Aloxistatin(E64d)isabroad-spectrumcell-permeablecysteineproteaseinhibitor.

Cysteineprotease^[1]

Inhibitionofprotease-resistantprionprotein(PrP-res)accumulationinScNBcellsbycysteineproteaseinhibitorAloxistatin(E64d)withIC₅₀of0.5±0.11μM.ForthecellsurfacePrP-sendetection,PrP-senisimmunoprecipitatedfrommediatreatedwithphosphatidylinositol-specificphospholipaseC(PIPLC)toreleasepulse-³⁵S-labeledPrP-senfromthecellsurface.Aloxistatinismaintainedat15μM,respectively,inthelabelingmediaofallbutthecontrolcells^[1].Aloxistatin(E64d)(whichspecificallyblockscysteineproteases,butnotserineproteasessuchasgranzymes)isabletocompletelyblockturnoveroftheCatLsubstrateZ-Phe-Arg-aminomethylcoumarin,whenpre-incubatedwithNK-92orYT5cells^[2].Aloxistatin(E64d)isabroad-spectrumcell-permeableinhibitorofcysteineproteases^[3].

OraladmiNISTrationofAloxistatin(E64d)toguineapigsresultsinadose-dependentreductioninbrain,CSFandplasmaAβ(40)andAβ(42).Aloxistatinalsocausesabiphasicdose-dependentreductioninbrainCTFβ.Aloxistatincausesadose-dependentincreaseinbrainsAβPPα.ThemeansAβPPαlevelsaresignificantlyhigherthanthenodosegroupforAloxistatindosesof5mg/kg/dayorgreaterwiththehighestAloxistatindoseresultinginthemaximumincreaseinsAβPPαofabout54%morethanthecontrolgroup.SimilartotheAβeffect,oralAloxistatinadministrationproducesabiphasicdose-dependentreductioninbraincathepsinBactivity.Theminimumeffectivedoseisabout1mg/kg/daywiththehighestAloxistatindosecausingthemaximumreductioninbraincathepsinBactivityofabout91%lowerthanthatofthecontrolgroup.Thus,AloxistatinreducesguineapigbraincathepsinBactivityinamannerwhichisconsistentwiththecompoundinhibitingcathepsinBβ-secretaseactivity^[4].Aloxistatin(E64d)inhibitstheincreasesintheexpressionofAT_1ARandACEgenesinrats.AdministrationofOlmesartanorAloxistatinreducestheincreaseinthesuperoxideproductionoftheintramyocardialcoronaryarteriesinHFrats^[5].

• [1].Doh-UraK,etal.Lysosomotropicagentsandcysteineproteaseinhibitorsinhibitscrapie-associatedprionproteinaccumulation.JVirol.2000May;74(10):4894-7.

  [2].KonjarS,etal.HumanandmouseperforinareprocessedinpartthroughcleavagebythelysosomalcysteineproteinasecathepsinL.Immunology.2010Oct;131(2):257-67.

  [3].MullinsSR,etal.Three-dimensionalculturesmodelingpremalignantprogressionofhumanbreastepithelialcells:roleofcysteinecathepsins.BiolChem.2012Dec;393(12):1405-16.

  [4].HookG,etal.Thecysteineproteaseinhibitor,E64d,reducesbrainamyloid-βandimprovesmemorydeficitsinAlzheimer"sdiseaseanimalmodelsbyinhibitingcathepsinB,butnotBACE1,β-secretaseactivity.JAlzheimersDis.2011;26(2):387-408.

  [5].ChengXW,etal.Superoxide-dependentcathepsinactivationisassociatedwithhypertensivemyocardialremodelingandrepresentsatargetforangiotensinIItype1receptorblockertreatment.AmJPathol.2008Aug;173(2):358-69.

TheCTLsandNKcells(0.8×10⁶/mL)aretreatedwiththeinhibitorsL1(10-20μM)orAloxistatin(20-30μM)for24hrat37°Cin24-wellplates.Cellsarethenusedin⁵¹Cr-releaseassaysorarelysedtoexamineperforininWesternblots.Theinhibitorisalsoaddedatthesameconcentrationduringthe4hrreactionsinsome⁵¹Cr-releaseassays,asindicated.CelllysatesarepreparedusingNP-40lysisbuffer(25mMHEPES,250mMNaCl,2.5mMethylenediaminetetraaceticacid,0.1%volume/volumeNonidetP-40)andtotalproteinconcentrationisdeterminedusingtheBradfordassay.Equalamountsofproteinareloadedandresolvedon8%SDS-PAGEgels.Humanormouseperforinisdetectedusingtheappropriateantibodiesasindicated.Anti-actinantibodyisusedasaloADIngcontrol^[2].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

Aloxistatin(E64d)isdissolvedinDMSOandstored,andthendilutedwithappropriatemedium(finalDMSO0.1%)beforeuse^[3].

