Stereochemistry | ABSOLUTE |
Molecular Formula | C22H31N5O4 |
Molecular Weight | 429.5126 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 2 / 2 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
NC(=N)C1=CC=C(CNC(=O)[C@@H]2CCN2C(=O)[C@H](NCC(O)=O)C3CCCCC3)C=C1
InChI
InChIKey=DKWNMCUOEDMMIN-PKOBYXMFSA-N
InChI=1S/C22H31N5O4/c23-20(24)16-8-6-14(7-9-16)12-26-21(30)17-10-11-27(17)22(31)19(25-13-18(28)29)15-4-2-1-3-5-15/h6-9,15,17,19,25H,1-5,10-13H2,(H3,23,24)(H,26,30)(H,28,29)/t17-,19+/m0/s1
Ximelagatran (Exanta or Exarta, H 376/95) is an anticoagulant that has been investigated extensively as a replacement for warfarin that would overcome the problematic dietary, drug interaction, and monitoring issues associated with warfarin therapy. In 2006, its manufacturer AstraZeneca announced that it would withdraw pending applications for marketing approval after reports of hepatotoxicity (liver damage) during trials, and discontinue its distribution in countries where the drug had been approved (Germany, Portugal, Sweden, Finland, Norway, Iceland, Austria, Denmark, France, Switzerland, Argentina and Brazil). Ximelagatran is a prodrug that is rapidly converted after oral administration to the active compound melagatran. Melagatran is able to inhibit thrombin activity directly and quickly. The melagatran molecule binds to the arginine side pocket of thrombin, inactivating the thrombin. Following oral administration of ximelagatran, oral bioavailability (measured as melagatran) is 18% to 25%. Peak melagatran levels after a ximelagatran dose of 48 mg twice daily are achieved within approximately 2 hours. Ximelagatran is rapidly and extensively converted to melagatran in the liver and other tissues. This conversion is achieved by ester hydrolysis and reduction via two intermediate metabolites, hydroxymelagatran, and ethylmelagatran. The predominant compound in plasma is the active drug, melagatran. The elimination half-life of melagatran after an oral dose of ximelagatran is 2.5 to 4.3 hours.
Originator
Approval Year
PubMed
Sample Use Guides
Ximelagatran is dosed twice daily (7). In patients with chronic nonvalvular atrial fibrillation, oral ximelagatran 36 mg twice daily has been shown to be effective. For VTE prophylaxis, two approaches to dosing ximelagatran have been used: monotherapy and combination therapy. A daily dose of 24 mg and 36 mg has been studied in patients undergoing knee arthroplasty. The first dose is given on the morning after surgery or at least 12 hours after surgery, and treatment is continued for 7 to 12 days. In patients undergoing total knee or hip replacement surgery, the most effective therapy has been a single dose of subcutaneous melagatran 2 mg just before surgery (knife-to-skin) followed by melagatran 3 mg subcutaneously after surgery and then oral ximelagatran 24 mg twice daily for a total treatment duration of 8 to 11 days.
Route of Administration:
Oral
The potent inhibition of thrombin by melagatran was demonstrated by a low inhibition constant (Ki) for thrombin (0.002 micromol/l) and prolongation of clotting time to twice the control value in coagulation assays at low concentrations (0.010, 0.59 and 2.2 micromol/l for thrombin time, activated partial thromboplastin time and prothrombin time, respectively). Furthermore, thrombin-induced platelet aggregation was inhibited at the same concentration (IC50-value 0.002 micromol/l) as the Ki-value for thrombin. In two assays of global fibrinolysis, inhibition was observed at a concentration of 1.1 micromol/l in a euglobulin plasma fraction model, while no inhibition was observed at a concentration of < or = 10 micromol/l in a plasma model.