SRT1720HydrochlorideisaselectiveactivatorofhumanSIRT1withanEC_1.5of0.16μM,andshowslesspotentactivitiesagaiinstSIRT2andSIRT3withEC_1.5sof37μMand>300μM,respectively.

EC1.5:0.16μM(SIRT1),37μM(SIRT2),>300μM(SIRT3)^[1]

SRT1720andSRT2183areabletoeffectivelydecreasetheacetylationofp53incellsevenintheabsenceofSIRT1,andthisisattributedtoinhibitionofhistoneacetyltransferasep300^[2].

SRT1720(10,30,100mg/kg,p.o.)significantlyreducesthehyperinsulinaemiaafter4weeks,partiallynormalizingelevatedinsulinlevelssimilartorosiglitazonetreatment.SRT1720treatmentsignificantlyreducesfastingbloodglucosetonearnormallevelsinLep^ob/obmice^[1].SRT1720hasABIlitytoprotectagainstthenegativeeffectsofdiet-inducedobesityinmice,andhasaconnectiontometabolicadaptationinfattyacidandoxidativemetabolismthroughdownstreamtargetsofSIRT1suchasPGC1αandFOXO1^[2].SRT1720(50-100mg/kg,p.o.),duringemphysemadevelopmentattenuateselastase-inducedairspaceenlargementandlungfunctionimpairmentaswellasreducesarterialoxygensaturationinWTmice^[3].

• [1].MilneJCetal.SmallmoleculeactivatorsofSIRT1astherapeuticsforthetreatmentoftype2diabetes.Nature.2007Nov29;450(7170):712-6

  [2].BaurJA,etal.AresirtuinsviabletargetsforimprovinghealthspanandLifespan?,NatRevDrugDiscov.2012Jun1;11(6):443-61

  [3].YaoH,etal.SIRT1protectsagainstemphysemaviaFOXO3-mediatedreductionofprematuresenescenceinmice.,JClinInvest.2012Jun1;122(6):2032-45.

  [4].GaoD,etal.ActivationofSIRT1AttenuatesKlothoDeficiency-InducedArterialStiffnessandHypertensionbyEnhancingAMP-ActivatedProteinKinaseActivity.Hypertension.2016Nov;68(5):1191-1199.

SRT1720isformulatedin2%HPMC+0.2%DOSS.

NineweekoldC57BL/6malemicearefedahighfatdiet(60%caloriesfromfat)untiltheirmeanbodyweightreachapproximately40g.Themicearethendividedintotestgroups(6-10pergroup).SRT1460(100mg/kg),SRT1720(100mg/kg),SRT501(500mg/kg)androsiglitazone(5mg/kg)areadministeredoncedailyviaoralgavage.Thevehicleusedis2%HPMC+0.2%DOSS.Individualmousebodyweightsaremeasuredtwiceweekly.At2,4,6,8and10weeksofdosingafedbloodglucosemeasureistakenandafter5weeksoftreatmentanIPGTTisconductedonallmicefromeachofthegroups.After10weeksoftreatment,anITTisconducted.StatisticalanalysisiscompletedusingtheJMPprogram.DataareanalyzedbyaonewayANOVAwithcomparisontocontrolusingaDunnett’sTest.Apvalue<0.05=""indicates=""a=""significant=""difference=""between=""groups.=""mce=""has=""not=""independently=""confirmed=""the=""accuracy=""of=""these=""methods.=""they=""are=""for=""reference="">

• [1].MilneJCetal.SmallmoleculeactivatorsofSIRT1astherapeuticsforthetreatmentoftype2diabetes.Nature.2007Nov29;450(7170):712-6

  [2].BaurJA,etal.Aresirtuinsviabletargetsforimprovinghealthspanandlifespan?,NatRevDrugDiscov.2012Jun1;11(6):443-61

  [3].YaoH,etal.SIRT1protectsagainstemphysemaviaFOXO3-mediatedreductionofprematuresenescenceinmice.,JClinInvest.2012Jun1;122(6):2032-45.

  [4].GaoD,etal.ActivationofSIRT1AttenuatesKlothoDeficiency-InducedArterialStiffnessandHypertensionbyEnhancingAMP-ActivatedProteinKinaseActivity.Hypertension.2016Nov;68(5):1191-1199.

506.02

C₂₅H₂₄ClN₇OS

1001645-58-4

RoomtemperatureincontinentalUS;mayvaryelsewhere

10mMinDMSO

SRT1720ispreparedinvehicle(normalsaline)^[4].

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

• [1].MilneJCetal.SmallmoleculeactivatorsofSIRT1astherapeuticsforthetreatmentoftype2diabetes.Nature.2007Nov29;450(7170):712-6

  [2].BaurJA,etal.Aresirtuinsviabletargetsforimprovinghealthspanandlifespan?,NatRevDrugDiscov.2012Jun1;11(6):443-61

  [3].YaoH,etal.SIRT1protectsagainstemphysemaviaFOXO3-mediatedreductionofprematuresenescenceinmice.,JClinInvest.2012Jun1;122(6):2032-45.

  [4].GaoD,etal.ActivationofSIRT1AttenuatesKlothoDeficiency-InducedArterialStiffnessandHypertensionbyEnhancingAMP-ActivatedProteinKinaseActivity.Hypertension.2016Nov;68(5):1191-1199.