Dabigatran

2 years -80 in solvent

Administered via i.v.

Dabigatran has entered in a phase III clinical trial in the treatment of atrial fibrillation.

BIBR 953 is a very potent anticoagulant. BIBR 953 shows that the terminal phenyl can be substituted by the more hydrophilic 2-pyridyl group without substantial loss of activity. BIBR 953 inhibits thrombin, plasmin, factor Xa, trypsin, tPA and activated protein C with Ki of 4.5 nM, 1.7 uM, 3.8 uM, 50 nM, 45 uM and 20 uM, respectively. [1] BIBR 953 specifically and reversibly inhibits thrombin. [2]

Measurement of thrombin inhibition, The thrombin inhibitory effects (IC50) of BIBR 953 is determined with a commercially available chromogenic assay. Human thrombin (0.042 U/mL) is preincubated for 10 minutes at 37 C with 10 different dilutions (concentration range of 0.003 uM -100 uM) of BIBR 953 dissolved in DMSO or with DMSO as control. Upon addition of the preincubation mixture to the chromogenic substrate, tosyl-glycyl-prolyl-arginine-4-nitranilide acetate, nitraniline is cleaved by thrombin and the increase in absorbance at 405 nm, related to the free nitraniline, is measured in a spectrophotometer. By plotting the absorbance at 405 nm vs the concentration of BIBR 953, the concentration that induces a 50% thrombin inhibition (IC50) is calculated. All measurements are performed in duplicate, and the mean values of both determinations are represented.

Dabigatran is a potent nonpeptide thrombin inhibitor with an IC50 of 9.3 nM in a cell-free assay.

Dabigatran is a reversible, competitive, direct thrombin inhibitor.