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Purity: ≥98%
Rivaroxaban (BAY59-7939; BAY-59-7939; trade name: Xarelto), an approved anticoagulant drug used to treat and prevent blood clots, is the first orally bioavailable, selective and direct inhibitor of Factor Xa with potential anti-coagulant activity. It inhibits Factor Xa with a Ki and IC50 of 0.4 nM and 0.7 nM in cell-free assays, respectively. Rivaroxaban binds to the Tyr288 in S1 pocket of factor Xa through the interaction of Tyr288 and the chlorine substituent of the chlorothiophene moiety. Rivaroxabanis used as an oral anticoagulant developed by Bayer amd was marketed in many countries with the trade name of Xarelto. Rivaroxaban is well absorbed from the gut and maximum inhibition of factor Xa occurs four hours after a dose. The effects lasts 8–12 hours, but factor Xa activity does not return to normal within 24 hours so once-daily dosing is possible.
| Targets |
FXa (IC50 = 0.7 nM); FXa (Ki = 0.4 nM)
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| ln Vitro |
An oral direct Factor Xa (FXa) inhibitor called rivaroxaban (BAY 59-7939) is being developed for the treatment and prevention of venous and arterial thrombosis. Rivaroxaban inhibits prothrombinase activity (IC50 2.1 nM) and human FXa (Ki 0.4 nM) competitively with selectivity that is >10,000 times better than that of other serine proteases. In comparison to rat plasma (IC50 290 nM), human and rabbit plasma exhibit a more effective inhibition of endogenous FXa by rivaroxaban (IC50 21 nM). In human plasma, it exhibits anticoagulant properties, activating partial thromboplastin time at 0.69 μM and increasing prothrombin time (PT)[2].
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| ln Vivo |
A strong and specific direct FXa inhibitor with good oral absorption and in vivo action is rivaroxaban (BAY 59-7939)[1]. When given as an intravenous bolus prior to thrombus induction, rivaroxaban (BAY 59-7939) decreases thrombus formation (ED50 0.1 mg/kg), suppresses FXa, and dose-dependently prolongs PT. At the ED50, there is a small change in PT and FXa (1.8-fold increase and 32% inhibition, respectively). At a dosage of 0.3 mg/kg, which virtually completely blocks thrombus formation, rivaroxaban exhibits a moderate prolongation of PT (3.2±0.5-fold) and a suppression of FXa activity (65±3%)[2].
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| Enzyme Assay |
In Vitro Studies:[1]
FXa and Related Serine Proteases. The enzymatic activity against human FVIIa, FIXa, FXa, FXIa, thrombin, plasmin, trypsin, urokinase, and activated protein C was measured using chromogenic or fluorogenic substrates in 96-well microtiter plates at 25 °C. The enzymes were incubated with the test compound or its solvent (DMSO) for 10 min, and the reactions were initiated by the addition of the appropriate substrate. Color change was monitored continuously at 405 nm by a Spectra Rainbow Thermo Reader, and fluorescence was measured at 360/465 nm by a SPECTRAFluor Plus microplate reader. Substrates and enzymes were dissolved in aqua bidest or the appropriate assay buffer. Prothrombin Time (PT) Assay.[1] Commercially available kits were used to measure PT. Clotting times were measured in a coagulometer, according to the manufacturer's instructions. Increasing concentrations of inhibitor or solvent were added to plasma and incubated for 10 min at 37 °C. Clotting times were measured and compared with those from the appropriate control plasma. In VitroPlasma-Protein Binding. [1] In vitro plasma-protein binding was evaluated by an equilibrium dialysis method (Scholtan 1962). [14C]-5 was added to each aliquot of rat, dog, and human plasma to make target concentrations of 0.1, 1.0, 3.0, 10, 30, and 100 mg L-1; in addition, a target concentration of 400 mg L-1 was prepared, but only for human plasma. After incubation for 15 min at 37 °C, 0.8 mL of the spiked plasma was dialyzed with an equal volume of phosphate-buffered isotonic solution (PBS, pH 7.4) for 1 h at 37 °C in an equilibrium dialyzer equipped with 0.8 mL Teflon half cells separated by a cellulose membrane (Diachema 10.14 cellulose membrane, MWCO 5000 kDa; Dianorm GmbH). The radioactivity of [14C]-5 in the buffer and the plasma was determined by LSC. The fraction of unbound 5 (fu [%]) was calculated as follows: fu = cu/c × 100, where cu is the concentration of unbound 5 and c is the total concentration of 5. View More
