Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEBI689648Cat.No.:HY-101217CASNo.:1633009-87-6分?式:C??H??N?O?分?量:298.34作?靶點(diǎn):CytochromeP450作?通路:MetabolicEnzyme/Protease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:30mg/mL(100.56mM;Needultrasonicandwarming)MassSolvent1mg5mg10mgConcentration制備儲(chǔ)備液1mM3.3519mL16.7594mL33.5188mL5mM0.6704mL3.3519mL6.7038mL10mM0.3352mL1.6759mL3.3519mL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%salineSolubility:≥2.5mg/mL(8.38mM);Clearsolution1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE2.請(qǐng)依序添加每種溶劑：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥2.5mg/mL(8.38mM);Clearsolution3.請(qǐng)依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(8.38mM);ClearsolutionBIOLOGICALACTIVITY?物活性BI689648?種新型的，?選擇性醛酮合酶抑制劑，能抑制CYP11B1和CYP11B2，其IC50值分別為310和2.1nM。IC50&TargetIC50:310nM(CYP11B1),2.1nM(CYP11B2)[1]體外研究ComparewiththeFADsandLCI699,BI689648ishighlyselectiveinvitro,providinganIC50forCYP11B2of2.1nMandaselectivityfactorof149overCYP11B1.FAD286,bycomparison,showsasimilarIC50forCYP11B2(2.5nM);however,itsgreaterpotencyagainstCYP11B1(94nM)resultsinacomparativelymodestselectivityfactorof38,approximately4-foldlessthanBI689648[1].體內(nèi)研究Afteroraladministrationincynomonkeys,BI689648(5mg/kg)exhibitsapeakplasmaconcentrationof~500nM.ForBI689648(aldosteroneEC50=2nM),appreciablechangesin11-DOCareonlynotedatplasmaconcentrations>2000nMor>1000-folditsaldosteroneEC50whileFAD286showsawindowof~100-fold.BI689648exhibitsminimalimpacton11-DCandonlyatveryhighplasmaconcentrations(~10μM)[1].PROTOCOLCellAssay[1]Homogenizedadrenalglandsareusedtoevaluatetestcompounds(includingBI689648)ina96-wellplateformat.Amixtureofconcentratedhomogenateandsubstrateisaddedtocompounddilutionsforanalysis.ValuesfortheconcentrationrequiredtoinhibitCS(CYP11B1)andAS(CYP11B2)enzymeactivityby50%(IC50)arecalculated[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalForaldosteronesynthaseinhibitors(ASI)evaluation,thestudycohortconsistsof66healthyanimals.EachAdministration[1]separatestudyday,12cynomonkeysarerandomizedtoreceivevariousdosesofASIorvehiclecontrol(n=3/group);theanimalsarereusedacrossstudies,allowingaminimumof2weekswashoutbetweenstudies.Aggregationofdataacrossmultiplestudiesisusedtoderiveinvivoeffectiveconcentration(EC)valuesforaldosteroneandcortisolbycurve-fitting.Conscious,nonchairedmonkeysreceivevehicle(n=35),S-FAD(n=9),FAD286(n=24),LCI699(n=36),orBI689648(n=26)atdosesrangingfrom0.003mg/kgto10mg/kg.Maximaladrenocorticotropin(ACTH)-inducedaldosteroneandcortisolproductionoccursquickly,within15minutesafterchallenge,atwhichtimebloodiscollectedforplasmaaldosterone,cortisol,andtestcompoundconcentrations[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.REFERENCES2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE[1].WeldonSM,etal.SelectivityofBI689648,aNovel,HighlySelectiveAldosteroneSynthaseInhibitor:ComparisonwithFAD286andLCI699inNonhumanPrimates.JPharmacolExpTher.2016Oct;359(1):142-50.McePdfHeightCautio