J-104132-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors • ScreeningLibraries • Proteinswww.MedChemEJ-104132Cat.No.:HY-10383CASNo.:198279-45-7分子式:C₃₁H₃₃NO₇分子量:531.6作用靶点:EndothelinReceptor作用通路:GPCR/GProtein储存方式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY生物活性J-104132(L-753037)是一种强效、口服活性的、选择性和竞争性的ETA/ETB受体(ETA/ETBreceptor)拮抗剂，其对ETA和ETB受体的Ki值分别为0.034nM和0.104nM。J-104132在体外可抑制ET-1(HY-P71446)诱导的信号传导和血管收缩。J-104132通过双重阻断ETA/ETB受体，在体内可减轻高血压、血管重塑和糖尿病内皮功能障碍。J-104132可用于糖尿病血管并发症的研究[1][3]。IC50&TargetETAETB0.034nM(Ki)0.104nM(Ki)体外研究J-104132potentlyinhibitsET-1-stimulatedphosphatidylinositolhydrolysis(IC50=0.059nM)inhumanETA/CHOcells,butfailstostimulateanyresponsebyitselfatafullyinhibitoryconcentration(3nM)[1].J-104132(0.001-10μM)specificallyandcompetitivelyantagonizesET-1-inducedcontractionsinrabbitiliacarteries,asitshiftstheET-1concentration-responsecurverightwardwithoutaffectingthemaximalresponseanddoesnotinhibitcontractionsinducedbyKClorNorepinephrine(HY-13715)[1].J-104132(3nM,20min)doesnotchangetheAch(HY-B0282)-inducedrelaxationindiabeticratsaortae[3].体内研究J-104132(1,3,and10mg/kg,p.o.,singledose)dose-dependentlyandpersistentlyinhibitsthepressorresponseelicitedbybigET-1inSDrats[1].J-104132(0.1,0.3and1mg/kg,p.o.ori.v.,singledose)dose-dependentlyinhibitsthepressorresponseelicitedbyET-1inSDrats[1].J-104132(0.01,0.03,0.1and0.3mg/kg/h,i.v.,infusionfor2h)shiftsET-1dose-responsecurvetotherightinadose-relatedmannerindogs[1].J-104132(10mg/kg,i.g.,for2weeksstarting12hafterballooninjury)decreasestheneointima/mediaratioinmaleSDratsandinbothmaleandfemaleETB-deficientrats,butithasnoeffectinfemalewild-typerats1/4 MasterofBioactiveMolecules—您身边的抑制剂大师www.MedChemE[2].J-104132(10mg/kg,p.o.,dailyfor4weeksstarting7weeksafterSTZ)restorestheimpairedacetylcholine(ACh)-inducedendothelium-dependentrelaxationinStreptozotocin(STZ)(HY-13753)-induceddiabeticrats[3].AnimalModel:MaleSDrats(6-7weeks)challengedwithbigET-1(0.5nmol/kg,i.v.)[1]Dosage:1,3and10mg/kgAdministration:p.o.,singledoseResult:AlmostcompletelyinhibitedthepressorresponseelicitedbybigET-1at30minafteradministrationatdosesof1,3,and10mg/kg.GraduallyrecoveredinhibitionofthepressorresponseelicitedbybigET-1within3to4hat1mg/kg.Inhibitionwasmaintainedformorethan8hoursafteradministrationofthe3and10mg/kgdoses.AnimalModel:MaleSDrats(200-400g)challengedwithET-1(0.5nmol/kg,i.v.)[1]Dosage:0.1,0.3and1mg/kgAdministration:p.o.ori.v.,singledoseResult:Showeddose-relatedinhibitionofET-1-inducedpressorresponsesafterp.o.andi.v.administration.TherelativepotenciesofJ-104132afterp.o.administrationwerethreetimeslessthanthoseafteri.v.administration.AnimalModel:Mongtrldogs(10-15kg)challengedwithET-1(1-100pmol/minfor30minintotherenalartery)[1]Dosage:0.01,0.03,0.1and0.3mg/kg/hAdministration:i.v.,infusionfor2hResult:ShiftedET-1dose-responsecurvetotherightinadose-relatedmanner.ShiftedtheET-1dose-responsecurveapproximately12-foldat0.03mg/kg/h.AnimalModel:Mongtrldogs(10-15kg)challengedwithET-1(1-100pmol/minfor30minintothebrachialartery)[1]Dosage:0.01,0.03,0.1and0.3mg/kg/hAdministration:i.v.,infusionfor2h2/4 MasterofBioactiveMolecules—您身边的抑制剂大师www.MedChemEResult:Ledtoa15-to20-foldshiftinthedose-responsecurveat0.3mg/kg/hcomparedwiththevehicle.Shiftedthedose-responsecurvetoET-1inthisvascularbedbymorethan20-foldatdoseof0.3mg/kg/h.Showednomarkedalterationsinheartrate,althoughsystemicarterialpressurewasobservedtoslowlydeclinebyapproximately18%overtheentireprotocolperiodatthe0.3mg/kg/hdosage.AnimalModel:MaleandfemaleWild-typeandETB-deficientrats(12-15weeks)challengedwithballooninjuryprocedure[2]Dosage:10mg/kgAdministration:i.g.,for2weeksstarting12hafterballooninjuryResult:Markedlydecreasedtheneointima/mediaratioinboththewild-typeandETB-deficientmalerats.Markedlydecreasedtheneointima/mediaratiointheETB-deficientfemaleratsbutnotinthewild-typefemalerats.TheETB-deficientratsexhibitedsignificantlyincreasedplasmaET-1levels,inbothmalesandfemalescomparedwiththewild-typerats.ShowednosignificantdifferencesinETAorETBreceptormRNAexpression.AnimalModel:MaleandfemaleSDrats(10weeks)challengedwithballooninjuryprocedure[2]Dosage:10mg/kgAdministration:i.g.,for2weeksstarting12hafterballooninjuryResult:Didnotaffectbodyweight,uteriwetweight,orSBPfor2weekstreatment.Significantlydecreasedtheneointima/mediaratiointhemalerats.Didnotaffecttheneointima/mediaratioinfemalerats.SignificantlyincreasedplasmaET-1levelscomparedwithvehicletreatedgroupinfemaleSDrats.AnimalModel:MaleWistarrats(7weeks)injectedwithSTZ(75mg/kg)[3]Dosage:10mg/kgAdministration:p.o.,dailyfor4weeksstarting7weeksafterSTZResult:SignificantlyattenuatedtheimpairmentofACh-inducedendothelium-dependentrelaxationindiabeticrats.Didnotalterplasmaglucose,totalcholesterol,HDL,VLDL,LDLortriglycerideindiabetic3/4 MasterofBioactiveMolecules—您身边的抑制剂大师www.MedChemErats.RevealedthattheexpressionratioeNOS/GAPDHdidnotdifferamonggroups.Reversedtheincreaseoftheexpressionofp22phoxmRNAinducedbydiabeticinrats.Significantlydecreasedtheelevatedlevelofsuperoxideanionintheaortaeofdiabeticrats.REFERENCESKitadaK,etal.EndothelinETBreceptorisinvolvedinsexdifferencesinthedevelopmentofballooninjury-inducedneointimalformation.J