Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemES1P1agonist7Cat.No.:HY-175984分?式:C??H??N?O?分?量:406.43作?靶點:LPLReceptor作?通路:GPCR/GProtein儲存?式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY?種強(qiáng)效、具備?服活性的β-抑制蛋?偏向型S1P1激動劑(EC50(G?protein)=12.7nM?物活性S1P1agonist7，EC50(β?arrestin)=3.23nM)，具有強(qiáng)效的免疫調(diào)節(jié)活性和良好的安全性。S1P1agonist7具備優(yōu)異的代謝穩(wěn)定性、微弱?中度的CYP抑制能?，以及不作?于S1P3受體的?選擇性。S1P1agonist7在實驗性??免疫性腦脊髓炎??模型中展現(xiàn)出良好的藥代動?學(xué)特性，能夠有效降低循環(huán)淋巴細(xì)胞數(shù)量，并顯著減輕疾病的嚴(yán)重程度。S1P1agonist7可?于多發(fā)性硬化癥研究[1]。體外研究S1P1agonist7(compound28)showsa4.51-foldβ-arrestinbiasrelativetoFingolimod(HY-11063)indockingstudies,withanEC50valuesof12.7nMforG-proteinsignalingand3.23nMforβ-arrestinrecruitment[1].S1P1agonist7(1-10μM,15-60min)displayshighstabilityacrossallmicrosomalspecies(human,rat,andmouse),andshowsnosignificantinhibitionagainstmostCYPisozymesat10μM[1].S1P1agonist7(serialdilutionstartingfrom100μM,90min)demonstrateshighselectivityforS1P1inChem-4/G??andCHO-K1EDG1cells,exhibitingEC50valuesof0.014μMinG-proteinsignalingand0.0023μMinβ-arrestinrecruitment,withonlylowadditionalactivityatS1P?[1].S1P1agonist7(0.041-10μM,2min)doesnotinduceanyobservablechangesinpeakfrequencyorbeatrate,evenatthehighesttestedconcentrationsinhumaninducedpluripotentstemcells(iPSC)-derivedcardiomyocytes[1].體內(nèi)研究S1P1agonist7(1,3,and10mg/kg,i.g.,singledose)reducesperipheralbloodlymphocytecount(PLC)inC57BL/6Nmice[1].S1P1agonist7(10mg/kg,i.g.,dailyfor23days)confersrobustprotectionagainstEAEinMOG35?55(HY-P1240)inducedEAEmice,moderatingitsonset,progression,andassociatedpathologicaldamage[1].1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEAnimalModel:FemaleC57BL/6Nmice(8weeksold)immunizedwithMOG/CFAemulsionandreceivedPTXontwoconsecutivedaystoinduceEAE[1]Dosage:10mg/kgAdministration:i.g.,dailyfor23daysResult:Delayeddiseaseonsetandreducedsymptomseverity,asindicatedbylowercumulativeandmeanmaximumclinicalscores.Maintaineditsprophylacticeffectuntilthepeakofdiseaseseverity,whichoccurredaround17dpi.PreventedbodyweightlossandlowereddiseaseincidenceinEAEmice,indicatingaprotectiveeffect.Moderateddiseaseprogression,andledtoasteadyreductioninsymptomseverityuntil34dpi,demonstratingamoderatetherapeuticeffectcomparabletothatofSiponimod(HY-12355).Significantlyreducedthecumulativeclinicalscorefrom19dpi(thepeakofEAE)to34dpi.Preventedbodyweightlosscomparedtothevehicle-treatedgroup.Markedlyreduceddemyelinationinthespinalcord'sdorsalcolumnandventralwhitematter.Reducedimmunecellinfiltrationandpartiallypreservedmyelinintegrity.AnimalModel:FemaleC57BL/6Nmice(8weeksold)[1]Dosage:1,3,and10mg/kgAdministration:i.g.,singledoseResult:ReducedPLCto24.4%ofbaselineat4hpostadministration,outperformingFingolimod(36.3%).PromotedarapidrecoveryofPLCsto70.8%ofbaselinewithin28hours,incontrasttoFingolimod(HY-11063),whichcausesprolongedlymphopenia.Producedarapidreductioninlymphocytecountstoapproximately40%ofbaselineat3hpostadministrationandachievedmaximalsuppressionatthe3and10mg/kgdosesby6hpostadministration,whiletriggeringanearlyreboundinthe1mg/kggroupbythesametime,suggestingtheonsetofrecovery.Elicitedastrongerpharmacodynamicresponseat3and10mg/kg,andpermittedfulllymphocyterecoveryinallgroupswithin24hours.REFERENCES[1].LeeCY,etal.DiscoveryofNovelβ-ArrestinBiasedSphingosine-1-Phosphate-1ReceptorAgonistsfortheTreatmentofMultiple2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemESclerosis.JMedChem.2025Sep11;68(17):18289-18313.McePdfHeightC