Description

Cardiovascular Disease

Description

BIBR 953 (Dabigatran, Pradaxa) is potent nonpeptide thrombin inhibitor with an IC50 of 9.3 nM.

Targets

IC₅₀

In Vitro

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 μM, 3.8 μM, 50 nM, 45 μM and 20 μM, respectively. ^[1] BIBR 953 specifically and reversibly inhibits thrombin. ^[2]

In Vivo

BIBR 953 exhibits the most favorable activity profile following i.v. administration to rats. ^[1] The bioavailability of dabigatran after p.o. administration of dabigatran etexilate is 7.2%. Dabigatran is predominantly excreted in the feces after p.o. treatment and in the urine after i.v. treatment. The mean terminal half-life of dabigatran is approximately 8 hours. Dabigatran acylglucuronides accounts for 0.4% and 4% of the dose in urine after p.o. and i.v. dosing, respectively. ^[3]

Clinical Trials

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

Features

Dabigatran is a reversible, competitive, direct thrombin inhibitor.

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 μM -100 μM) 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.

Animal Models

Rats

Formulation

Doses

Administration

Administered via i.v.