Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEIrdabisantCat.No.:HY-109968CASNo.:1005402-19-6Synonyms:CEP-26401分?式:C??H??N?O?分?量:313.39作?靶點:HistamineReceptor作?通路:GPCR/GProtein;Immunology/Inflammation;NeuronalSignaling儲存?式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY?物活性Irdabisant(CEP-26401)?種具有選擇性、?服活性和?腦屏障滲透性的組胺H3受體(histamineH3receptor,H3R)拮抗劑/逆激動劑，對??H3R和?H3R的Ki分別為7.2nM和2.0nM。Irdabisant對hERG電流的抑制活性相對較低，IC50為13.8μM。Irdabisant在??社會認知模型中具有認知增強和喚醒作?。Irdabisant可?于精神分裂癥或認知障礙的研究。IC50&TargetratH3receptorhumanH3receptor7.2nM(Ki)2nM(Ki)體外研究Irdabisant(CEP-26401,compound8a)showsantagonistactivitywithKb,appvaluesof1.0nMand0.4nMforratH3RandhumanH3R,respectively;showsinverseagonistactivitywithEC50valuesof2.0nMand1.1nMforratH3RandhumanH3R,respectively[1].IrdabisanthasmoderateactivityatMuscarinicM2(Ki=3.7±0.0μM)andAdrenergicα1A(Ki=9.8±0.3μM)receptors,Dopaminetransporters(Ki=11±2μM),Norepinephrinetransporters(Ki=10±1μM),andphosphodiesterasePDE3(IC50=15±1μM)[1].IrdabisantinhibitsthecytochromeP450enzymesCYP1A2,2C9,2C19,2D6,and3A4withIC50valuesofgreaterthan30μM,indicatinglesspotentialfordrug-druginteractions[1].體內(nèi)研究CEP-26401(0.01-0.3mg/kg;p.o.;singledosage)dose-dependentlyinhibitsH3RagonistRAMH-induceddipsogenia[1].CEP-26401(0.0001-0.1mg/kg;i.v.orp.o.;singledosage)improvesperformanceintheratsocialrecognitionmodelofshort-termmemory[1].1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemECEP-26401(3-30mg/kg;p.o.;singledosage)exhibitswake-promotingactivityinrat[2].CEP-26401(3-30mg/kg;i.p.)increasesprepulseinhibition(PPI)inDBA/2NCrlmice[2].CEP-26401(1mg/kgfori.v.and3mg/kgforp.o.;singledosage)israpidlyabsorbedwithhighoralbioavailabilityinratandmonkey,andshowsamoderateclearanceinmonkeyanddogcomparedtotherat[1].PharmacokineticParametersofIrdabisant(compound8a)inrats,dogsandmonkeys[1].RatDogMonkeyi.v.t1/2(h)i.v.Vd(L/kg)9.43.5±1.13.8±0.9i.v.CL(mL/min/kg)4213.2±1.57.7±1.8p.o.t1/2(L/kg)p.o.AUC(ng·h/mL)9841190±1801919±611p.o.Cmax(ng/mL)270230±70760±74p.o.F(%)8322±283±18Braintoplasmaratio2.6±0.22.4±0.4/AnimalModel:MaleSprague-Dawleyrats(i.p.10mg/kgRAMH-induceddipsogeniamodel)[1]Dosage:0.01-0.3mg/kgAdministration:p.o.;singledosageResult:Dose-dependentlyinhibitedH3RagonistRAMH(HY-100999)-induceddipsogenia(whichmanifestsaswaterdrinking)withanEC50valueof0.06mg/kg.AnimalModel:MaleSprague-Dawleyrats(adultratswerebrieflyexposedtoajuvenileratforbuildsocialrecognitionmodel)[2]Dosage:0.0001,0.001,0.01and0.1mg/kgfori.p.;0.01and0.1mg/kgforp.o.Administration:i.v.orp.o.;singledosageResult:Effectivelyreducedtheratioofinvestigationduration(RID)atdosesovertherangefrom0.001to0.1mg/kgi.p.andat0.01and0.1mg/kgp.o.,demonstratingpotentenhancementofshort-termsensorymemoryinthismodel.AnimalModel:MaleSprague-Dawleyrats[2]Dosage:3,10and30mg/kgAdministration:p.o.;singledosageResult:Exhibitedrobustwakepromotionwiththetreatedanimalsawake90%ofthetimeupto3hpostdosingat30mg/kg.AnimalModel:MaleDBA/2NCrlmice(19-27g;7-9weeks)[2]Dosage:3,10and30mg/kgAdministration:i.p.;singledosageResult:Increasedprepulseinhibition(PPI)inDBA/2NCrlmice,whereastheantipsychotic2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemERisperidone(HY-11018)iseffectiveat0.3and1mg/kgi.p..AnimalModel:MaleSprague-Dawleyrats,malebeagledogsandmalecynomolgusmonkeys[1]Dosage:1mg/kgfori.v.and3mg/kgforp.o.Administration:i.v.andp.o.Result:Exhibitedrapidabsorptionwithhighoralbioavailabilityinratandmonkey,andshowedamoderateclearanceinmonkeyanddogcomparedtotherat.REFERENCES[1].HudkinsRL,etal.Discoveryandcharacterizationof6-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one(CEP-26401,irdabisant):apotent,selectivehistamineH3receptorinverseagonist.JMedChem.2011Jul14;54(13):4781-92.[2].RaddatzR,etal.CEP-26401(irdabisant),apotentandselectivehistamineH?receptorantagonist/inverseagonistwithcognition-enhancingandwake-promotingactivities.JPharmacolExpTher.2012Ja