Hotline:400-820-3792Inhibitors ? ScreeningLibraries ? Proteinswww.MedChemERPR107393Cat.No.:HY-100299ACASNo.:190841-57-7分子式:C??H??Cl?N?O分子量:403.34作用靶點(diǎn):FarnesylTransferase作用通路:MetabolicEnzyme/Protease儲(chǔ)存方式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY生物活性RPR107393是一種口服有效的選擇性角鯊烯合酶(SQS)抑制劑。RPR107393抑制大鼠肝微粒體角鯊烯合酶，IC50值為0.8nM。RPR107393通過(guò)增加細(xì)胞內(nèi)法呢醇及其衍生物來(lái)抑制脂肪酸的生物合成，從而降低甘油三酯的生物合成。RPR107393可降低大鼠和狨猴的血漿膽固醇。RPR107393可用于代謝性疾病的相關(guān)研究，例如高膽固醇血癥、高甘油三酯血癥和動(dòng)脈粥樣硬化[1][2]。IC50&TargetIC50:0.8±0.2nM(ratlivermicrosomalsqualenesynthase)[1]體外研究RPR107393(10min)isapotentinhibitorofratlivermicrosomalsqualenesynthase,withIC50valuesof0.6to0.9nM,andisinactive(3%inhibitionat1mM)againstHMG-CoAreductasefromratlivermicrosomes[1].RPR107393(6h)concentration-dependentlyinhibitscholesterolbiosynthesis(IC50=880nM)andtriglyceridebiosynthesis(IC50=410nM)inrathepatocytes[2].RPR107393(10μM,2-24h)decreasestheincorporationof[1-14C]aceticacidintolipidsinrathepatocytesinatime-dependentmanner,withmaximalinhibitionofcholesterolandtriglyceridebiosynthesisoccurringat2hand24h,respectively[2].RPR107393(1μM,4h)inhibitscholesterolandtriglyceridebiosynthesisby82.4%and70.0%inrathepatocytes,respectively,withthelattereffectpotentiatedbyMVLsupplementation,suggestingamechanisminvolvingincreasedFPPderivatives[2].RPR107393(1-10μM,4h)increasescarnitine-dependentmitochondrialβ-oxidation(by26.5%at1μMand39.5%at10μM),itreducesoveralltriglyceridebiosynthesisthroughaβ-oxidation-independentpathway[2].RPR107393(10μM,4h)suppressestriglyceridebiosynthesisinrathepatocytes,reducingfattyacidandtriglyceridesynthesisby67.7%and68.5%,respectively,throughinhibitingfattyacidsynthesisratherthanlatermetabolicstages[2].1/3 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemE體內(nèi)研究RPR107393(10,25and30mg/kg,p.o.,sigledose,b.i.d.for2-4days,orq.d.for7days)exertspotenthypolipidemiceffectsafteroraladministrationinrats[1].RPR107393(20mg/kg,p.o.,b.i.d.orq.d.for7days)selectivelylowersLDLcholesterolwhilemaintainingafavorableHDLprofileinmarmosets[1].AnimalModel:Sprague-Dawleyrats(130-150g)[1]Dosage:10and25mg/kgAdministration:p.o.,sigledoseResult:Reducedcholesterolbiosynthesisby92%at10mg/kg,withanapproximateED50valueof5mg/kg.Reducedcholesterolbiosynthesisby74%after6h,andthetimefor50%inhibitionwas~7hrat10mg/kg.Inhibitedhepaticcholesterolbiosynthesiswithaninhibitionof82%at25mg/kgafter10h,buttheeffectwasnolongerapparentat21h.Inhibitedcholesterolbiosynthesisassociatedwithanaccumulationofradiolabeleddiacidproductsintheliver.AnimalModel:Sprague-Dawleyrats(130-150g)[1]Dosage:30mg/kgAdministration:p.o.,b.i.d.for2-4daysResult:Loweredserumcholesterolby35%after2daysandbynearly50%after3days.Thereductionincholesterolwasgreaterintheverylow-densitylipoprotein(VLDL)andlow-densitylipoprotein(LDL)fractions(66-88%)thaninthehigh-densitylipoprotein(HDL)fraction(maximum,35%).Reducedserumtriglyceridesbyupto70%.InducedhepaticmicrosomalHMG-CoAreductaseactivityby12to34-fold.AnimalModel:Sprague-Dawleyrats(130-150g)givenachowdietorthesamedietsupplementedwith2%cholestyramine(HY-104081)[1]Dosage:30mg/kgAdministration:p.o.,q.d.for7daysResult:TheRandSenantiomersreducedserumcholesterolby9%and24%,andtriglyceridesby46%and57%,respectively.Coadministrationwith2%cholestyramineinthedietreducedserumcholesterolby49%.TheRenantiomeradministeredalonedidnotlowerserumLDLcholesterol,whereascoadministrationwithcholestyramineresultedina30%reduction.2/3 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemEThereductionsinLDLcholesterolwiththeSenantiomerintheabsenceandthepresenceofcholestyraminewere33%and61%,respectively.ThereductionwasgreaterintheVLDLandLDLfractionsthanintheHDLfraction.AnimalModel:Malecommonmarmosets(Callithrixjacchus)[1]Dosage:20mg/kgAdministration:p.o.,b.i.d.for7daysResult:Reducedplasmacholesterolby50%.ThereductioninplasmacholesterolwasselectivelyintheLDLfraction(≤50%),whereascholesterolintheHDLfractionwasunchanged.ProducedagreaterreductioninplasmacholesterolthanLovastatin(HY-N0504)orPravastatin(HY-B0165)(whichproduced≤31%reductionat50mg/kg,b.i.d.).AnimalModel:Malecommonmarmosets(Callithrixjacchus)[1]Dosage:20mg/kgAdministration:p.o.,q.d.for7daysResult:Bothenantiomersreducedtotalplasmacholesterolbyapproximately27%.TheRandSenantiomersreducedLDLcholesterolby50%and43%,respectively.ShowednosignificantchangedinHDLcholesterollevels.REFERENCESAminD,etal.RPR107393,apotentsqualenesynthaseinhibitorandorallyeffectiveCholesterol-loweringagent:comparisonwithinhibitorsofHMG-CoAreductase.JPharmacolExpTher.1997May;281(2):746-52.HiyoshiH,etal.Squalenesynthaseinhibitorssuppresstriglyceridebiosynthesisthroughthefarnesolpathway