PLX5622-hemifumarate-DataSheet-生命科學(xué)試劑-MedChemExpress

Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEPLX5622hemifumarateCat.No.:HY-114153A分?式:C??H??F?N?O?分?量:453.45作?靶點(diǎn):c-Fms作?通路:ProteinTyrosineKinase/RTK儲(chǔ)存?式:4°C,sealedstorage,awayfrommoisture*Insolvent:-80°C,6months;-20°C,1month(sealed

storage,awayfrommoisture)溶解性數(shù)據(jù)體外實(shí)驗(yàn)DMSO:100mg/mL(220.53mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制備儲(chǔ)備液1mM2.2053mL11.0266mL22.0531mL5mM0.4411mL2.2053mL4.4106mL10mM0.2205mL1.1027mL2.2053mL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(sealedstorage,awayfrommoisture)。-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(guò)程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過(guò)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%salineSolubility:≥3.25mg/mL(7.17mM);Clearsolution2.請(qǐng)依序添加每種溶劑：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥3.25mg/mL(7.17mM);Clearsolution3.請(qǐng)依序添加每種溶劑：10%DMSO>>90%cornoil1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemESolubility:≥3.25mg/mL(7.17mM);ClearsolutionBIOLOGICALACTIVITY?物活性PLX5622hemifumarate?度選擇性的、能透過(guò)?腦屏障的、?服有效的CSF1R抑制劑，IC50值為0.016μM，Ki值為5.9nM，可?于病程發(fā)展前和過(guò)程中，擴(kuò)?的和特異性的?膠質(zhì)細(xì)胞的消除。PLX5622hemifumarate具有較好的藥理學(xué)特性。IC50&TargetCSF1R[1]體外研究PLX5622(1-20μM;3days)hemifumarateeffectivelydepletesmicrogliawithoutaffectingoligodendrocytesorastrocytesincerebellarslices.PLX5622(4μM;3days)hemifumaratecausesa30-40%reductioninNG2+orPDGFRα+cells,andthisincreasedto90-95%at20μM.NoreductionofNG2+orPDGFRα+OPCsisobservedinslicesexposedto1μMor2μMPLX5622despiterobust(~95%)depletionofthemicroglialcells[3].體內(nèi)研究PharmacodynamicsofPLX5622hemifumarateinpreclinicalstudiesPLX5622(1200ppm;chow;for3weeksor3days;adultC57/Bl6wildtypemice)hemifumarateleadstoaround80%ofmicroglialostafter3daysoftreatmentanda99%microglialossafter3weeksoftreatment.PLX5622(adultC57/Bl6wildtypemiceaged3months;dietfor3weeks)decreasesmicrogliaincortex,striatum,cerebellumandhippocampus[4].PLX5622(50?mg/kg;intraperitonealinjection;once(neonatalrat)ortwice(adultrat)aday;foratotalof14days)hemifumaratedepletesmicrogliaby80-90%within3daysoftreatment,whichincreasesto>90%by7days.After14daysofPLX5622treatment,microgliaisdepletedby>96%inbothneonatesandadultswhilepreservingbaselineastrocytequantity.(Asingledailyinjectionof0.65%PLX5622suspendedin5%dimethylsulfoxideand20%KolliphorRH40in0.01?MPBSissufficientforneonatalmicrogliadepletion,adultdepletionrequiresinjectionstwicedaily)[5].PLX5622(formulatedinAIN-76Astandardchowat1200mg/kg;for28days)hemifumarateleadstoreductioninmicrogliathroughouttheCNSin14-month-old5xfADmice[6].PharmacokineticsofPLX5622hemifumarateinpreclinicalspecies[4]SpeciesIVPO(gavage)Dose(mg/kg)AUC0-∞(ng?hr/mL)CL(mL/min/kg)Vss(L/kg)t1/2(hr)Dose(mg/kg)AUC0-∞(ng?hr/mL)Cmax(ng/mL)FMouse1.9215,5002.10.342.645215,00026,30059%Rat(male)1.132,6304599,60012,00095%Rat(female)1.135,1103.71.03.945181,00015,60089%Dog1.006,2303.02.3154596,5003,63034%Monkey1.352,100111.62.2NDNDNDNDPreparationofgavagedosingsuspensionsforPLX5622hemifumarate[4]PLX5622hemifumarateisdissolvedinDMSOataconcentrationthatis20xthefinaldosingsolution.Thecompoundstockisprotectedfromlight.Afreshstockismadeeachweek.Thecomponentsofthediluentgenerallyarepreparedadayormoreinadvancebecausetheytaketimetodissolvecompletely:a)2%hydroxypropylmethylcellulose(HPMC):2.0gpowderwasbroughtto100mLdeionizedwater;b)25%Polysorbate80(PS80):25gwasbroughtto100mLdeionizedwater.Tomake100mLdiluent,add25mLof2%HPMCstock(0.5%final)and4mLof25%PS80stock(1%final)to71mLdeionizedwatertohavefinal100mL.Finalcompositionaftermixingwithcompound:0.5%HPMC,1%PS80,2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE5%DMSO.Oneachdosingday,thecompoundstockisdiluted20-foldasfollows:19volumesofdiluentaremeasuredintothetube,and1volumeofthe20xcompound/DMSOstockisadded.Thecapisclosedandthecontentofthetubeismixedbyinversionandplacedinasonicatingwaterbathtomakeauniformsuspension.戶使?本產(chǎn)品發(fā)表的科研?獻(xiàn)?Nature.2021Feb;590(7847):612-617.?BrainBehavImmun.2022Oct3;S0889-1591(22)00398-1.?BasicResCardiol.2022Oct24;117(1):52.?CellRep.2020Aug11;32(6):108041.?Elife.2021Jun23;10:e67772.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].SpangenbergE,etal.SustainedmicroglialdepletionwithCSF1RinhibitorimpairsparenchymalplaquedevelopmentinanAlzheimer'sdiseasemodel.NatCommun.2019Aug21;10(1):3758.[2].LeeS,etal.Targetingmacrophageandmicrogliaactivationwithcolonystimulatingfactor1receptorinhibitorisaneffectivestrategytotreatinjury-triggeredneuropathicpain.MolPain.2018Jan-Dec;14:1744806918764979.[3].LiuY,etal.Concentration-dependenteffectsofCSF1Rinhibitorsonoligodendrocyteprogenitorcellsexvivoandinvivo.ExpNeurol.2019;318:32-41.[4].BadimonA,etal.Negativefeedbackcontrolofneuronalactivitybymicroglia.Nature.2020;586(7829):417-423.[5].Andrew