Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEBMS-935177Cat.No.:HY-101793CASNo.:1231889-53-4分?式:C??H??N?O?分?量:502.56作?靶點(diǎn):Btk作?通路:ProteinTyrosineKinase/RTK儲(chǔ)存?式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性數(shù)據(jù)體外實(shí)驗(yàn)DMSO:≥130mg/mL(258.68mM)*"≥"meanssoluble,butsaturationunknown.MassSolvent1mg5mg10mgConcentration制備儲(chǔ)備液1mM1.9898mL9.9491mL19.8981mL5mM0.3980mL1.9898mL3.9796mL10mM0.1990mL0.9949mL1.9898mL請(qǐng)根據(jù)產(chǎn)品在不同溶劑中的溶解度選擇合適的溶劑配制儲(chǔ)備液；?旦配成溶液，請(qǐng)分裝保存，避免反復(fù)凍融造成的產(chǎn)品失效。儲(chǔ)備液的保存?式和期限：-80°C,6months;-20°C,1month。-80°C儲(chǔ)存時(shí)，請(qǐng)?jiān)?個(gè)?內(nèi)使?，-20°C儲(chǔ)存時(shí)，請(qǐng)?jiān)?個(gè)?內(nèi)使?。BIOLOGICALACTIVITY?物活性BMS-935177有效，選擇性，可逆的布魯頓酪氨酸激酶(Btk)抑制劑，IC50值為3nM。IC50&TargetIC50:3nM(BTK)[1]1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE體外研究InBcellsstimulatedthroughtheBCR,BMS-935177selectivelyinhibitsseveraldifferentreadouts.BMS-935177inhibitscalciumfluxinhumanRamosBcells(IC50=27nM)andinhibitsCD69surfaceexpressioninperipheralBcellsstimulatedwithantiIgMandanti-IgG.However,BMS-935177hasnoeffectonCD69surfaceexpressioninBcellsstimulatedthroughtheCD40receptorwithCD40ligand.AgainstIgG-containingimmunecomplexdrivenlowaffinityactivatingFcγreceptor(FcγRIIaandFcγRIII)endpointsinperipheralbloodmononuclearcells(PBMCs),BMS-935177effectivelyinhibitsTNFαproductionwithanIC50valueof14nM.BMS-935177showsmeanIC50valuesof550±100(n=11)and2060±240nM(n=3)inhumanandmousewholeblood,respectively[1].體內(nèi)研究Whendosedorallyoncedailyat5,20,and45mg/kgtomice,BMS-935177inhibitsanti-KLHantibodiesoftheIgGisotypeatday14,withstatisticallysignificantreductionsatalldoses.Insatellitemicefromthisstudydosedwith6at5mg/kg,theplasmaconcentrationismaintainedabovethemousewholebloodBCR-stimulatedCD69IC50valueof2μMforonlyapproximately5h.Atoncedailyoraldosesof10,20,and30mg/kgbeginningonthedayofprimaryimmunization,BMS-935177providesacleardose-dependentreductioninboththeseverityandincidenceofclinicallyevidentdiseaseinthisrodentmodelofRA.At10mg/kgofBMS-935177,diseaseseverityisreducedabout40%comparedtovehicletreatment,andthepercentageofanimalsshowinganysignsofdiseaseisreducedbyathird[1].PROTOCOLKinaseAssay[1]BMS-935177isdissolvedat10mMinDMSOandevaluatedat11concentrations.ToV-bottom384-wellplatesareaddedBMS-935177,humanrecombinantBTK(1nM),fluoresceinatedpeptide(1.5μM),ATP(20μM(Kmapp)),andassaybuffer(20mMHEPES,pH7.4,10mMMgCl2,0.015%Brij35surfactant,and4mMDTTin1.6%DMSO),withafinalvolumeof30μL.Afterincubationatroomtemperaturefor60min,thereactionisterminatedbyadding45μLof35mMEDTAtoeachsample.Thereactionmixtureisanalyzedonthebyelectrophoreticseparationofthefluorescentsubstrateandphosphorylatedproduct(excitation,488nm;emission,530nm)[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalRats[1]Administration[1]MaleSprague?Dawleyrats(255-298g)areusedinthePKstudies.ToinvestigatetheoralbioavailabilityofBMS-935177aftercrystallinemicrosuspensiondoses,ratsreceiveBMS-935177byoralgavage(1,5,and20mg/kg),T99.5%10mMcitratebuffer,pH4,0.02%DOSS,MethocelA4M.Serialbloodsamplesareobtainedafteroraldosingat0.25,0.5,0.75,1,2,4,6,8,and24hpostdose.Plasmasamples,obtainedbycentrifugationat4°C(1500-2000g),arestoredat?20°Cuntilanalysis[1].Mice[1]EfficacyofBMS-935177(10and30mg/kg)vsvehicleanddexamethasone(Dex)isstudiedinamouseanti-collagenantibody-inducedarthritis(CAIA)inflammationmodel.Miceareinjectedintraperitoneally(ip)withamixtureoffourmonoclonalantimousetypeIIcollagenantibodies(1mgofeach).Dailyoraldosingisimmediatelystartedwithvehicle(EtOH:TPGS:PEG300,5:5:90),BMS-935177(10or30mg/kg),ordexamethasone(dex,1mg/kg).Threedayslater,themiceareinjectedipwith1.25mg/kgLPS.Thereafter,micearemonitored3×/weekforthedevelopmentandseverityofpawinflammation[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEREFERENCES[1].DeLuccaGV,etal.SmallMoleculeReversibleInhibitorsofBruton'sTyrosineKinase(BTK):Structure-ActivityRelationshipsLeadingtotheIdentificationof7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)p