Medchemexpress/INT-777(Synonyms: S-EMCA)/HY-15677/100mg

INT-777isapotentTGR5agonistwithEC₅₀of0.82μM.

EC50:0.82μM(TGR5)

INT-777isanovelpotentandselectiveTGR5agonistwithremarkableinvivoactivity^[1].INT-777(3μM)increasesATPproductioninthehumanenteroendocrinecelllineNCI-H716inacAMP-dependentmanner^[2].INT-777(10μM)lowersIscandincreasesTEERwhenaddedontheSEROsalsideofseromuscularstrippeddistalcolonsegments.INT-777effectonbasalsecretionisreducedinneuron-freeandTTX-treatedmucosal-submucosalpreparations^[3].

INT-777(30mg/kg/day,p.o.)increasesenergyexpenditureandreduceshepaticsteatosisandobesityuponhighfatfeeding,andimprovesinsulinsensitivity,inTGR5-Tgmice^[2].INT-777(1μM/min/kg,p.o.)hasapotentcholereticeffect,preventscarboxylCoAactivationandsubsequentconjugation,therebyfavoringitscholehepaticshuntpathwaywithaductularabsorptionandapotentcholereticeffectinHF-fedTGR5-Tgmalemice^[4].

• [1].PellicciariR,etal.Discoveryof6alpha-ethyl-23(S)-methylcholicacid(S-EMCA,INT-777)asapotentandselectiveagonistfortheTGR5receptor,anoveltargetfordiabesity.JMedChem.2009Dec24;52(24):7958-61.

  [2].ThomasC,etal.TGR5-mediatedbileacidsensingcontrolsglucosehomeostasis.CellMetab.2009Sep;10(3):167-77.

  [3].DubocH,etal.ReductionofepithelialsecretioninmaleratdistalcolonicmucosabybileacidreceptorTGR5agonist,INT-777:roleofsubmucosalneurons.NeurogastroenterolMotil.2016Jun3.doi:10.1111/nmo.

  [4].PellicciariR,etal.Discoveryof6alpha-ethyl-23(S)-methylcholicacid(S-EMCA,INT-777)asapotentandselectiveagonistfortheTGR5receptor,anoveltargetfordiabesity.Format:AbstractSendtoJMedChem.2009Dec24;52(24):7958-61.

INT-777isdissolvedinDMSO.

TheexperimentsarecarriedoutinSTC-1orNCI-H716cellstreatedwithvehicle(DMSO)orINT-777.INT-777isassessedforitsagonisticactivityonTGR5.cAMPproductionisperformed.CytochromeCoxidaseactivityisevaluatedbyfollowingtheoxidationoffullyreducedcytochromeCat550nm.ATP/ADPratioandGLP-1releaseismeasuredaccordingtothemanufacturer"sinstruction.PrimarybrownADIpocytesarepreparedandilealexplantsareprepared.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

INT-777ismixedwithdiet.

Age-matchedmalemiceareusedforallexperiments.Geneticallyengineeredmousemodels(GEMMs),i.e.TGR5-TgandTGR5-/-micearegenerated.Diet-inducedobesity(DIO)intheGEMMsorC57BL/6Jmiceisinducedbyfeeding8-week-oldmicewithaHF-diet(60%Cal/fat,D12492)foratleast8weeks,asmentionedinthetextandfigurelegends.Inthedietaryinterventionexperiments,INT-777ismixedwithdietatthedosesufficienttoreachaninvivodoseof30mg/kg/d.MousephenotypingexperimentsareperformedaccordingtoEMPRESSprotocolsandaimedtoassessfoodandwaterintake,bodycomposition,energyexpenditure,glucoseandlipidhomeostasis,andplasmabiochemistry.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

• [1].PellicciariR,etal.Discoveryof6alpha-ethyl-23(S)-methylcholicacid(S-EMCA,INT-777)asapotentandselectiveagonistfortheTGR5receptor,anoveltargetfordiabesity.JMedChem.2009Dec24;52(24):7958-61.

  [2].ThomasC,etal.TGR5-mediatedbileacidsensingcontrolsglucosehomeostasis.CellMetab.2009Sep;10(3):167-77.

  [3].DubocH,etal.ReductionofepithelialsecretioninmaleratdistalcolonicmucosabybileacidreceptorTGR5agonist,INT-777:roleofsubmucosalneurons.NeurogastroenterolMotil.2016Jun3.doi:10.1111/nmo.

  [4].PellicciariR,etal.Discoveryof6alpha-ethyl-23(S)-methylcholicacid(S-EMCA,INT-777)asapotentandselectiveagonistfortheTGR5receptor,anoveltargetfordiabesity.Format:AbstractSendtoJMedChem.2009Dec24;52(24):7958-61.

450.65

C₂₇H₄₆O₅

1199796-29-6

RoomtemperatureincontinentalUS;mayvaryelsewhere

DMSO:≥31mg/mL

*"<1 mg/ml"="" means="" slightly="" soluble="" or="" insoluble.="" "≥"="" means="" soluble,="" but="" saturation="">