Uses
BIBR-1048 (Dabigatran) is an anticoagulant from the class of the direct thrombin inhibitors. It is being studied for various clinical indications and in many cases it offers an alternative to warfarin as the preferred orally administered blood thinner sin
Definition
ChEBI: An aromatic amide obtained by formal condensation of the carboxy group of 2-{[(4-{N'-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H-benzimidazole-5-carboxylic acid with the secondary amino group of
thyl N-pyridin-2-yl-beta-alaninate. A prodrug for dabigatran, a thrombin inhibitor and anticoagulant which is used for the prevention of stroke and systemic embolism.
Originator
Boehringer Ingelheim (Germany)
Synthesis
The chemical synthesis of
dabigatran etexilate starts with the acylation of ethyl 3-(2-pyridylamino)propionate
with 4-(methylamino)-3-nitrobenzoyl chloride to produce
the corresponding amide. Subsequent reduction of the nitro group by
catalytic hydrogenation, and cyclization of the resultant phenylenediamine
with N-(4-cyanophenyl)glycine leads to a benzimidazole intermediate.
The cyano group is then transformed into an amidine by
employing the Pinner reaction. Finally, acylation of the amidino group
with hexyl chloroformate gives rise to dabigatran etexilate.
in vitro
dabigatran showed anticoagulant effects in a concentration-dependent manner. it doubled the activated partrial thromboplastin time, prothrombin time and ecarin clotting in human ppp. [1]
Drug interactions
Potentially hazardous interactions with other drugs
Analgesics: possible increased risk of bleeding with
NSAID’s; increased risk of haemorrhage with
ketorolac or IV diclofenac - avoid.
Anti-arrhythmics: concentration increased
by amiodarone, reduce dose of dabigatran;
concentration increased by dronedarone - avoid.
Antibacterials: concentration reduced by rifampicin
- avoid; possibly increased risk of bleeding with
clarithromycin.
Anticoagulants: increased risk of haemorrhage with
other anticoagulants - avoid.
Antidepressants: possible increased risk of bleeding
with SSRIs; concentration possibly reduced by St
John’s wort - avoid.
Antifungals: concentration increased by ketoconazole
and possibly itraconazole - avoid
Ciclosporin: concentration possibly increased by
ciclosporin - avoid.
Sulfinpyrazone: possible increased risk of bleeding.
Tacolimus: concentration possibly increased by
tacrolimus - avoid.
Ticagrelor: concentration of dabigatran increased.
Verapamil: reduce dose of dabigatran to 150 mg
daily, 75 mg in GFR=30-50mL/min.
Metabolism
Dabigatran etexilate is a prodrug which does not exhibit
any pharmacological activity. After oral administration,
dabigatran etexilate is rapidly absorbed and converted to
dabigatran by esterase-catalysed hydrolysis in plasma and
in the liver. Dabigatran is a potent, competitive, reversible
direct thrombin inhibitor and is the main active principle
in plasma.
Mainly excreted in the urine (85%) and 6% via the faeces.
References
1. wienen w, stassen jm, priepke h et al. in-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. thromb haemost. 2007 jul;98(1):155-62.2. connolly sj, ezekowitz md, yusuf s et al. dabigatran versus warfarin in patients with atrialfibrillation. n engl j med. 2009 sep 17;361(12):1139-51.
