SitagliptinisapotentinhibitorofDPP4withIC50of19nMinCaco-2cellextracts.DescriptionSitagliptinisapotentinhibitorofDPP4withIC50of19nMinCaco-2cellextracts.IC50&TargetIC50:19nM(DPP4)InVitroSitagliptinphosphateexhibitsapotentinhibitoryeffectonDPP-4withIC50of19nMfromCaco-2cellextracts[1]. SitagliptinreducesinvitromigrationofisolatedsplenicCD4T-cellsthroughapathwayinvolvingcAMP/PKA/Rac1activation[2]. Stagliptinexertsanovel,directactioninordertostimulateGLP-1secretionbytheintestinalLcellthroughaDPP-4-independent,proteinkinaseA-andMEK-ERK1/2-dependentpathway.Itreducestheeffectofautoimmunityongraftsurvival[3]. InVivoInvivo,theED50valueofsitagliptinphosphateforinhibitionofplasmaDPP-4activityiscalculatedtobe2.3mg/kg7hourpostdoseand30mg/kg24hourpostdoseinfreelyfedHan-Wistarrats[1]. Thestreptozotocin-inducedtype1diabetesmousemodelexhibitselevatedDPP-4levelsintheplasmathatcanbesubstantiallyinhibitedinmiceonanSitagliptinphosphatediet.Thisisachievedbyapositiveeffectontheregulationofhyperglycemia,potentiallythroughprolongationofisletgraftsurvival[4]. TheplasmaclearanceandvolumeofdistributionofSitagliptinphosphatearehigherinrats(40-48mL/min/kg,7-9L/kg)thanindogs(9mL/min/kg,3L/kg);anditshalf-lifeisshorterinrats,2hourscomparedwith4hoursindogs[5]. ClinicalTrialViewMoreCollapseReferences[1].Thomas,L.,etal.(R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione(BI1356),anovelxanthine-baseddipeptidylpeptidase4inhibitor,hasasuperiorpotencyandlongerdurationofacti[2].Kim,S.J.,etal.,DipeptidylpeptidaseIVinhibitionwithMK0431improvesisletgraftsurvivalindiabeticNODmicepartiallyviaT-cellmodulation.Diabetes,2009.58(3):p.641-51.[3].Sangle,G.V.,etal.,NovelBIOLOGicalactionofthedipeptidylpeptidase-IVinhibitor,sitagliptin,asaglucagon-likepeptide-1secretagogue.Endocrinology,2012.153(2):p.564-73.[4].Kim,S.J.,etal.,InhibitionofdipeptidylpeptidaseIVwithsitagliptin(MK0431)prolongsisletgraftsurvivalinstreptozotocin-induceddiabeticmice.Diabetes,2008.57(5):p.1331-9.[5].Beconi,M.G.,etal.Dispositionofthedipeptidylpeptidase4inhibitorsitagliptininratsanddogs.DrugMetabDispos,2007.35(4):p.525-32.PreparingStockSolutionsConcentrationVolumeMass1mg5mg10mg1mM2.4551mL12.2757mL24.5513mL5mM0.4910mL2.4551mL4.9103mL10mM0.2455mL1.2276mL2.4551mLPleaserefertothesolubilityinformationtoselecttheappropriatesolvent.KinaseAssay[1]DPP-4isextractedfromconfluentCaco-2cells.After5minutesofincubationatroomtemperaturewithlysisbuffer(10mMTris-HCl,150mMNaCl,0.04U/mLaprotinin,0.5%NonidetP40,pH8.0),cellsarecentrifugedat35,000gat4°Cfor30minutes,andthesupernatantisstoredat-80°C.Assaysareperformedbymixing20μLofappropriatecompounddilutionswith50μLofthesubstratefortheDPP-4enzyme,H-Ala-Pro-7-amido-4-trifluoromethylcoumarin(finalconcentrationintheassay,100μM)and30μLoftheCaco-2cellextract(diluted1000-foldwith100mMTris-HCl,100mMNaCl,pH7.8).Platesareincubatedatroomtemperaturefor1hour,andfluorescenceismeasuredatexcitation/emissionwavelengthsof405/535nmusingaSpectraMaxGeminiXS.DissociationkineticsofinhibitorsfromtheDPP-4enzymeisdeterminedaftera1-hourpreincubationofCaco-2cellextractswithhighinhibitorconcentrations(30nMforBI1356,3μMforvildagliptin).TheenzymaticreactionisstartedbyaddingthesubstrateH-Ala-Pro-7-amido-4-trifluoromethylcoumarinaftera3000-folddilutionofthepreincubationmixturewithassaybuffer.Undertheseconditions,thedifferenceinDPP-4activityatacertaintimepointinthepresenceorabsenceofaninhibitorreflectstheamountofthisinhibitorstillboundtotheDPP-4enzyme.Maximalreactionrates(fluorescenceunits/seconds×1000)at10-minuteintervalsarecalculatedusingtheSoftMaxsoftwareoftheSpectraMaxandcorrectedfortherateofanuninhibitedreaction[(vcontrol-vinhibitor)/vcontrol].