FPS-ZM1isahigh-affinityRAGEspecificinhibitorwithaK_iof25nM.

Ki:25nM(RAGE)^[1]

FPS-ZM1inhibitsAβ/RAGEbindinginCHOcellswithapproximately2-foldgreateraffinitythanitsparentmolecule,FPS2.FPS-ZM1inhibitsbindingofotherknownRAGEligandstosRAGE,includingS100calcium-bindingproteinBandamphoterin.FPS-ZM1ismoreeffectivethanFPS2inreducingAβ40-inducedincreasesinBACE1mRNAandproteinlevelsandthegenerationofsAPPβ,anAPPcleavageproductofBACE1indicativeofBACE1activity^[1].

FPS-ZM1isnontoxictomiceandreADIlycrossedtheblood-brainbarrier.InagedAPP^sw/0miceoverexpressinghumanAβ-precursorprotein,atransgenicmousemodelofADwithestablishedAβpathology,FPS-ZM1inhibitsRAGE-mediatedinfluxofcirculatingAβ40andAβ42intothebrain.Inbrain,FPS-ZM1bindsexclusivelytoRAGE,whichinhibitsβ-secretaseactivityandAβproductionandsuppressesmicrogliaactivationandtheneuro-inflammatoryresponse^[1].FPS-ZM1treatmentreducesthelevelofAβ1-40andAβ1-42inAGEsRats.ItInhibitsAGEs-mediatedincreaseofAβ-metabolism-relatedproteinsanddownregulatesAGEs-mediatedincreaseofpro-inflammatorycytokinesinthehippocampus.FPS-ZM1up-Regulatesanti-oxidantdefensesystemandattenuatedAGEsinducedmemoryimpairmentinAGEsrats^[2].

• [1].DeaneR,etal.AmultimodalRAGE-specificinhibitorreducesamyloidβ-mediatedbraindisorderinamousemodelofAlzheimerdisease.JClinInvest.2012Apr;122(4):1377-92.

  [2].HongY,etal.EffectsofRAGE-SpecificInhibitorFPS-ZM1onAmyloid-βMetabolismandAGEs-InducedInflammationandOxidativeStressinRatHippocampus.NeuRochemRes.2016May;41(5):1192-9.

  [3].LianYJ,etal.Ds-HMGB1andfr-HMGBinducedepressivebehaviorthroughneuroinflammationincontrasttononoxid-HMGB1.BrainBehavImmun.2017Jan;59:322-332.

HumansRAGEisimmobilized(10μg/mL)overnightat4°Cin96-wellmicrotiterplatesandblockedwith3%bovineserumalbumin.¹²⁵I-labeledAβ40,HMGB1,orS100Bat5nMintheabsenceandpresenceofvariousconcentrationsofFPS2orFPS-ZM1(10to1,000nM)isaddedtothewellscontainingimmobilizedsRAGEandincubatedfor1houratroomtemperatureinPBS.WellsarewashedwithcoldPBStoremoveunboundradiolabeledligands,andtheradioactivityisanalyzed^[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

TodeterminewhetherFPS2andFPS-ZM1aretoxictoCHOcells,thecellsaretreatedfor72hourswithdifferentconcentrationsofinhibitorsrangingfrom10nMto10μM.ThecellulartoxicityisdeterminedusingtheWST-8AssayKit^[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

Rat:Startingfrom1weekbeforeintrahippocampalinjection,FZM1andAGEs+FZM1ratsareintraperitoneallyinjectedwithFPS-ZM1(1mg/kg/datavolumeof2mL)for4weeks;ratsintheAGEsandthecontrolgroupsareintraperitoneallyinjectedwithnormalsalinewiththesamevolumefor4weeks.ThreeweeksafterAGEsintrahippocampalinjection,theescapelatencytimeofratsisassayedwithMorriswatermazetest,andthenallratsaresacrificed^[2].

Mouse:FPS2orFPS-ZM1areadministeredi.v.(1mg/kg)viathefemoralveinandarterialbloodsamples(30μL)collectedat1,5,10,15,and20minutesviathecannulatedfemoralartery.Plasmaisseparatedbycentrifugationat4°Candimmediatelystoredat–80°Cuntilanalysis^[1].

• [1].DeaneR,etal.AmultimodalRAGE-specificinhibitorreducesamyloidβ-mediatedbraindisorderinamousemodelofAlzheimerdisease.JClinInvest.2012Apr;122(4):1377-92.

  [2].HongY,etal.EffectsofRAGE-SpecificInhibitorFPS-ZM1onAmyloid-βMetabolismandAGEs-InducedInflammationandOxidativeStressinRatHippocampus.NeurochemRes.2016May;41(5):1192-9.

  [3].LianYJ,etal.Ds-HMGB1andfr-HMGBinducedepressivebehaviorthroughneuroinflammationincontrasttononoxid-HMGB1.BrainBehavImmun.2017Jan;59:322-332.

327.85

C₂₀H₂₂ClNO

945714-67-0

RoomtemperatureincontinentalUS;mayvaryelsewhere

10mMinDMSO

FPS-ZM1ispreparedinvehicle(normalsaline)^[3].

*"<1 mg/ml"="" means="" slightly="" soluble="" or="" insoluble.="" "≥"="" means="" soluble,="" but="" saturation="">

• [1].DeaneR,etal.AmultimodalRAGE-specificinhibitorreducesamyloidβ-mediatedbraindisorderinamousemodelofAlzheimerdisease.JClinInvest.2012Apr;122(4):1377-92.

  [2].HongY,etal.EffectsofRAGE-SpecificInhibitorFPS-ZM1onAmyloid-βMetabolismandAGEs-InducedInflammationandOxidativeStressinRatHippocampus.NeurochemRes.2016May;41(5):1192-9.

  [3].LianYJ,etal.Ds-HMGB1andfr-HMGBinducedepressivebehaviorthroughneuroinflammationincontrasttononoxid-HMGB1.BrainBehavImmun.2017Jan;59:322-332.