MCE蚂蚁淘在线

Rivaroxaban(BAY59-7939)isanoral,directFactorXa(FXa)inhibitorindevelopmentforthepreventionandtreatmentofarterialandvenousthrombosis.RivaroxabancompetitivelyinhibitshumanFXa(K_i0.4nM)with>10000-foldgreaterselectivitythanforotherserineproteases;italsoinhibitsprothrombinaseactivity(IC₅₀2.1nM).RivaroxabaninhibitsendogenousFXamorepotentlyinhumanandrabbitplasma(IC₅₀21nM)thanratplasma(IC₅₀290nM).Itdemonstratesanticoagulanteffectsinhumanplasma,doublingprothrombintime(PT)andactivatespartialthromboplastintimeat0.23and0.69μM,respectively^[2].

InVivo

Rivaroxaban(BAY59-7939)isapotentandselective,directFXainhibitorwithexcellentinvivoactivityandgoodoralbioavailABIlity^[1].Rivaroxaban(BAY59-7939),admiNISTeredbyi.v.bolusbeforethrombusinduction,reducesthrombusformation(ED₅₀0.1mg/kg),inhibitsFXa,andprolongsPTdosedependently.PTandFXaareaffectedslightlyattheED₅₀(1.8-foldincreaseand32%inhibition,respectively).At0.3mg/kg(doseleADIngtoalmostcompleteinhibitionofthrombusformation),RivaroxabanmoderatelyprolongsPT(3.2±0.5-fold)andinhibitsFXaactivity(65±3%)^[2].

ClinicalTrial

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References

[1].RoehrigS,etal.Discoveryofthenovelantithromboticagent5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide(BAY59-7939):anoral,directfactorXainhibitor.JMedChem.2005Sep22;48(19)
[2].PerzbornE,etal.InvitroandinvivostudiesofthenovelantithromboticagentBAY59-7939--anoral,directFactorXainhibitor.JThrombHaemost.2005Mar;3(3):514-21.

PreparingStockSolutions

ConcentrationVolumeMass	1mg	5mg	10mg

1mM	2.2942mL	11.4710mL	22.9421mL
5mM	0.4588mL	2.2942mL	4.5884mL
10mM	0.2294mL	1.1471mL	2.2942mL

Pleaserefertothesolubilityinformationtoselecttheappropriatesolvent.

KinaseAssay
^[2]

TheactivityofRivaroxaban(BAY59-7939)againstpurifiedserineproteasesismeasuredusingchromogenicorfluorogenicsubstratesin96-wellmicrotiterplatesat25°C.TheenzymesareincubatedwithRivaroxabanoritssolvent,DMSO,for10min.Thereactionsareinitiatedbytheadditionofthesubstrate,andthecolororfluorescenceismonitoredcontinuouslyat405nmusingaSpectraRainbowThermoReader,orat630/465nmusingaSPECTRAfluorplus,respectively,for20min.Enzymaticactivityisanalyzedinthefollowingbuffers(finalconcentrations):humanFXa(0.5nM),rabbitFXa(2nM),ratFXa(10nM),orurokinase(4nM)in50mMTris-HClbuffer,pH8.3,150mMNaCl,and0.1%bovineserumalbumin(BSA);PefachromeFXa(50-800μM)orchromozymU(250μM)withthrombin(0.69nM),trypsin(2.2nM),orplasmin(3.2nM)in0.1μMTris-HCl,pH8.0,and20mMCaCl₂;chromozymTH(200μM),chromozymplasmin(500μM),orchromozymtrypsin(500μM)withFXIa(1nM)orAPC(10nM)in50mMphosphatebuffer,pH7.4,150mMNaCl;andS2366(150or500μM)withFVIIa(1nM)andtissuefactor(3nM)in50mMTris-HClbuffer,pH8.0,100mMNaCl,5mMCaCl₂and0.3%BSA,H-D-Phe-Pro-Arg-6-amino-1-naphthalene-benzylsulfon-amideH₂O(100μM)andmeasuredfor3h.TheFIXab/FXassay,comprisingFIXab(8.8nM)andFX(9.5nM)in50mMTris-HClbuffer,pH7.4,100mMNaCl,5mMCaCl₂and0.1%BSA,isstartedbytheadditionofI-1100(50μM),andmeasuredfor60min.Theinhibitoryconstant(K_i)againstFXaiscalculatedaccordingtotheCheng-Prusoffequation(K_i=IC₅₀/1+[S]/K_m),where[S]isthesubstrateconcentration,andK_mistheMichaelis-Mentenconstant.K_misdeterminedfromaLineweaver-Burkplot.TheIC₅₀istheamountofinhibitorrequiredtodiminishtheinitialvelocityofthecontrolby50%^[2].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

AnimalAdministration
^[2]

Rivaroxaban(BAY59-7939)isdissolvedinpolyethyleneglycol/H2O/glycerol(Rat)^[2].

Rat^[2]
Fasted,maleWistarrats(HsdCpb:WU)areused.RatvenousstasismodelThrombusformationisinducedinanesthetizedrats(n=10perdosegroup),withminormodifications.TheaBDominalvenacavaisexposedandtwoloosesutures(8-10mmapart)areplacedbelowtheleftrenalvenousbranch.Rivaroxabandissolvedinpolyethyleneglycol/H₂O/glycerol(996g/100g/60g),orvehicleisgivenbyintravenous(i.v.)bolusinjectionintoatailvein15minbeforethrombusinduction.Thromboplastin(0.5mg/kg)isinjectedintoafemoralveinand,after15s,theproximalanddistalsuturesaretied.Fifteenminuteslater,theligatedsegmentisremoved,thethrombuswithdrawnandweighed.Bloodsamplesareobtainedbycardiacpunctureimmediatelybeforethrombusremoval.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

References

[1].RoehrigS,etal.Discoveryofthenovelantithromboticagent5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide(BAY59-7939):anoral,directfactorXainhibitor.JMedChem.2005Sep22;48(19)
[2].PerzbornE,etal.InvitroandinvivostudiesofthenovelantithromboticagentBAY59-7939--anoral,directFactorXainhibitor.JThrombHaemost.2005Mar;3(3):514-21.

MolecularWeight

435.88

Formula

C₁₉H₁₈ClN₃O₅S

CASNo.

366789-02-8

Storage

Powder	-20°C	3years
	4°C	2years
Insolvent	-80°C	6months
	-20°C	1month

Shipping

RoomtemperatureincontinentalUS;mayvaryelsewhere

Solvent&Solubility

10mMinDMSO

*"<1 mg/ml"="" means="" slightly="" soluble="" or="" insoluble.="" "≥"="" means="" soluble,="" but="" saturation="">

Purity:99.96%

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