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.CellAssay[2]CD4T-cellsareplatedonmembraneinsertsinserum-freeRPMI1640,andcellmigrationisassayedusingTranswellchambers(Corning),inthepresenceorabsenceofpurifiedporcinekidneyDPP-4(32.1units/mg;100mU/mLfinalconcentration)andDPP-4inhibitor(100μM).After1hour,cellsontheuppersurfaceareremovedmechanically,andcellsthathavemigratedintothelowercompartmentarecounted.Theextentofmigrationisexpressedrelativetothecontrolsample.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalAdmiNISTration[1]Sitagliptinisformulatedin0.5%aqueoushyroxyethylcellulose.OvernightfastedC57BL/6Jmicearechallenged45minaftercompoundadministrationwithanoralglucoseload(2g/kg).Bloodsamplesforglucosemeasurementareobtainedbytailbleedpredoseandatserialtimepointsaftertheglucoseload.Toevaluatethedurationoftheeffectonglucosetolerance,vehicleorDPP-4inhibitorsareadministered16hbeforetheglucosechallenge.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.References[1].Thomas,L.,etal.(R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione(BI1356),anovelxanthine-baseddipeptidylpeptidase4inhibitor,hasasuperiorpotencyandlongerdurationofacti[2].Kim,S.J.,etal.,DipeptidylpeptidaseIVinhibitionwithMK0431improvesisletgraftsurvivalindiabeticNODmicepartiallyviaT-cellmodulation.Diabetes,2009.58(3):p.641-51.[3].Sangle,G.V.,etal.,Novelbiologicalactionofthedipeptidylpeptidase-IVinhibitor,sitagliptin,asaglucagon-likepeptide-1secretagogue.Endocrinology,2012.153(2):p.564-73.[4].Kim,S.J.,etal.,InhibitionofdipeptidylpeptidaseIVwithsitagliptin(MK0431)prolongsisletgraftsurvivalinstreptozotocin-induceddiabeticmice.Diabetes,2008.57(5):p.1331-9.[5].Beconi,M.G.,etal.Dispositionofthedipeptidylpeptidase4inhibitorsitagliptininratsanddogs.DrugMetabDispos,2007.35(4):p.525-32.MolecularWeight407.31FormulaC₁₆H₁₅F₆N₅OCASNo.486460-32-6StoragePowder-20°C3years 4°C2yearsInsolvent-80°C6months -20°C1monthShippingRoomtemperatureincontinentalUS;mayvaryelsewhereSolvent&Solubility10mMinDMSO*"

托烷司琼临床评价药物相关作用适应症托烷司琼CAS号:89565-68-4英文名称:Tropisetron英文同义词:icf205-930;TROPICACID;TROPISETRON;SS-TROPISETRON;BETA-TROPISETRON;Tropisetron(ICS205930);TROPISHTRONHYDROCHLORIDE;Indole-3-carbonylchloride;3-Tropanylindole-3-carboxylate;lαH，5Αh-Tropan-3α-ylindole-3-carboxylate中文名称:托烷司琼中文同义词:托普西隆;托普西龙;曲匹西龙;托烷司琼;Β-托烷司琼;CS-348;Β-内托烷司琼;吲哚-3-甲酰氯;Β-托烷司琼(光学异构体);Β-托烷司琼,托烷司琼异构体CBNumber:CB3236404分子式:C17H20N2O2分子量:284.35MOLFile:89565-68-4.mol化学性质安全信息用途供应商112化学性质安全信息用途供应商112托烷司琼化学性质熔点:201-202°C沸点:448.5±35.0°C(Predicted)密度:1.26储存条件:2-8°C溶解度:H2O:soluble形态:solid酸度系数(pKa):15.38±0.30(Predicted)颜色:whiteCAS数据库:Chemicalbook89565-68-4(CASDataBaseReference)安全信息WGKGermany:3托烷司琼化学药品说明书托烷司琼|药物应用信息托烷司琼性质、用途与生产工艺临床评价Sorbe等报道本品对含顺铂(剂量50～89mg/m2)化疗方案引起的急性呕吐完全控制率为63%。58例恶性肿瘤化疗所致恶心、呕吐者，应用托烷司琼或昂丹司琼8mg分别在同一病人前后2个化疗周期的第1d给药前30min静脉注射，并用地塞米松10mg静脉滴注。结果两药控制急性及迟发性恶心、呕吐的疗效基本相似，均可达81%～100%。本品对强致吐化疗药物顺铂的止吐疗效突出。药物相关作用饮食可略为延长本品的吸收。本品与利福平、苯巴比妥等肝酶诱导药同时使用，可加快代谢，故快代谢型者需增加剂量，慢者则不必。西咪替丁等肝酶抑制药对本品血药浓度无明显影响。适应症托烷司琼临床用于预防和治疗癌症化疗引起的恶心和呕吐。化学性质结晶，熔点201-202℃(二氯甲烷-乙酸乙酯)。单盐酸托烷司琼(TropisetronMonohydroehloride)：C17H20N2O2?HCI。[105826-92-4]。熔点283-285℃(分解)。用途有高效性和选择性的5-HT3受体拮抗剂。用于化疗所致的呕吐。用途为5-羟色胺拮抗药生产方法托品醇(I)和酰氯(Ⅱ)反应，可得托烷司琼。托烷司琼上下游产品信息上游原料托品醇下游产品