Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEGSK2193874Cat.No.:HY-100720CASNo.:1336960-13-4分?式:C??H??BrF?N?O分?量:691.62作?靶點:TRPChannel作?通路:MembraneTransporter/IonChannel;NeuronalSignaling儲存?式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性數(shù)據(jù)體外實驗DMSO:100mg/mL(144.59mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制備儲備液1mM1.4459mL7.2294mL14.4588mL5mM0.2892mL1.4459mL2.8918mL10mM0.1446mL0.7229mL1.4459mL請根據(jù)產(chǎn)品在不同溶劑中的溶解度選擇合適的溶劑配制儲備液；?旦配成溶液，請分裝保存，避免反復凍融造成的產(chǎn)品失效。儲備液的保存?式和期限：-80°C,6months;-20°C,1month。-80°C儲存時，請在6個?內(nèi)使?，-20°C儲存時，請在1個?內(nèi)使?。體內(nèi)實驗請根據(jù)您的實驗動物和給藥?式選擇適當?shù)娜芙?案。以下溶解?案都請先按照InVitro?式配制澄的儲備液，再依次添加助溶劑：(為保證實驗結果的可靠性，澄的儲備液可以根據(jù)儲存條件，適當保存；體內(nèi)實驗的?作液，建議您現(xiàn)?現(xiàn)配，當天使?；以下溶劑前顯?的百分?指該溶劑在您配制終溶液中的體積占?；如在配制過程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過加熱和/或超聲的?式助溶)1.請依序添加每種溶劑：10%DMSO>>40%PEG300>>5%Tween-80>>45%salineSolubility:≥2.08mg/mL(3.01mM);Clearsolution1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE2.請依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥2.08mg/mL(3.01mM);Clearsolution3.請依序添加每種溶劑：5%DMSO>>95%(20%SBE-β-CDinsaline)Solubility:2.5mg/mL(3.61mM);Suspendedsolution;NeedultrasonicBIOLOGICALACTIVITY?物活性GSK2193874具有?服活性的有效的選擇性TRPV4拮抗劑，作?于rTRPV4和hTRPV4，IC50分別為2nM和40nM。IC50&TargetIC50:2nM(rTRPV4),40nM(hTRPV4)[1]體外研究GSK2193874isprofiledagainstTRPchannelsandisselectiveagainstTRPV1,TRPA1,TRPC3,TRPC6,andTRPM8(IC50>25μM)[1].GSK2193874isaselective,orallyactiveTRPV4blockerthatinhibitsCa2+influxthroughrecombinantTRPV4channelsandnativeendothelialTRPV4currents.Inwhole-cellpatch-clampstudies,GSK2193874inhibitsactivationofrecombinantTRPV4currentswhenappliedtotheextracellularsolutionat3nMandabovebutisineffectiveatupto10μMwhenappliedtotheinsideofthecellbyinclusionintheintracellularpipettesolution[2].體內(nèi)研究Thepharmacokinetic(PK)propertiesforGSK2193874areevaluatedinbothratanddogandfoundtohavehalf-livesandoralexposuresuitablefororaldosinginchronicanimalmodels(RatPK:ivCL=7.3mL/min/kg,pot1/2=10h,%F=31.DogPK:ivCL=6.9mL/min/kg,pot1/2=31h,%F=53).Inaddition,GSK2193874showsnobloodpressureorheartrateeffectinratswhendoseupto30mg/kg.GSK2193874isthefirst-in-classorallybioavailableTRPV4inhibitorthatdemonstratedabilitytoimprovepulmonaryfunctionsinanumberofheartfailuremodels[1].GSK2193874showslowclearance(7.3mL/min/kg)andgoodratoralbioavailability(31%)[2].PROTOCOLAnimalRats[2]Administration[2]AdultmaleSprague-Dawleyrats(n=7to8pergroup)aretreatedwithvehicle(6%Cavitron)orGSK2193874(30mg/kgperday)viaoralgavageforatleast4daysbeforeosmoticchallenges.Ratsundergoacuteandchronichyper-andhypo-osmoticchallenges.Sprague-Dawleyratsareadministeredvehicle(0.9%NaCl,25mL/kg),NSC269420(30mg/kg),orhydrochlorothiazide(30mg/kg)viaoralgavage.Urineisthencollectedover4hoursfollowedbybloodsampling.Ratsrecoverfor4daysandthenreceiveGSK2193874(30mg/kgperdayoralgavage)for5daysbeforerepeatingthediureticchallenge.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.戶使?本產(chǎn)品發(fā)表的科研?獻?Autophagy.2021Nov;17(11):3592-3606.?JNanobiotechnology.2022Jul6;20(1):314.2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE?ActaPharmacolSin.2022Sep23.?CellCalcium.2022Jun;104:102590.?JEthnopharmacol.2022Feb11;290:115105.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].CheungM,etal.DiscoveryofGSK2193874:AnOrallyActive,Potent,andSelectiveBlockerofTransientReceptorPotentialVanilloid4.ACSMedChemLett.2017Mar20;8(5):549-554.[2].ThorneloeKS,etal.AnorallyactiveTRPV4channelblockerpreventsandresolvespulmonaryedemainducedbyheartfailure.SciTranslMed.2012Nov7;4(159):159ra148.McePdfHeig