Medchemexpress/Dolutegravir(Synonyms: S/GSK1349572; GSK1349572)/HY-13238/10mM*1mL in DMSO

DolutegravirisaninhibitorofHIV-1integrase-catalyzedstrandtransferwithIC₅₀of2.7nM.

IC50:2.7nM(HIV-1integrase)^[1]

TheEC₅₀ofDolutegravir(S/GSK1349572)againstHIV-1is0.51nMinPBMCs,0.71nMinMT-4cells,and2.2nMinthePHIVassay,whichusesapseudotypedself-inactivatingvirus.The50%cytotoxicconcentrations(CC₅₀)forDolutegravirinproliferatingIM-9,U-937,MT-4,andMolt-4cellsare4.8,7.0,14,and15μM,respectively.InunstimulatedandstimulatedPBMCs,theCC₅₀are189μMand52μM,respectively.BasedontheEC₅₀ofDolutegraviragainstHIV-1inPBMCs(i.e.,0.51nM),thistranslatestoacell-basedtherapeuticindexofatleast9,400^[1].

Followingasingleintravenous(IV)admiNISTrationofDolutegravir,theplasmaclearanceislowinrats(0.23mL/min/kg)andmonkeys(2.12mL/min/kg).Thehalf-livesintheratandmonkeyaresimilar,approximately6h,andthesteady-statevolumeofdistribution(V_SS)islow.Followingoraladministration,DolutegravirisrapidlyabsorbedwithahighoralbioavailABIlitywhenadministeredasasolutiontofastedmaleratsandasinglemonkey(75.6and87.0%,respectively).Dolutegravirexposure(C_maxandAUC)increasedwithincreasingdosefollowingoraladministrationofasUSPensiontonon-fastedratsupto250mg/kgandnon-fastedmonkeysupto50mg/kg,althoughtheincreaseislessthanproportional^[2].

• [1].KobayashiM,etal.InVitroantiretroviralpropertiesofS/GSK1349572,anext-generationHIVintegraseinhibitor.AntimicrobAgentsChemother.2011Feb;55(2):813-21.

  [2].MossL,etal.Thecomparativedispositionandmetabolismofdolutegravir,apotentHIV-1integraseinhibitor,inmice,rats,andmonkeys.Xenobiotica.2015Jan;45(1):60-70.

Dolutegravir(S/GSK1349572)isdissolvedinstocksolutions,andthendilutedwithappropriatemediabeforeuse^[1].

Invitrogrowthinhibition(cytotoxicity)studiesareconductedwithS/GSK1349572(0.16,0.8,4,and20nM)inproliferatinghumanleukemicandlymphomiccelllines(IM-9,U-937,MT-4,andMolt-4)aswellasinstimulatedandunstimulatedhumanPBMCs.ATPlevelsarequantifiedbyusingtheCellTiter-Gloluciferasereagenttomeasuretheabilityofacompoundtoinhibitcellgrowthasanindicatorofthecompound"spotentialforcytotoxicity^[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

Dolutegravir(S/GSK1349572)isformulatedasasolutioninN,N-dimethylacetamideanddilutedwith50mMN-methylglucaminein3%mannitol(intravenous)^[2].
Dolutegravir(S/GSK1349572)isformulatedasasolutioninD:Solutol:50mMN-methylglucaminein3%mannitol(1:1:8,v:w:v)(orallyadministeredtofastedratsandmonkeys)^[2].
Dolutegravir(S/GSK1349572)isformulatedasasuspensionin0.5%hydroxypropylmethylcellulose(HPMC)/0.1%polyoxyethylenesorbitanmonooleate(Tween80)(orallyadministeredtonon-fastedratsandmonkeys)^[2].

ForratandmonkeyPKstudies,Dolutegravirisadministeredasthefreeacidorthesodiumsalt.Alldosesarepresentedintermsofthefreeacid.Dolutegravirisadministeredbyintravenous(IV)short-term(within2min)bolus(1mg/kg)tothreemaleratsandtwomalemonkeys.Forsingleoraladministration,Dolutegravirasasolution(5mg/kg)isadministeredtothreefastedmaleratsandtwofastedmalemonkeys.Dolutegravirisadministeredassingleoraldosesof5,50,100,and250mg/kgtonon-fastedmalerats(n=2/doselevel)and3,10,and50mg/kgtonon-fastedfemalemonkeys.Forintravenousadministration,bloodsamplesarecollectedfromrats(0.2mLviajugularveincannula)andmonkeys(approximately0.2or0.5mLviasaphenousveininahindlimb)intoNa₂EDTA-treatedsyringesat0.083,0.25,0.5,1,2,4,6,8,and24h.Fororaladministration,samplesarecollectedat0.25(ratsonly),0.5,1,2,4,6[rats(solutionandsuspension)andmonkey(solutiononly)],8,and24h.Followingcollection,thebloodisimmediatelyputonweticeandthencentrifugedwithinanhourat1740gfor10minat4°Ctoobtainplasma.Allsamplesarestoredatapproximately-20°CorcolderpriortoanalysisbyusingamethodbasedonproteinprecipitationandLC-MS/MSanalysis.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

• [1].KobayashiM,etal.InVitroantiretroviralpropertiesofS/GSK1349572,anext-generationHIVintegraseinhibitor.AntimicrobAgentsChemother.2011Feb;55(2):813-21.

  [2].MossL,etal.Thecomparativedispositionandmetabolismofdolutegravir,apotentHIV-1integraseinhibitor,inmice,rats,andmonkeys.Xenobiotica.2015Jan;45(1):60-70.

419.38

C₂₀H₁₉F₂N₃O₅

1051375-16-6

RoomtemperatureincontinentalUS;mayvaryelsewhere

DMSO:10mg/mL

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