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Medchemexpress/Asunaprevir(Synonyms: BMS-650032)/HY-14434/2mg

AsunaprevirisapotenthepatitisCvirus(HCV)NS3proteaseinhibitor,withtheIC50of0.2nM-3.5nM.

CustomerValidation

  • •NatCommun.2014Oct30;5:5352.
  • •ProcNatlAcadSciUSA.2017Feb21;114(8):1922-1927.
  • •IntJRADIatOncolBiolPhys.2016Nov15;96(4):867-876.
  • •AntiviralRes.2017Mar;139:18-24.
  • •SciRep.2016Oct5;6:34652.
Description

AsunaprevirisapotenthepatitisCvirus(HCV)NS3proteaseinhibitor,withtheIC50of0.2nM-3.5nM.

IC50&Target

IC50:0.2nM-3.5nM(HCVNS3protease)

InVitro

Inmultipleexperiments,populationsofresistantcoloniesaremarkedlyreducedwhencellsaretreatedwithacombinationofDCVandAsunaprevir[1].Asunaprevir(ASV)inhibitstheNS3proteolyticactivityofgenotype1a(H77strain)andgenotype1b(J4L6Sstrain),withIC50sof0.7and0.3nM,respectively. TheEC50sofASVagainstrepliconsencodingtheNS3proteasedomainsrepresentinggenotypes1a,1b,and4a,rangefrom1.2to4.0nM[2].Repliconcellsaremaintainedunderselectivepressurewithasunapreviratconcentrationsof10and30timestheEC50values(50or150nMfinalconcentrations,respectively).Forgenotype1bresistanceselection,repliconcellsaremaintainedinthepresenceofasunaprevirat10or30timestheEC50values(30or90nMfinalconcentrations,respectively)[3].Asunaprevir,admiNISTeredatsingleormultipledosesof200to600mgtwicedaily,isgenerallywelltolerated,achievingrapidandsubstantialdecreasesinHCVRNAlevelsinsubjectschronicallyinfectedwithgenotype1HCV[4].

InVivo

Asunaprevir(ASV,3-15mg/kg,p.o.)displaysahepatotropicdisposition(liver-to-plasmaratiosrangingfrom40-to359-foldacrossspecies)inseveralanimalspecies.Twenty-fourhourspostdose,liverexposuresacrossallspeciestestedare≥110-foldabovetheinhibitorEC50observedwithHCVgenotype-1replicons[2].

References

  • [1].PelosiLA,etal.EffectonHCVReplicationbyCombinationsofDirectActingAntiviralsIncludingNS5AInhibitorDaclatasvir.AntimicrobAgentsChemother.2012Jul30.

    [2].McPheeF,etal.PreclinicalProfileandCharacterizationoftheHepatitisCVirusNS3ProteaseInhibitorAsunaprevir(BMS-650032).AntimicrobAgentsChemother.2012Aug6.

    [3].McPheeF,etal.ResistanceanalysisofthehepatitisCvirusNS3proteaseinhibitorasunaprevir.AntimicrobAgentsChemother.2012Jul;56(7):3670-81.

    [4].PasquinelliC,etal.Single-andmultiple-ascending-dosestudiesoftheNS3proteaseinhibitorasunaprevirinsubjectswithorwithoutchronichepatitisC.AntimicrobAgentsChemother.2012Apr;56(4):1838-44.

PreparingStockSolutions
ConcentrationVolumeMass1mg5mg10mg
1mM1.3364mL6.6819mL13.3638mL
5mM0.2673mL1.3364mL2.6728mL
10mM0.1336mL0.6682mL1.3364mL
Pleaserefertothesolubilityinformationtoselecttheappropriatesolvent.
CellAssay
[2]

Asunaprevirisdilutedinassaybufferin10%DMSO.

Cytotoxicityisdeterminedbyincubatingcells(3,000to10,000cells/well)withseriallydilutedtestcompoundsorDMSOfor5days(MT-2cells)or4days(allothercelltypes).CellviABIlityisquantitatedusinganMTSassayforMT-2oraCell-TiterBluereagentassayforHEK-293,HuH-7,HepG2,andMRC5cells,and50%cytotoxicconcentrations(CC50s)arecalculated.FortheHCVandBVDVrepliconassays,CC50saredeterminedfromthesamewellsthatarelaterusedtodetermineEC50s.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

AnimalAdministration
[2]

Asunaprevirisdilutedinvehicle(PEG-400-ethanol,9:1).

Mice(n=9pergroup;overnightfast)receiveAsunaprevir(ASV)byoralgavage(5mg/kg;vehicleofPEG-400-ethanol,9:1).Bloodsamples(∼0.2mL)areobtainedbyretro-orbitalbleedingat0.25,0.5,1,3,6,8,and24hafterdosing.Withineachgroup,threeanimalsarebledat0.25,3,and24h,threeat0.5and6h,andthreeat1and8h,resultinginacompositepharmacokineticprofile.Liversandbrainsarealsoremovedfrommiceattheterminalsamplingpoints.Rats(n=3pergroup;overnightfast)receiveASV(amorphousfreeacid)byoralgavage(3,5,10,and15mg/kg)inPEG-400-ethanol(9:1).Serialbloodsamples(∼0.3mL)areobtainedfromthejugularveinpredosing(0h)andat0.25,0.5,0.75,1,2,4,6,8,24,and48hpostdosing.Toassesstissueexposure,ratsareorallyadministeredASV(5or15mg/kg,samevehicleasabove),andblood,liver,andheartsamplesfromtworats/groupareobtainedat0.17,0.5,1,2,4,6,8,24,48,and72hafterdosing.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

References

  • [1].PelosiLA,etal.EffectonHCVReplicationbyCombinationsofDirectActingAntiviralsIncludingNS5AInhibitorDaclatasvir.AntimicrobAgentsChemother.2012Jul30.

    [2].McPheeF,etal.PreclinicalProfileandCharacterizationoftheHepatitisCVirusNS3ProteaseInhibitorAsunaprevir(BMS-650032).AntimicrobAgentsChemother.2012Aug6.

    [3].McPheeF,etal.ResistanceanalysisofthehepatitisCvirusNS3proteaseinhibitorasunaprevir.AntimicrobAgentsChemother.2012Jul;56(7):3670-81.

    [4].PasquinelliC,etal.Single-andmultiple-ascending-dosestudiesoftheNS3proteaseinhibitorasunaprevirinsubjectswithorwithoutchronichepatitisC.AntimicrobAgentsChemother.2012Apr;56(4):1838-44.

MolecularWeight

748.29

Formula

C₃₅H₄₆ClN₅O₉S

CASNo.

630420-16-5

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

RoomtemperatureincontinentalUS;mayvaryelsewhere

Solvent&Solubility

DMSO:≥42.9mg/mL

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

Purity:99.27%