Design,Synthesis And Anticoagulant Activity Evaluation Studies Of A Class Of N-ethyl Dabigatran Deribatives

Dabigatran is a new oral anticoagulant drug belonging to the class of direct thrombin inhi-bitor.This drug is superior to other anticoagulants because of the following practical advantages: predictable anticoagulant effect, oral administration, no need for monitoring, and few drug interactions. Dabigatran etexilate has a good market prospect. However, the bioavailability after oral administration of dabigatran etexilate is 7.2%, and it also has a risk of life-threatening hemorrhage.In this paper, a class of N-ethyl dabigatran derivatives was designed based on pharmaco-logical strategies for inhibition of thrombin activity and the structure-activity relationship stu-dies of the previous dabigatran derivatives. Activities of these novel compounds were predicted based on CoMFA model and most of the compounds had comparable predicted activity with dabigatran. All of screened compounds were synthesized and characterized by 1H NMR, 13C NMR and HRMS. Subsequently, these compounds were evaluated inhibitory activity on thrombin. Among these compounds,9a-9e,9h,91-9n and 9p exhibited comparable inhibitory activity to dabigatran (IC50= 1.20 nM), additionally, compound 9p (IC50= 0.96 nM) exhibited better inhibitory activity than dabigatran. Moreover, compound 9p also exhibited a fairly good inhibitory activity for arteriovenous thrombosis with inhibition rate of (85.35±0.72)%, which was comparable to that of dabigatran (85.07±0.61)%. These results, along with related mo-lecular docking studies, could provide an important basis for further development of compound 9p as a potent thrombin inhibitor.