X-ray Crystallography.[1] Enzyme assays[2] The activity of BAY 59-7939 against purified serine proteases was measured using chromogenic or fluorogenic substrates in 96-well microtiter plates at 25 °C. The enzymes were incubated with BAY 59-7939 or its solvent, dimethyl sulfoxide (DMSO), for 10 min. The reactions were initiated by the addition of the substrate, and the color or fluorescence was monitored continuously at 405 nm using a Spectra Rainbow Thermo Reader, or at 630/465 nm using a SPECTRAfluor plus, respectively, for 20 min (if not otherwise stated). Enzymatic activity was analyzed in the following buffers (final concentrations): human FXa (0.5 nm), rabbit FXa (2 nm), rat FXa (10 nm), or urokinase (4 nm) in 50 mm Tris–HCl buffer, pH 8.3, 150 mm NaCl, and 0.1% bovine serum albumin (BSA); Pefachrome FXa (50–800 µm) or chromozym U (250 µm) with thrombin (0.69 nm), trypsin (2.2 nm), or plasmin (3.2 nm) in 0.1 µm Tris–HCl, pH 8.0, and 20 mm CaCl2; chromozym TH (200 µm), chromozym plasmin (500 µm), or chromozym trypsin (500 µm) with FXIa (1 nm) or APC (10 nm) in 50 mm phosphate buffer, pH 7.4, 150 mm NaCl; and S 2366 (150 or 500 µm) with FVIIa (1 nm) and tissue factor (3 nm) in 50 mm Tris–HCl buffer, pH 8.0, 100 mm NaCl, 5 mm CaCl2 and 0.3% BSA, H-D-Phe-Pro-Arg-6-amino-1-naphthalene-benzylsulfonamide·H2O (100 µm) and measured for 3 h as described previously. The FIXaβ/FX assay, comprising FIXaβ (8.8 nm) and FX (9.5 nm) in 50 mm Tris–HCl buffer, pH 7.4, 100 mm NaCl, 5 mm CaCl2 and 0.1% BSA, was started by the addition of I-1100 (50 µm), and measured for 60 min. FXa activity in plasma [2] Human, rat, or rabbit plasma (45 µL) was mixed with 5 µL hirudin (10 µg mL−1), 5 µL BAY 59-7939 or DMSO, and 50 µL RVV (human, 0.7 mU mL−1; rat/rabbit, 3.5 mU mL−1), dissolved in 50 µm CaCl2 at 37 °C. Chromozym X (50 µL; 600 µm) was added after 15 min. The increase in optical density was measured at 37 °C, as described above. Coagulation assays[2] Activated partial thromboplastin time (aPTT) and prothrombin time (PT) were measured using commercially available kits. BAY 59-7939 or DMSO (3 µL) were added to 100 µL platelet-poor plasma (PPP) and incubated for 10 min at 37 °C. Clotting times were measured in a coagulometer (Biomatic 4000), in accordance with the manufacturer's instructions (final volume 303 µL). Anticoagulant activity was defined as the concentration required to double the plasma clotting times [CT2 (µm)]. Plasma preparation[2] Human blood was collected by venipuncture from healthy subjects who had not been medicated during the last 10 days. Rabbit blood was obtained by puncture of the A. carotis, and rat blood was withdrawn from the abdominal aorta under anesthesia. Blood was collected into plastic tubes containing 1/10 volume of 3.8% trisodium citrate. PPP was obtained by immediate centrifugation at 2500 g for 10 min at 4 °C, and stored at − 20 °C. |
| Animal Protocol |
Dssolved in polyethylene glycol/H2O/ glycerol (996 g/100 g/60 g) (for i.v.); and dissolved in solutol/ethanol/H2O [40%/10%/50% (v/v/v)] (for p.o.);
≤0.3 mg/kg for both i.v. and for p.o.; i.v. injection or Oral gavage; Fasted, male Wistar rats (HsdCpb:WU) and fasted, female New Zealand White rabbits (Esd:NZW). In Vivo Studies: [1] Arteriovenous (AV) Shunt Model. The antithrombotic activity was determined in an AV shunt in anesthetized rats, as described previously 21 with minor modifications: The right common carotid artery and the left jugular vein were cannulated with two 100 mm-long, saline-filled, polyethylene catheters. The catheters were connected with a 30 mm-long polyethylene tube containing a rough nylon thread (40 mm × 0.15 mm), folded to create a 20 mm-long double string. The test compound dissolved in poly(ethylene glycol)/water/glycerol (996 g/100 g/60 g) or vehicle was given by intravenous bolus injection into a tail vein 10 min before thrombus induction. Alternatively, the test compound dissolved in solutol/ethanol/water (40%/10%/50% [v/v/v]) or vehicle was administered orally 90 min before thrombus induction. The shunt was opened for 15 min, and the nylon thread covered with the thrombus was then withdrawn and weighed. Blood samples were withdrawn from the carotid artery just after thrombus removal. View More
