Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEZimlovisertibCat.No.:HY-19836CASNo.:1817626-54-2Synonyms:PF-06650833分?式:C??H??FN?O?分?量:361.37作?靶點(diǎn):IRAK作?通路:Immunology/Inflammation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:62.5mg/mL(172.95mM;ultrasonicandwarmingandheatto60°C)MassSolvent1mg5mg10mgConcentration制備儲(chǔ)備液1mM2.7672mL13.8362mL27.6725mL5mM0.5534mL2.7672mL5.5345mL10mM0.2767mL1.3836mL2.7672mL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?。體內(nèi)實(shí)驗(yàn)請(qǐng)根據(jù)您的實(shí)驗(yàn)動(dòng)物和給藥?式選擇適當(dāng)?shù)娜芙?案。以下溶解?案都請(qǐng)先按照InVitro?式配制澄的儲(chǔ)備液，再依次添加助溶劑：(為保證實(shí)驗(yàn)結(jié)果的可靠性，澄的儲(chǔ)備液可以根據(jù)儲(chǔ)存條件，適當(dāng)保存；體內(nèi)實(shí)驗(yàn)的?作液，建議您現(xiàn)?現(xiàn)配，當(dāng)天使?；以下溶劑前顯?的百分?指該溶劑在您配制終溶液中的體積占?；如在配制過程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過加熱和/或超聲的?式助溶)1.請(qǐng)依序添加每種溶劑：10%DMSO>>40%PEG300>>5%Tween-80>>45%saline1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemESolubility:≥2.08mg/mL(5.76mM);Clearsolution2.請(qǐng)依序添加每種溶劑：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥2.08mg/mL(5.76mM);Clearsolution3.請(qǐng)依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥2.08mg/mL(5.76mM);ClearsolutionBIOLOGICALACTIVITY?物活性Zimlovisertib(PF-06650833)?種有效的，選擇性的和?服可?物利?的?介素-1受體相關(guān)激酶4(IRAK4)的抑制劑，其IC50值為0.2nM，在PBMC分析中，IC50值為2.4nM。Zimlovisertib有潛??于類風(fēng)濕性關(guān)節(jié)炎，狼瘡和淋巴瘤等疾病的研究。IC50&TargetIRAK40.2nM(IC50)體外研究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].體內(nèi)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?邊的抑制劑?師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