Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEGSK3186899Cat.No.:HY-112622CASNo.:1972617-87-0Synonyms:DDD-853651分?式:C??H??F?N?O?S分?量:491.53作?靶點(diǎn):Parasite作?通路:Anti-infection儲(chǔ)存?式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性數(shù)據(jù)體外實(shí)驗(yàn)DMSO:250mg/mL(508.62mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制備儲(chǔ)備液1mM2.0345mL10.1723mL20.3446mL5mM0.4069mL2.0345mL4.0689mL10mM0.2034mL1.0172mL2.0345mL請(qǐng)根據(jù)產(chǎn)品在不同溶劑中的溶解度選擇合適的溶劑配制儲(chǔ)備液；?旦配成溶液，請(qǐng)分裝保存，避免反復(fù)凍融造成的產(chǎn)品失效。儲(chǔ)備液的保存?式和期限：-80°C,6months;-20°C,1month。-80°C儲(chǔ)存時(shí)，請(qǐng)?jiān)?個(gè)?內(nèi)使?，-20°C儲(chǔ)存時(shí)，請(qǐng)?jiān)?個(gè)?內(nèi)使?。體內(nèi)實(shí)驗(yàn)請(qǐng)根據(jù)您的實(shí)驗(yàn)動(dòng)物和給藥?式選擇適當(dāng)?shù)娜芙?案。以下溶解?案都請(qǐng)先按照InVitro?式配制澄的儲(chǔ)備液，再依次添加助溶劑：(為保證實(shí)驗(yàn)結(jié)果的可靠性，澄的儲(chǔ)備液可以根據(jù)儲(chǔ)存條件，適當(dāng)保存；體內(nèi)實(shí)驗(yàn)的?作液，建議您現(xiàn)?現(xiàn)配，當(dāng)天使?；以下溶劑前顯?的百分?指該溶劑在您配制終溶液中的體積占?；如在配制過(guò)程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過(guò)加熱和/或超聲的?式助溶)1.請(qǐng)依序添加每種溶劑：10%DMSO>>40%PEG300>>5%Tween-80>>45%saline1/2MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemESolubility:≥2.08mg/mL(4.23mM);Clearsolution2.請(qǐng)依序添加每種溶劑：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥2.08mg/mL(4.23mM);Clearsolution3.請(qǐng)依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥2.08mg/mL(4.23mM);ClearsolutionBIOLOGICALACTIVITY?物活性GSK3186899(DDD-853651)CRK12的?個(gè)抑制劑，其對(duì)L.donovani的EC50值為1.4μM。IC50&TargetCRK12[1].體外研究GSK3186899(Compound7)isactiveagainstL.donovaniinanintra-macrophageassaywithanEC50valueof1.4μM,andshowsgoodselectivityagainstmammalianTHP-1hostcells(EC50value>50μM).ThisisnotaspotentasreporteddataforamphotericinB(EC50valueof0.07μMintheintra-macrophageassay),butiscomparabletotheclinicallyuseddrugsmiltefosineandparomomycin(EC50valuesof0.9μMand6.6μM,respectively).GSK3186899isalsoactiveincidalaxenicamastigoteassay(EC50valueof0.1μM).Ataconcentrationof0.2μM,GSK3186899iscytocidalat96h;increasingtheconcentrationto1.8μMreducedthistimeto48h.GSK3186899demonstratesalessthan10-foldvariationinpotencyagainstapanelofLeishmania-derivedlines.GSK3186899isalsomoreactiveinapanelofLeishmanialinesusinghumanperipheralbloodmononuclearcellsasthehostcells[1].體內(nèi)研究Inthemousemodelofinfection,GSK3186899demonstratescomparableactivitytothefront-linedrugmiltefosine,reducingparasitelevelsby99%whendosedorallytwiceadayfor10daysat25mg/kg.Theefficacyoftreatmentisdependentondose,frequency,andduration(10daysbetterthan5).Thenon-clinicalsafetydataforGSK3186899suggestsasuitabletherapeuticwindowforprogressionintoregulatorypreclinicalstudies.Non-GLPpreclinicalassessmentofcardiovasculareffectsandgenotoxicitydoesnotrevealanyissuesthatwouldpreventfurtherdevelopment.Inaddition,therearenonotableadverseeffectsinaratseven-dayrepeat-doseoraltoxicitystudywithrespecttoclinicalchemistryandhistopathologyatalldosestested.BoththeinvivoefficacyandsafetyprofileofGSK3186899supportprogressiontodefinitivesafetystudies[1].REFERENCES[1].WyllieS,etal.Cyclin-dependentkinase12isadrugtargetforvisceralleishmaniasis.Nature.2018Aug;560(7717):192-197.McePdfHeightCaution:Producthasnotbeenfullyval