HPGDS-inhibitor-3-DataSheet-生命科學(xué)試劑-MedChemExpress

Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEHPGDSinhibitor3Cat.No.:HY-146662CASNo.:2255311-93-2分?式:C??H??N?O?分?量:353.46作?靶點(diǎn):PGEsynthase作?通路:Immunology/Inflammation儲(chǔ)存?式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY?物活性HPGDSinhibitor3?種具有?服活性且?效的外周限制性造?前列腺素D合成酶(H-PGDS)抑制劑，IC50為9.4nM，EC50為42nM。HPGDSinhibitor3具有良好的選擇性，在??、??和?體內(nèi)的藥動(dòng)學(xué)參數(shù)良好，且?中樞神經(jīng)系統(tǒng)毒性。HPGDSinhibitor3具有抗炎活性[1]。IC50&TargetIC50:9.4nM(H-PGDS)[1]EC50:42nM(H-PGDS)[1]體內(nèi)研究HPGDSinhibitor3(compound1y)(1-3mg/kg;POandIV;single)hasalowerIVclearance,similarsteadystatevolumeofdistribution,longerterminalhalf-life,andhighoralbioavailability,aswellasverylowbrainexposuresinmouse,ratanddog[1].HPGDSinhibitor3(0.003-1mg/kg;PO;single)attenuatesPGD2releasetobaselinelevelsinadose-dependentmanner;alsoinhibitsLPS-inducedPGD2increaseinplasmaandskeletalmuscleinadose-dependentmanner[1].HPGDSinhibitor3(0.003-1mg/kg;PO;single)[1].HPGDSinhibitor3(1,3,and10mg/kg;PO;q.d.,for16days)significantlyenhancesfunctionalrecoveryofinjuredlimbs,andhastensthetimetofullfunctionalrecoveryofinjuredlimbmuscles[1].HPGDSinhibitor3(10,30and100mg/kg;PO;oncedaily,for7daysor4days)exhibitswelltoleratedat30mg/kg/dayinratbutnottoleratedat100mg/kg/day;showswelltoleratedat30mg/kg/dayindogsbutnottoleratedat75mg/kg/day[1].PharmacokineticParametersofHPGDSinhibitor3inmice,ratsanddogs[1].MouseIV,1mg/kgPO,3mg/kgRat1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEIV,0.4mg/kgPO,2.4mg/kgDogIV,0.5mg/kgPO,1mg/kgT1/2(h)CL(mL/min/kg)9.04.51.9Vss(L/kg)F(%)7110092Brain:bloodratio0.06AnimalModel:MaleC57BL/6Jmice(murinemastcelldegranulationmodelofinflammation)[1]Dosage:0.003,0.01,0.03,0.1,0.3and1.0mg/kgAdministration:PO;single(anesthetized1hourlater,intraperitoneallyinjectedwith0.2mLPBSor48/80(0.75mg/mL))Result:AttenuatedPGD2releasetobaselinelevelsinadose-dependentmannerwithanED50of0.009mg/kg(bloodEC50=3.4nM)inthisacuteinflammationmodel.AnimalModel:MaleC57BL6/Nmice(12weeks,n=6)[1]Dosage:0.003,0.01,0.03,0.1,0.3and1.0mg/kgAdministration:PO;single(intraperitoneallyinjectionofPBSor20ng/kgLPS1hourlater)Result:InhibitedLPS-inducedPGD2increaseinplasmaandskeletalmuscleinadose-dependentmanner.AnimalModel:MaleC57Bl/6mice(10-12weeks,n=7-8;chroniceccentriccontraction-inducedmuscleinjurymodels)[1]Dosage:1,3,and10mg/kgAdministration:PO;q.d.,for16daysResult:Significantlyenhancedfunctionalrecoveryofinjuredlimbs,andsignificantlyhastenedthetimetofullfunctionalrecoveryofinjuredlimbmuscles,withmaximalefficacyobservedat≥10mg/kgq.d..AnimalModel:Mdxmouse(6-8mouths,duchennemusculardystrophymodel)[1]Dosage:0.1,0.3,1,3,and10mg/kgAdministration:PO;q.d.,for43daysResult:Significantlyimprovedfunctionalrecovery(~90%to100%restoration),followingeccentriccontraction-inducedmuscleinjuryinmdxmice.AnimalModel:MaleWistarHanratanddog[1]2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEDosage:10,30and100mg/kgforrat;10,30,and75mg/kgfordogAdministration:PO;oncedaily;for7days(rat)orfor4days(dog)Result:Inrat,theAUCvaluesat10,30,and100mg/kg/daywere120,410,and820μg?hr/mL,respectively;respectiveCmaxvalueswere8.7,24,and57μg/mL.Indog,itshowedwelltoleratedatdoselevelsupto30mg/kg/daywithnoabnormalmicroscopicfindings;butexhibiteddiscolorationinthesmallintestineandesophagus(female)at75mg/kg/day.AnimalModel:Mice,rats,dongs[1]Dosage:1mg/kgIVand3mg/kgp.oinmice,0.4mg/kgIVand2.4mg/kgPOinrat,0.5mg/kgIVand1mg/kgPOindogAdministration:IVandPO;single(PharmacokineticsAnalysis)Result:HadalowerIVclearance,similarsteadystatevolumeofdistribution,longerterminalhalf-life,andhighoralbioavailability,aswellasverylowbrainexposuresinmouse,ratanddog.REFERENCES[1].CadillaR,DeatonDN,DoY,etal.Theexplorationofaza-quinolinesashematopoieticprostaglandinDsynthase(H-PGDS)inhibitorswithlowbrainexposure.BioorgMedChem.2020;28(2