Zimlovisertib-PF-06650833-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEZimlovisertibCat.No.:HY-19836CASNo.:1817626-54-2Synonyms:PF-06650833分⼦式:C₁₈H₂₀FN₃O₄分⼦量:361.37作⽤靶点:IRAK作⽤通路:Immunology/Inflammation储存⽅式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性数据体外实验DMSO:62.5mg/mL(172.95mM;ultrasonicandwarmingandheatto60°C)MassSolvent1mg5mg10mgConcentration制备储备液1mM2.7672mL13.8362mL27.6725mL5mM0.5534mL2.7672mL5.5345mL10mM0.2767mL1.3836mL2.7672mL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、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%saline1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemESolubility:≥2.08mg/mL(5.76mM);Clearsolution2.请依序添加每种溶剂：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥2.08mg/mL(5.76mM);Clearsolution3.请依序添加每种溶剂：10%DMSO>>90%cornoilSolubility:≥2.08mg/mL(5.76mM);ClearsolutionBIOLOGICALACTIVITY⽣物活性Zimlovisertib(PF-06650833)⼀种有效的，选择性的和⼝服可⽣物利⽤的⽩介素-1受体相关激酶4(IRAK4)的抑制剂，其IC50值为0.2nM，在PBMC分析中，IC50值为2.4nM。Zimlovisertib有潜⼒⽤于类风湿性关节炎，狼疮和淋巴瘤等疾病的研究。IC50&TargetIRAK40.2nM(IC50)体外研究ThekinomeselectivityprofileofZimlovisertib(Compound40)isassessedinapanelof278kinases(Invitrogen)at200nMinhibitorconcentrationusingtheATPKmforeachkinase.Approximately100%inhibitionisobservedforIRAK4[1].LactamZimlovisertibisassessedinawholecellfunctionalVEGF2Rassay(PAE-KDRcellline).Noactivityisobservedatconcentrationsuptoandincluding30μM.Inavoltageclampassay,ZimlovisertibinhibitshERGcurrentby25%at100μM[1].TheabilityofZimlovisertibtoinhibitfivemajorCYP450enzymesisassessedusingpooledhumanlivermicrosomesandprobesubstratesfortheCYP450enzymes.Ataconcentrationof3μMofZimlovisertib,lessthan5%inhibitionofCYPs1A2,2C8,2C9,2D6,and3A4isobserved.LactamZimlovisertibisexaminedfortimedependentinhibitioneffectsonsixmajorCYP450enzymes(CYP1A2,2B6,2C8,2C9,2C19,and2D6)usingpooledhumanlivermicrosomesandprobesubstrates.At100μMofZimlovisertib,notimedependentCYPinhibitionisobserved.ThepotentialinductionofCYP3AbyZimlovisertibisassessedusingcryopreservedhumanhepatocytesandaffordeda4.4-foldincreaseinmRNAat10μM[1].体内研究Zimlovisertib(0.3-30mg/kg;oraladministration;for2.5hours;maleSprague-Dawleyrats)treatmentsignificantlyinhibitsLPS-inducedTNF-αinadosedependentmanner.MeanexposuresofZimlovisertibinplasmaare2.1nM,7.7nM,19nMand150nMfree,respectively,at2.5hoursafteroraladministrationofZimlovisertibat0.3,1,3,and30mg/kg.ThefractionunboundinratplasmaofZimlovisertibis0.3[1].AnimalModel:MaleSprague-Dawleyrats[1]Dosage:0.1mg/kg,1mg/kg,3mg/kg,30mg/kgAdministration:Oraladministration;for2.5hoursResult:SignificantlyinhibitedLPS-inducedTNF-αinadosedependentmanner.REFERENCES2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemE[1].SeganishWM.Inhibitorsofinterleukin-1receptor-associatedkinase4(IRAK4):apatentreview(2012-2015).ExpertOpinTherPat.2016Aug;26(8):917-32.[2].LeeKL,etal.DiscoveryofClinicalCandidate1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide(PF-06650833),aPotent,SelectiveInhibitorofInterleukin-1ReceptorAssociatedKinase4(IRAK4),byFragmenMcePdfHeightCaution:Pro