Dabigatran etexilate (BIBR-1048)- Pharmacology

Dabigatran etexilate (Pradaxa, BIBR 1048, Boehringer Ingelheim) is the prodrug of dabigatran (originally known as BIBR 953), a potent, nonpeptidic small molecule that specifically and reversibly inhibits both free and clot-bound thrombin by binding to the active site of the thrombin molecule.[1] 

Dabigatran was discovered using a structure-activity approach, based on the x-ray crystal structure of a peptide-like benzamidine-based thrombin inhibitor, N-a-naphthylsulphonylglycyl-4-amidinophenylalanine piperidine (a-NAPAP), complexed with bovine thrombin. The amidine group of dabigatran forms a salt bridge with the carboxylate of aspartate residue Asp189. Hydrophobic interactions are formed by the piperidine ring and the moiety with the proximal and distal pocket of the active site of thrombin. Because of its high polarity, dabigatran is not orally available; therefore, the prodrug of dabigatran, dabigatran etexilate, was developed to facilitate gastrointestinal absorption. This was achieved by adding an ethyl group at the carboxylic acid group and a hexyloxycarbonyl side chain at the amidine group (Figure 1).[2-3]

Dabigatran competitively inhibits human thrombin in a concentration-dependent manner, with an inhibition constant (Ki) of 4.5 nmol/L, comparable with melagatran (11.2 nmol/L). Thrombin is the most potent physiological agonist of platelet activation and aggregation. Dabigatran displays highly selective, rapid, and reversible binding to thrombin and potently inhibits platelet aggregation with a concentration that produces 50% inhibition similar to the Ki of thrombin. In addition, dabigatran inhibits tissue factor-induced thrombin generation in human platelet-poor plasma in a concentration-dependent manner and decreases endogenous thrombin generation. Dabigatran potently inhibits platelet aggregation, with a concentration that produces 50% inhibition (IC50) similar to the Ki of thrombin.[4] The antithrombotic and anticoagulant effects of dabigatran and its prodrug were investigated in a rabbit model of venous thrombosis. In the rabbit jugular vein, dabigatran reduced thrombus formation in a dose-dependent manner with a dose that produced a 50% effective response (ED50) of 4.65 mg/kg, demonstrating effective antithrombotic activity. Thrombus formation was almost maximally reduced with 10 mg/kg of dabigatran etexilate within 1 hour pretreatment, indicating a fast onset of action.[5] 

The preclinical data showed oral dabigatran etexilate to be an effective antithrombotic agent that warranted clinical development for the prophylaxis and treatment of venous thromboembolism (VTE).

References

1.Wienen W, Stassen JM, Priepke H, Ries UJ, Hauel N. Invitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate[J]. Thromb Haemost. 2007, 98(1):155-162.
2.Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W. Structure-based design of novel potent nonpeptide thrombin inhibitors[J]. J Med Chem. 2002, 45(9):1757-1766.
3.Stangier J, Rathgen K, Stahle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects[J]. Br J Clin Pharmacol. 2007, 64(3):292-303.
4.Wienen W, Stassen JM, Priepke H. Antithrombotic and anticoagulant effects of the direct thrombin inhibitor dabigatran, and its oral prodrug, dabigatran etexilate, in a rabbit model of venous thrombosis[J]. J Thromb Haemost 2007, 5 (6): 1237-42
5.Wienen W, Nar H, Ries UJ. Antithrombotic effects of the direct thrombin inhibitor BIBR-953ZW and its orally active prodrug BIBR-1048MS in a model of venous thrombosis in rabbits [J]. J Thromb Haemost 2001, 86 Suppl.: OC853