BX471-ZK-811752-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEBX471Cat.No.:HY-12080CASNo.:217645-70-0Synonyms:ZK-811752分⼦式:C₂₁H₂₄ClFN₄O₃分⼦量:434.89作⽤靶点:CCR作⽤通路:GPCR/GProtein;Immunology/Inflammation储存⽅式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性数据体外实验DMSO:≥100mg/mL(229.94mM)H2O:<0.1mg/mL(ultrasonic)(insoluble)*"≥"meanssoluble,butsaturationunknown.MassSolvent1mg5mg10mgConcentration制备储备液1mM2.2994mL11.4972mL22.9943mL5mM0.4599mL2.2994mL4.5989mL10mM0.2299mL1.1497mL2.2994mL请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；⼀旦配成溶液，请分装保存，避免反复冻融造成的产品失效。储备液的保存⽅式和期限：-80°C,6months;-20°C,1month。-80°C储存时，请在6个⽉内使⽤，-20°C储存时，请在1个⽉内使⽤。体内实验请根据您的实验动物和给药⽅式选择适当的溶解⽅案。以下溶解⽅案都请先按照InVitro⽅式配制澄的储备液，再依次添加助溶剂：(为保证实验结果的可靠性，澄的储备液可以根据储存条件，适当保存；体内实验的⼯作液，建议您现⽤现配，当天使⽤；以下溶剂前显⽰的百分⽐指该溶剂在您配制终溶液中的体积占⽐；如在配制过程中出现沉淀1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemE、析出现象，可以通过加热和/或超声的⽅式助溶)1.请依序添加每种溶剂：10%DMSO>>40%PEG300>>5%Tween-80>>45%salineSolubility:≥2.5mg/mL(5.75mM);Clearsolution2.请依序添加每种溶剂：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥2.5mg/mL(5.75mM);Clearsolution3.请依序添加每种溶剂：10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(5.75mM);Clearsolution4.请依序添加每种溶剂：50%PEG300>>50%salineSolubility:5mg/mL(11.50mM);Clearsolution;NeedultrasonicBIOLOGICALACTIVITY⽣物活性BX471(ZK-811752)以⼀种⼝服有效的，选择性，⾮多肽的CCR1拮抗剂，Ki值为1nM，对其选择性对CCR2，CCR5和CXCR4的250倍。IC50&TargetMIP-1α-CCR1RANTES-CCR1MCP-3-CCR11nM(Ki)2.8nM(Ki)5.5nM(Ki)体外研究BX471isapotentfunctionalantagonistbasedonitsabilitytoinhibitanumberofCCR1-mediatedeffectsincludingCa2+mobilization,increaseinextracellularacidificationrate,CD11bexpression,andleukocytemigration.BX471demonstratsagreaterthan10,000-foldselectivityforCCR1comparedwith28G-protein-coupledreceptors[1].BX471isalsoabletodisplace125I-MIP-1α/CCL3bindingtomouseCCR1inaconcentration-dependentmannerwithaKiof215±46nM.IncreasingconcentrationsofBX471inhibitstheCa2+transientsinducedbyMIP-1α/CCL3inbothhumanandmouseCCR1withIC50of5.8±1nMand198±7nM,respectively[2].BX471(0.1-10μM)showsadose-dependentinhibitionofRANTES-mediatedandshear-resistantadhesiononIL-1β-activatedmicrovascularendotheliuminshearflowinisolatedbloodmonocytes.BX471alsoinhibitstheRANTES-mediatedadhesionofTlymphocytestoactivatedendothelium[4].体内研究BX471(4mg/kg,p.o.ori.v.)isorallyactivewithabioavailabilityof60%indogs.Furthermore,BX471effectivelyreducesdiseaseinaratexperimentalallergicencephalomyelitismodelofmultiplesclerosis[1].BX471(20mg/kg,s.c.)reachespeakplasmalevelsof9μMbyaround30minutes,andthisrapidlydeclinestoapproximately0.4μMafter2hours.From4to8hoursthedrugplasmalevelsdropsto0.1μMorlower.Micetreatedwith20mg/kgofBX471for10daysshowsareductionofinterstitialCD45positiveleukocytesofapproximately55%.BX471hasaborderlinesignificanteffectonthenumberofCCR5-positiveCD8cellsintheperipheralblood.BX471reducestheamountofFSP1-positivecellsby65%inUUOkidneysascomparedwithvehiclecontrol[2].PretreatmentwitihBX471reducesmacrophageandneutrophilaccumulationinkidneyafterischemia-reperfusioninjury[3].PROTOCOLAnimalFastedmalebeagledogs(n=3pertreatmentgroup)aregivenBX471eitherbyoralgavageorbyintravenousAdministration[1]injectionviathecephalicveinatadoseof4mg/kg.Thecompoundisdissolvedinavehicleof40%aqueous2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEcyclodextrin.Serialbloodsamplesarecollectedutilizinganin-dwellingcatheterinthejugularveinattheindicatedtimepointsupto6hpost-dosing.EDTAisusedasananticoagulant.Thesamplesarecentrifuged(1000×gfor10minat4°C),andplasmaisstoredfrozenuntilanalyzedfordruglevelsbyHPLC-MS(electrospraymodeoperatedunderapositiveionmode).Plasmasamplesarethawedanddenaturedbytheadditionoffourpartsofice-coldmethanolcontainingafixedamountofaninternalstandardtoonepartofplasma.Theresultingproteinprecipitateisremovedbycentrifugationat5000×g,andthesupernatantsareanalyzeddirectly.ConcurrentlyplasmacalibrationstandardsofBX471arepreparedovertherangeofquantification,processed,andanalyzedunderidenticalconditions.AFISONS,VGPlatformsinglequadrupoleinstrumentisusedintheseanalyseswithanelectrosprayinletoperatedat3.57kV.ChromatographicseparationisaccomplishedusingaYMCAQoctadecylsilanereversedphasecolumn(4.6×250mm)followingashortisocraticelutionmethod(35%methanol,65%watercontaining0.1%trifluoroaceticacid).Thetotalcolumnflow(1mL/min)issplitpost-columntoinfuse50μL/minintothemassspectrometer.Thechromatogramsarecollectedoveratotalruntimeof7.5min/samplefollowinga50-μLinjectiononthecolumn.Theionsarecollectedinasingleionpositiveionizationmode.Acalibrationcurveforquantificationisgeneratedbyplottingioncurrentratiosbetweentheinternalstandardpeakandtheanalyteintheplasmastandardsoverthequantificationrange.Calculationsofpercentoralavailabilityisdeducedfromtheareaundercurvemeasurements.PharmacokineticparametersarecalculatedusingWinNonLinversion3.0.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.户使⽤本产品发表的科研⽂献•CellRes.2018Mar;28(3):323-335.•CancerCell.2021Mar8;39(3):423-437.e7.•SignalTransductTargetTher.2021Feb28;6(1):91.•SciAdv.2021May26;7(22):eabb5943.•JExpClinCancerRes.2022Mar3;41(1):81.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].LiangM,etal.Identificationandcharacterizationofapotent,selective,andorallyactiveantagonistoftheCCchemokinereceptor-1.JBiolChem.2000Jun23;275(25):19000-8.[2].AndersHJ,etal.AchemokinereceptorC