Rat venous stasis model [2] Arteriovenous shunt model in rats and rabbits [2] An arteriovenous (AV) shunt in anesthetized rats and rabbits was performed as described previously, with minor modifications. The right common carotid artery and the left jugular vein were cannulated with two 100-mm-long, saline-filled catheters. In rats (n = 10 per dose group), the polyethylene catheters were connected with a 30-mm-long polyethylene tube containing a rough nylon thread (40 × 0.15 mm), folded into a double string. In rabbits (n = 6 per dose group), polyurethane vein catheters (outside diameter 2.1 mm) were connected with a 40-mm-long polyethylene tube, containing a rough nylon thread (60 × 0.15 mm), folded into a double string. BAY 59-7939, dissolved in solutol/ethanol/H2O [40%/10%/50% (v/v/v)], or vehicle was given orally 90 min before the shunt was opened for 15 min. The nylon thread was then withdrawn and weighed. Blood samples were withdrawn from the carotid artery just after thrombus removal. Rat tail-bleeding model[2] BAY 59-7939 (n = 10 per dose group) or vehicle was given orally 90 min before the tails of anesthetized rats were transected 2 mm from the tip and vertically immersed in saline at 37 °C. The time until continuous blood flow ceased for > 30 s was measured, with a maximum observation time of 10 min (longer bleeding times were assigned a value of 10 min). Rabbit ear-bleeding model[2] Ear-bleeding time (EBT) was determined in anesthetized rabbits (n = 5 per dose group), as described previously. A standardized 3-mm-long incision was made at different sites of the right ear in each animal 90 and 105 min after administration of oral BAY 59-7939 or vehicle. Blood from the incision was removed with filter paper every 30 s. The time until the bleeding stopped was measured. |
| References |
[1]. Roehrig S, et al. Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor. J Med Chem. 2005 Sep 22;48(19)
[2]. Perzborn E, et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939--an oral, direct Factor Xa inhibitor. J Thromb Haemost. 2005 Mar;3(3):514-21. |
| Molecular Formula |
C19H18CLN3O5S
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|---|---|
| Molecular Weight |
435.88
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| Exact Mass |
435.0655
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| Elemental Analysis |
C, 52.35; H, 4.16; Cl, 8.13; N, 9.64; O, 18.35; S, 7.36
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| CAS # |
366789-02-8
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| Related CAS # |
Rivaroxaban-d4;1132681-38-9
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| Appearance |
Typically exists as solids (or liquids in special cases) at room temperature
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| LogP |
1.84
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| tPSA |
116.42
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| SMILES |
O=C(C1=CC=C(Cl)S1)NC[C@H]2CN(C3=CC=C(N4C(COCC4)=O)C=C3)C(O2)=O
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| InChi Key |
KGFYHTZWPPHNLQ-AWEZNQCLSA-N
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| InChi Code |
InChI=1S/C19H18ClN3O5S/c20-16-6-5-15(29-16)18(25)21-9-14-10-23(19(26)28-14)13-3-1-12(2-4-13)22-7-8-27-11-17(22)24/h1-6,14H,7-11H2,(H,21,25)/t14-/m0/s1
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| Chemical Name |
(S)-5-chloro-N-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)thiophene-2-carboxamide
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| Synonyms |
BAY 59-7939; Rivaroxaban; BAY59-7939; BAY-59-7939; trade name: Xarelto.
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (5.74 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.74 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 0.5% methylcellulose+0.2% Tween 80:5 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2942 mL | 11.4710 mL | 22.9421 mL | |
| 5 mM | 0.4588 mL | 2.2942 mL | 4.5884 mL | |
| 10 mM | 0.2294 mL | 1.1471 mL | 2.2942 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT06314763 | Recruiting | Drug: Rivaroxaban 20mg Drug: Sotorasib 960mg |
Drug Drug Interaction Study | Radboud University Medical Center | November 9, 2023 | Phase 4 |
| NCT02970773 | Withdrawn | Drug: Rivaroxaban Oral Tablet | Spinal Cord Injuries Thromboembolism |
Swiss Paraplegic Research, Nottwil | December 4, 2017 | Phase 4 |
| NCT05410275 | Not yet recruiting | Drug: Rivaroxaban | Chronic Hemodialysis Patients | University Hospital, Tours | December 1, 2022 | Phase 3 |
| NCT02047006 | Completed | Drug: Rivaroxaban 10 mg | Chronic Renal Failure | AZ Sint-Jan AV | September 2013 | Phase 4 |
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