BIIB042-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors • ScreeningLibraries • Proteinswww.MedChemEBIIB042Cat.No.:HY-103537ACASNo.:1257396-73-8分子式:C₂₉H₂₉F₄NO₂分子量:499.54作用靶点:γ-secretase;Amyloid-β作用通路:NeuronalSignaling;StemCell/Wnt储存方式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY生物活性BIIB042是一种强效、口服有效、可穿透血脑屏障且具有选择性的γ-分泌酶(γ-secretase)调节剂(GSM)。BIIB042可降低细胞内Aβ42水平并增加Aβ38水平。BIIB042可显著降低CF-1小鼠和Fischer大鼠脑内Aβ42水平，以及食蟹猴血浆中Aβ42水平。BIIB042可降低Tg2576小鼠脑内Aβ42水平和Aβ斑块负荷。BIIB042可用于阿尔茨海默病(AD)的相关研究[1][2]。体外研究BIIB042(compound10a)inhibitsCOX1andCOX2veryweakly(IC50=35and27μM,respectively)andexhibitsweakinhibitionofthehERGchannel(IC50=15μM)[1].BIIB042exhibitsgoodcellularpermeabilityandisnotasubstrateforeffluxtransporters[1].BIIB042demonstratesgoodmetabolicstabilityinlivermicrosomesanddoesnotinhibitmajorcytochromeP450enzymes[1].BIIB042(3-30μM,20h)hasnoeffectonHES-1proteinlevelsinMC-IXCcells,indicatingitsselectiveactiononamyloidprecursorproteinprocessingwithoutimpactingNotchsignaling[2].BIIB042(20h)reducesthelevelsofAβ42(IC50=64.3nM),increasedthelevelsofAβ38(EC50=146nM)andhaslittleeffectonthelevelsofAβ40inH4-APPcells[2].WesternBlotAnalysis[2]CellLine:MC-IXCcellsConcentration:3,10and30μMIncubationTime:20hResult:DidnotalterHES1proteinlevels.1/3 MasterofBioactiveMolecules—您身边的抑制剂大师www.MedChemE体内研究BIIB042(0-60mg/kg,p.o.(indiet),dailyfor65days)significantlyincreasesAβ38levelsanddecreasesAβ42levelsinbrainofTg2576mice[2].BIIB042(0.3-30mg/kg,p.o.(indiet),dailyfor6months)significantlydecreasesAβ42levelsinbrain,andreducesparenchymalamyloidplaqueburdenofTg2576mice[2].BIIB042(0-100mg/kg,i.g.,singledose)dose-dependentlylowersAβ42andelevatesAβ38inthebrainandplasmaofCF-1mice,demonstratingapotentandbrain-penetrantGSMprofile[2].AnimalModel:Tg2576mice(5monthsold)[2]Dosage:0,3,10,30and60mg/kgAdministration:p.o.(indiet),dailyfor65daysResult:SignificantlyincreasedAβ38levelsinbraininadose-dependentmanner.SignificantlydecreasedAβ42levelsinbraininadose-dependentmanner.ShowednosignificantchangesinlevelsofAβ40.SignificantlyreducedinsolubleAβ42at10,30and60mg/kgcomparedtovehicle.ShowednosignificantchangesininsolubleAβ38.AnimalModel:Tg2576mice(10monthsold)[2]Dosage:0.3,1,10and30mg/kgAdministration:p.o.(indiet),dailyfor6monthsResult:SignificantlyreducedsolubleandinsolubleAβ42levelsinthebrainandplasmaat30mg/kg.Significantlyreducedparenchymalamyloidplaqueburdeninboththecortexandhippocampusat30mg/kg.ShowedatrendtowardsincreasedAβlevelsat0.3and1mg/kg.AnimalModel:CF-1mice[2]Dosage:0,3,10,30and100mg/kgAdministration:i.g.,singledoseResult:Inducedsignificantanddose-dependentdecreasesinAβ42atalltesteddoses.Showedadose-dependentincreasesinAβ38at10,30and100mg/kg.InducedAβpharmacodynamicresponsesinplasma,withsimilareffectsasinbrainwithdecreasesinAβ42,increasesinAβ38andsmallchangesinAβ40athigherdoses.Brainconcentrationswereapproximately80%ofplasmaconcentrationsatthe4htimepointacrossalldoses.REFERENCES2/3 MasterofBioactiveMolecules—您身边的抑制剂大师www.MedChemEPengH,etal.DiscoveryofBIIB042,aPotent,Selective,andOrallyBioavailableγ-SecretaseModulator.ACSMedChemLett.2011Aug5;2(10):786-91.ScannevinRH,etal.BIIB042,anovelγ-secretasemodulator,reducesamyloidogenicAβisoformsinprimatesandrodentsandplaquepathologyinamousemodelofAlzheimer'sdisease.Neuropharmacology.2016Apr;103:57-68.McePdfHeightCaution:P