Background
Otamixaban (FXV673) is a potent, selective, rapid acting, competitive and reversible inhibitor of factor Xa with IC50 value of 0.4 nM.[5]
Factor Xa is a serine endopeptidase which is activated into factor Xa by both factor IX with its cofactor, factor VIII known as intrinsic Xase, and factor VII with its cofactor, tissue factor. Factor Xa (fXa) is a pivotal serine protease situated at the juncture of the intrinsic and extrinsic pathways of the blood coagulation cascade.[2] Its singular role in thrombin activation and potentiating effects on clot formation makes it as a target for therapeutic intervention. FXa is responsible for the initiation of the coagulation cascade,[3] cleaving prothrombin to its active form thrombin, which then acts to convert soluble fibrinogen to insoluble fibrin and to activate platelets. Stabilization of the platelet aggregation by fibrin mesh ultimately leads to clot formation.[4] Thus, the inhibition of fXa (in the physiologically relevant prothrombinase complex) represents an attractive target for the development of novel antithrombotic agents.[5]
Otamixaban (FXV673) selectively and competitively inhibit FXa, suppressing prothrombin activity at the sites of blood clot (thrombus) formation. This leads to a decrease in blood clot formation in a dose dependent manner.[1] Reducing blood clot formation will decrease blood flow blockages, thus possibly lowering the risk of myocardial infarction, unstable angina, venous thrombosis, and ischemic stroke.[6] In conclusion, FXV673 is an effective inhibitor of fXa in the physiologically relevant human prothrombinase complex. Recently a new series of specific, direct acting inhibitors of Factor Xa has been developed. And they may be more effective against Factor Xa in that they inhibit both free Factor Xa and Factor Xa in the prothrombinase complex.[7]
参考文献:
1.K. R. Guertin et al. Optimization of the-Aminoester Class of Factor Xa Inhibitors.Part 2: Identification of FXV673 as a Potent and Selective Inhibitor with Excellent In Vivo Anticoagulant Activity. Bioorg. Med. Chem. Lett. 12 (2002) 1671–1674.
2.Meyer-Michel Samama. et al. Monitoring plasma levels of factor Xa inhibitors: how, why and when? Expert Rev. Hematol.2013, 6(2), 155-164.
3.Rebello SS1. et al. Antithrombotic efficacy of a novel factor Xa inhibitor, FXV673, in a canine model of coronary artery thrombolysis. Br J Pharmacol. 2001 Aug;133(7):1190-8.
4.Valeria Chu. et al. Pharmacological Characterization of a Novel Factor Xa Inhibitor, FXV673. Thrombosis Research 103 (2001) 309–324.
5.Katsung, B., S. Masters and A. Trevor. Basic and Clinical Pharmacology 11th Edition. United States of America: McGraw-Hill, 2009.
6.Rebello SS1. et al. Role of short-term inhibition of factor Xa by FXV673 in arterial passivation: a study in a chronic model of thrombosis in conscious dogs. J Cardiovasc Pharmacol. 2001,38(2):288-97.
7.Turpie AG. "Oral, Direct Factor Xa Inhibitors in Development for the Prevention and Treatment of Thromboembolic Diseases". Arterioscler Thromb Vasc Biol,2007,27 (6): 1238-47.
Protocol
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Vitro experiment [1]:
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Samples
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plasma derived from humans, primates, dogs, rabbits and rats
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Preparation method
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The solubility of this compound in DMSO is >22.4mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
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Reacting condition
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100 ng/mL
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Applications
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The anticoagulant effect of Otamixaban in plasma was rabbit>human>monkey>rat>dog. Humans were approximately 2.5 fold more sensitive to otamixaban than dogs in both the PT and aPTT assays. 100 ng/mL would be the effective plasma concentration to target for human clinical studies.
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Animal experiment [1]:
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Animal models
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rat model of ferrous chloride-induced arterial thrombosis
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Dosage form
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50 μg/kg bolus and 5 μg/kg/min i.v. maintenance infusion
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Application
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In rat model of ferrous chloride-induced arterial thrombosis, Otamixaban exhibited a dose-dependent increase in time to occlusion with a maximal effective dose at about 50 μg/kg bolus and 5 μg/kg/min i.v. maintenance infusion. Compared to control, this dose caused a 40% reduction in thrombus mass.
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
[1] Guertin KR1, Choi YM. The discovery of the Factor Xa inhibitor otamixaban: from lead identification to clinical development. Curr Med Chem. 2007;14(23):2471-81.
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