: Article
• Language: English
• Subjects: Anti-platelet aggregation; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; beta-Alanine - analogs & derivatives; beta-Alanine - chemistry; Caffeic Acids - chemistry; chemistry; Dabigatran; Dose-Response Relationship, Drug; Drug Design; Ferulic acid; Fibrinolytic Agents - chemical synthesis; Fibrinolytic Agents - chemistry; Fibrinolytic Agents - pharmacology; Humans; in vivo studies; Methyl ferulate; Molecular Structure; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - chemical synthesis; Platelet Aggregation Inhibitors - chemistry; Platelet Aggregation Inhibitors - pharmacology; Prevention and treatment of thrombosis; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Pyridines - pharmacology; Thrombin - metabolism; Thrombin inhibitors; thrombosis; Venous Thrombosis - drug therapy
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.01.126

The activity for inhibiting thrombosis of X-2 might originate from two parts: the anti-thrombin effect of dabigatran and the anti-platelet aggregation activity of methyl ferulate. 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±1.0μmol/kg) possesses a more potent activity for inhibiting venous thrombosis than that of dabigatran etexilate (ED50=7.8±1.5μmol/kg).