title: Synthesis and antithrombotic evaluation of novel dabigatran prodrugs containing a cleavable moiety with anti-platelet activity.
abstract: 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).
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China.
authors.forename: Xiao-Zhi
authors.initials: XZ
authors.lastname: Yang
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Yang
authors.forename: Yun-Gen
authors.initials: YG
authors.lastname: Xu
authors.forename: Xiao-Juan
authors.initials: XJ
authors.lastname: Diao
authors.forename: Guang-Wei
authors.initials: GW
authors.lastname: He
authors.forename: Guo-Qing
authors.initials: GQ
authors.lastname: Gong
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D000069604:Dabigatran; D015195:Drug Design; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000494:pharmacology; D020246:Venous Thrombosis / Q000188:drug therapy / Q000378:metabolism
chemical_list: C115263:2-hydroxymethyl-3,5,6-trimethylpyrazine; D001562:Benzimidazoles; D010975:Platelet Aggregation Inhibitors; D011355:Prodrugs; D011719:Pyrazines; D011725:Pyridines; D000244:Adenosine Diphosphate; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D013917:Thrombin; D000069604:Dabigatran