Ximelagatran

Ximelagatran is an orally available inhibitor of thrombin [1].

Thrombin is a serine protease that converts soluble fibrinogen into insoluble fibrin, which ultimately results in the reduction of blood loss. Thrombin plays an important role in haemostasis and thrombosis [1].

Ximelagatran is an orally available thrombin inhibitor. In rats with thrombus, oral administration of ximelagatran dose-dependently reduced thrombus size with ID50 value of 15 μmol/kg. Ximelagatran (20 μmol/ kg) reduced thrombus weight to 11.1 ± 1.3 mg, compared to 27.3 ± 2.7 mg in the control group [1]. In healthy male volunteers, oral administration of ximelagatran (60 mg p.o.) significantly reduced the levels of thrombin-antithrombin complex (TAT) and prothrombin fragment 1+2 (F1+2) in shed blood at 2 and 4 h post-dosing, which returned to the normal levels at 10 h post-dosing [2]. In patients with both pulmonary embolism (PE) and deep vein thrombosis (DVT), oral administration of ximelagatran (48 mg twice daily for 6-9 days) increased plasma activated partial thromboplastin time by 2-fold and improved clinical symptoms, including dyspnoea, cough, chest pain, oedema and pain in the affected leg [3].

References:
[1].  Carlsson S, Elg M, Mattsson C. Effects of ximelagatran, the oral form of melagatran, in the treatment of caval vein thrombosis in conscious rats. Thromb Res, 2002, 107(3-4): 163-168.
[2].  Sarich TC, Eriksson UG, Mattsson C, et al. Inhibition of thrombin generation by the oral direct thrombin inhibitor ximelagatran in shed blood from healthy male subjects. Thromb Haemost, 2002, 87(2): 300-305.
[3].  Wåhlander K, Lapidus L, Olsson CG, et al. Pharmacokinetics, pharmacodynamics and clinical effects of the oral direct thrombin inhibitor ximelagatran in acute treatment of patients with pulmonary embolism and deep vein thrombosis. Thromb Res, 2002, 107(3-4): 93-99.

Synthesis of ximelagatran, melagatran, hydroxymelagatran, and ethylmelagatran in H-3 labeled form.[Pubmed:24285415]

J Labelled Comp Radiopharm. 2013 May 30;56(6):334-7.

In support of a study designed to better understand the liver toxicity of Ximelagatran, Ximelagatran, and melagatran, hydroxymelagatran and ethylmelagatran were prepared in tritium labeled form. Incorporation of tritium was achieved by hydrogen isotope exchange using Crabtree's catalyst and later with N-heterocyclic containing Ir catalyst. The tritiated product was then converted into the four target compounds to afford them in high purity and specific activity.

In Silico and In Vitro Analysis of Interaction between Ximelagatran and Human Leukocyte Antigen (HLA)-DRB1*07:01.[Pubmed:28338626]

Int J Mol Sci. 2017 Mar 24;18(4). pii: ijms18040694.

Idiosyncratic Ximelagatran-induced hepatotoxicity has been reported to be associated with human leukocyte antigen (HLA)-DRB1*07:01 and Ximelagatran has been reported to inhibit the binding of the ligand peptide to HLA-DRB1*07:01 in vitro. In order to predict the possible interaction modes of Ximelagatran with HLA-DR molecules, in silico docking simulations were performed. Molecular dynamics (MD) simulations were also performed to predict the effect of Ximelagatran on the binding mode of the ligand peptide to HLA-DRB1*07:01. A series of in silico simulations supported the inhibitory effect of Ximelagatran on the binding of the ligand peptide to HLA-DRB1*07:01 in vitro. Furthermore, direct interactions of Ximelagatran with HLA-DR molecules were evaluated in vitro, which supported the simulated interaction mode of Ximelagatran with HLA-DRB1*07:01. These results indicated that Ximelagatran directly interacts with the peptide binding groove of HLA-DRB1*07:01 and competes with the ligand peptide for the binding site, which could alter the immune response and lead to the idiosyncratic Ximelagatran-induced hepatotoxicity.

Expression and Function of mARC: Roles in Lipogenesis and Metabolic Activation of Ximelagatran.[Pubmed:26378779]

PLoS One. 2015 Sep 17;10(9):e0138487.

Recently two novel enzymes were identified in the outer mitochondrial membrane, mARC1 and mARC2. These molybdenum containing enzymes can reduce a variety of N-hydroxylated compounds, such as N-hydroxy-guanidines and sulfohydroxamic acids, as well as convert nitrite into nitric oxide (NO). However, their endogenous functions remain unknown. Here we demonstrate a specific developmental pattern of expression of these enzymes. mARC1, but not mARC2, was found to be expressed in fetal human liver, whereas both, in particular mARC2, are abundant in adult liver and also expressed in omental and subcutaneous fat. Caloric diet restriction of obese patients caused a decreased expression of mARC2 in liver, similar to that seen in the livers of starved rats. Knock down of mARC2 expression by siRNA in murine adipocytes had statistically significant effect on the level of diglycerides and on the fatty acid composition of some triglycerides, concomitantly a clear trend toward the reduced formation of most of triglyceride and phospholipid species was observed. The involvement of mARC2 in the metabolism of the hepatotoxic drug Ximelagatran was evaluated in hepatocytes and adipocytes. Ximelagatran was shown to cause oxidative stress and knock down of mARC2 in adipocytes prevented Ximelagatran induced inhibition of mitochondrial respiration. In conclusion, our data indicate that mARC1 and mARC2 have different developmental expression profiles, and that mARC2 is involved in lipogenesis, is regulated by nutritional status and responsible for activation of Ximelagatran into a mitotoxic metabolite(s).

Predicting potential liver toxicity from phase 2 data: a case study with ximelagatran.[Pubmed:24623062]

Stat Med. 2014 Jul 30;33(17):2914-23.

Ximelagatran was denied marketing approval in the USA and was withdrawn from those markets in which it had been approved, because of concerns over potential liver toxicity. A retrospective analysis of phase 2 data relating to liver toxicity is performed using the methods of extreme value modelling. The analysis reveals that the phase 2 data were predictive of the phase 3 results and, had the methods been available at the time, such analysis would have provided valuable information relating to the decision to proceed with further development of the compound.

Ximelagatran (H 376/95) is an orally active thrombin inhibitor that selectively and competitively inhibits both free and clot-bound thrombin. Ximelagatran is an anticoagulant agent with a rapid onset of anticoagulant effect, predictable, dose-dependent pharmcokinetics and pharmacodynamics.

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