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当前位置： 首页 > 产品中心 > Small_molecule > Medchemexpress/Simeprevir(Synonyms: TMC435)/HY-10241/10mM*1mL in DMSO
商品详细Medchemexpress/Simeprevir(Synonyms: TMC435)/HY-10241/10mM*1mL in DMSO
Medchemexpress/Simeprevir(Synonyms: TMC435)/HY-10241/10mM*1mL in DMSO
Medchemexpress/Simeprevir(Synonyms: TMC435)/HY-10241/10mM*1mL in DMSO
商品编号： HY-10241-10mM*1mLinDMSO
品牌： MedChemExp
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产品分类： 小分子
公司分类： Small_molecule
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商品介绍
SimeprevirisapotentHCVNS3/4Aproteaseinhibitor,andinhibitsHCVreplicationwithEC50of8nM.

CustomerValidation

  • •ProcNatlAcadSciUSA.2017Feb21;114(8):1922-1927.
  • •JMedChem.2016Nov23;59(22):10268-10284.
  • •IntJRADIatOncolBiolPhys.2016Nov15;96(4):867-876.
  • •IntJAntimicrobAgents.2015Oct;46(4):381-8.
  • •AntimicrobAgentsChemother.2014Aug;58(8):4555-64.
  • •AntiviralRes.2017Oct23;148:5-14.
  • •AntiviralRes.2017Mar;139:18-24.
  • •VirusRes.2017Mar18;235:37-48.
  • •BiomedResInt.2017;2017:1236801.
Description

SimeprevirisapotentHCVNS3/4Aproteaseinhibitor,andinhibitsHCVreplicationwithEC50of8nM.

IC50&Target

EC50:8nM

InVitro

InHuh7-Luccells,antiviralactivityofsimeprevir(TMC435350)isdosedependent,andtheEC50andEC90valuesdeterminedforTMC435350are8nMand24nM,respectively.InhibitionofTMC435350onNS3/4Aproteaseistimedependent,andtheoverall Kisareestimatedtobe0.5nMforgenotype1aand0.4nMforgenotype1b,respectively[1].TMC435350isapotentinhibitorofHCVNS3/4Aprotease(Ki=0.36nM)andviralreplication(repliconEC50=7.8nM)[2].

InVivo

Inrats,TMC435350(40mg/kg,p.o.)isextensivelydistributedtotheliverandintestinaltract(tissue/plasmaareaundertheconcentration-timecurveratiosof>35),andtheabsolutebioavailABIlityis44%[1].

ClinicalTrial
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References

  • [1].LinTI,etal.InvitroactivityandpreclinicalprofileofTMC435350,apotenthepatitisCvirusproteaseinhibitor.AntimicrobAgentsChemother.2009Apr;53(4):1377-85.Epub2009Jan26.

    [2].RaboissonP,etal.Structure-activityrelationshipstudyonanovelseriesofcyclopentane-containingmacrocyclicinhibitorsofthehepatitisCvirusNS3/4AproteaseleadingtothediscoveryofTMC435350.BioorgMedChemLett.2008Sep1;18(17):4853-8.

PreparingStockSolutions
ConcentrationVolumeMass1mg5mg10mg
1mM1.3334mL6.6672mL13.3344mL
5mM0.2667mL1.3334mL2.6669mL
10mM0.1333mL0.6667mL1.3334mL
Pleaserefertothesolubilityinformationtoselecttheappropriatesolvent.
KinaseAssay
[1]

InvitroinhibitionofNS3/4AactivityisdeterminedusingafluorescenceresonanceenergytransfercleavageassaywiththeRetS1peptidesubstrate,derivedfromthegenotype1aNS4A-4Bjunction,andbacteriallyexpressedfull-lengthNS3proteasedomain,supplementedwithanNS4Apeptide.Briefly,NS3/4AispreincubatedinthepresenceofTMC435350for10min,andthentheRetS1substrateisaddedandfluorescenceiscontinuouslymeasuredfor20min(excitation,355nm;emission,500nm).Cleavageofthesubstrateisexpressedasapercentageofthecleavageseenwiththevehiclecontrol.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

CellAssay
[1]

SimeprevirisdilutedininafinalDMSOconcentrationof0.5%intheabsenceofG418.

Huh7-Luccellsareseededatadensityof2,500cells/wellina384-wellplateinDulbecco"smodifiedEagle"smediumplus10%fetalcalfserumandincubatedwitharangeofconcentrationsofseriallydilutedsimeprevir(TMC435350),inafinalDMSOconcentrationof0.5%intheabsenceofG418.After72hofincubation,SteadyLitereagentisaddedina1:1ratiotothemedium,andluciferasesignalismeasuredusingaViewLuxreader. MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

AnimalAdmiNISTration
[1]

Twenty-fourmalespecific-pathogen-freeSprague-Dawleyrats,weighingbetween200and300gatthetimeofdosing,aredividedintoeightgroupsofthreeratseach.Sevengroupsaredosedorally(p.o.)bygastricintubationofavitaminEacetate-d-α-tocopherylpolyethyleneglycol1000succinate-polyethyleneglycol400solutionofSimeprevir(TMC435350)at2mL/kgbodyweighttoprovideadoseof40mg/kg.Onegroupisdosedintravenously(i.v.)byslowbolusinjectioninatailveinofa20%2-hydroxypropyl-β-cyclodextrinformulationofTMC435350(containingTMC435350,100mg/mL2-hydroxypropyl-β-cyclodextrin,0.1NNaOHtopH8.0±0.1,andmannitol-andpyrogen-freewater)at2mL/kgbodyweighttoprovideadoseof4mg/kg.Waterandfoodareavailableadlibitumduringthestudy.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

References

  • [1].LinTI,etal.InvitroactivityandpreclinicalprofileofTMC435350,apotenthepatitisCvirusproteaseinhibitor.AntimicrobAgentsChemother.2009Apr;53(4):1377-85.Epub2009Jan26.

    [2].RaboissonP,etal.Structure-activityrelationshipstudyonanovelseriesofcyclopentane-containingmacrocyclicinhibitorsofthehepatitisCvirusNS3/4AproteaseleadingtothediscoveryofTMC435350.BioorgMedChemLett.2008Sep1;18(17):4853-8.

MolecularWeight

749.94

Formula

C₃₈H₄₇N₅O₇S₂

CASNo.

923604-59-5

Storage
Powder-20°C3years
 4°C2years
Insolvent-80°C6months
 -20°C1month
Shipping

RoomtemperatureincontinentalUS;mayvaryelsewhere

Solvent&Solubility

DMSO

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

Purity:99.34%