INT-747isapotentandselectiveFXRagonist(EC₅₀=99nM)endowedwithanticholestaticactivity.

EC50:99nM(FXR)

6-ECDCAincreasestheexpressionofFXR-regulatedgenesinrathepatocytes^[1].INT-747reducesexpressionofliverJNK-1andJNK-2^[2].INT-747(256μg/mL)showscompleteinhibitionofbacterialgrowthinallstrainstested.IntestinalpermeABIlityremainsunaffectedafterINT-747-additiontoanIFN-γ-exposedintestinalepitheliumofCaco-2cells^[3].

6-ECDCA(10mg/kg/day)completelyrevertedcholestasisinducedbyE₂17α.Administrationof6-ECDCApartiallypreventstheimpairmentintotalbileacidoutputcausedbyE₂17αbyincreasingtherelativeabundanceofβ-MCAandTCDCAandTDCA^[1].INT-747(10mg/kg)andHSincreasesthepulmonarycongestionintheanimals.INT-747doesnotimproverenalpathologyintheHS-fedanimals^[2].INT-747(5mg/kg)significantlyincreasessurvivalinBDLrats.INT-747-treatedBDLratsexhibitsasignificantselectiveilealincreaseinexpressionofpore-closingclaudin-1.IlealexpressionofZO-1issignificantlyup-regulatedinINT-747-treatedBDLrats^[3].

• [1].FiorucciS,etal.Protectiveeffectsof6-ethylchenodeoxycholicacid,afarnesoidXreceptorligand,inestrogen-inducedcholestasis.JPharmacolExpTher.2005May;313(2):604-12.

  [2].GhebremariamYT,etal.FXRagonistINT-747upregulatesDDAHexpressionandenhancesinsulinsensitivityinhigh-saltfedDahlrats.PLoSOne.2013Apr4;8(4):e60653.

  [3].VerbekeL,etal.TheFXRAgonistObeticholicAcidPreventsGutBarrierDysfunctionandBacterialTranslocationinCholestaticRats.AmJPathol.2015Feb;185(2):409-19.

INT-747isformulatedin1%methylcelluloseindistilledwater.

Initially,allanimals(at6-weeksage)areplacedonastandardrodentdietforaweek.Baselinebloodandurinesamplesarecollectedandbasalbloodpressure(BP)ismeasuredpriortogroupingtheanimals.Subsequently,theanimalsarerandomizedintolow(LS;n=9)orhighsalt(HS)dietgroups.HypertensionisinducedintheHSgroupbydailyhigh-saltdietfeedingandthegroupissubdividedtoreceiveoneoftwodosesofINT-747:lowdose(10mg/kg/day;n=15)orhighdose(30mg/kg/day;n=15)in1%methylcellulose;orvehicle(1%methylcelluloseindistilledwater;n=15)orallyeverydayfor6weeks.Inparallel,theLSgroupalsoreceive1%methylcellulose.BPismeasuredweeklyforthedurationofthestudyasdescribedbelow.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

• [1].FiorucciS,etal.Protectiveeffectsof6-ethylchenodeoxycholicacid,afarnesoidXreceptorligand,inestrogen-inducedcholestasis.JPharmacolExpTher.2005May;313(2):604-12.

  [2].GhebremariamYT,etal.FXRagonistINT-747upregulatesDDAHexpressionandenhancesinsulinsensitivityinhigh-saltfedDahlrats.PLoSOne.2013Apr4;8(4):e60653.

  [3].VerbekeL,etal.TheFXRAgonistObeticholicAcidPreventsGutBarrierDysfunctionandBacterialTranslocationinCholestaticRats.AmJPathol.2015Feb;185(2):409-19.

420.63

C₂₆H₄₄O₄

459789-99-2

RoomtemperatureincontinentalUS;mayvaryelsewhere

DMSO:≥33mg/mL

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