CellproliferationandapoptosisareassessedbystainingforaproliferationMarker,Ki67,oranapoptoticmarker,cleavedcaspase3,followingtheprotocoldescribedaboveforthepolaritymarkers.MCF10variantsaregrownin3DrBMoverlayculturesfor4daysandaretreatedwith0.1%DMSO,5μMCA074Meor5μMAloxistatin.ThepercentageofstructuresthatarepositiveforKi67orcleavedcaspase3isdeterminedbycountingatotalof100structuresontwoseparatecoverslipswithaZeissAxiophotepifluorescentmicroscope.StructuresareconsideredKi67positiveiftheycontainedatleastonecellstainingforKi67.Structuresareconsideredtobecaspase3positiveiftheycontainedatleastonecellthatispositiveforcleavedcaspase3andthepositivecell(s)isnotlocalizedinthecenterofadevelopinglumen^[3].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

Aloxistatin(E64d)issUSPendedinMe2SO^[4].

MiceandPig^[4]
GuineaPigs(male,Hartleystrain,averageweight400gcorrespondingtoanimalsabout6weeksold)areused.MaletransgenicmiceexpressinghumanAβPPcontainingthewtβ-secretasesiteandtheLondonmutantβ-secretasesitesequencesareused.Deliveringadrugbygavageofferstheadvantageofaccuratedosingbutistraumaticandthusonlysuitableforrelativelyshortdosingperiods(uptoaboutaweek).Deliverybygavageisusedfortheguineapigstudies.AloxistatinissuspendedinMe2SOattheindicatedconcentrations(0.1,1.0,5,and10mg/kg)andadministeredbygavagedailyusingafeedingtube.VehiclecontrolanimalsaretreatedbygavageofMe2SOalone.
Rat^[5]
MaleinbredDSratsareused.Weanedratsarefedlaboratorychowcontaining0.3%NaCluntil7weeksofage.DSratsfedan8%NaCldietafter7weeksmanifestcompensatedconcentricleftventricular(LV)hypertrophysecondarytohypertensionat12weeksandadistinctstageoffatalLVfailurewithlungcongestionat19weeks.DSratsarethereforefedan8%NaCldietfrom7weeksofageandarerandomizedtoanHFgroup,anAloxistatingroup(10mgperkgofbodymassperday,administeredintraperitoneallyeveryotherday),oranolmesartangroup(3mg/kgperdayinchow)from12to19weeksofage(n=10foreachgroup).Thedosesofolmesartan(anARB)andAloxistatinaredeterminedinpreliminaryexperimentsandpreviousstudies.DSratsmaintainedonthe0.3%NaCldietservedasage-matchedcontrols(controlgroup,n=10).At19weeksofage,alloftheratsareeuthanizedbyanintraperitonealoverdoseofsodiumpentobarbital(50mg/kg),andtheheartsareremovedforBIOLOGicalandhistologicalanalyses.ArterialbloodiscollectedfromtheaBDominalaortaforthemeasurementofreninactivity.Systolicbloodpressureandheartratearemeasuredinconsciousratsfrom7weeksofage,everyweek,usinganoninvasivetail-cuffmethod.Inseparateexperiments,12-week-oldDSrats,fedalow-saltdietfrom7weeksofage,aregivenvehicle,olmesartan,orAloxistatininthesamemannerasintheaboveexperiments(n=5foreachgroup),andtheLVtissuesformeasuringtargetingmRNAsandproteinlevelsareimmediatelyplacedinliquidnitrogenandstoredat-80°C.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

• [1].Doh-UraK,etal.Lysosomotropicagentsandcysteineproteaseinhibitorsinhibitscrapie-associatedprionproteinaccumulation.JVirol.2000May;74(10):4894-7.

  [2].KonjarS,etal.HumanandmouseperforinareprocessedinpartthroughcleavagebythelysosomalcysteineproteinasecathepsinL.Immunology.2010Oct;131(2):257-67.

  [3].MullinsSR,etal.Three-dimensionalculturesmodelingpremalignantprogressionofhumanbreastepithelialcells:roleofcysteinecathepsins.BiolChem.2012Dec;393(12):1405-16.

  [4].HookG,etal.Thecysteineproteaseinhibitor,E64d,reducesbrainamyloid-βandimprovesmemorydeficitsinAlzheimer"sdiseaseanimalmodelsbyinhibitingcathepsinB,butnotBACE1,β-secretaseactivity.JAlzheimersDis.2011;26(2):387-408.

  [5].ChengXW,etal.Superoxide-dependentcathepsinactivationisassociatedwithhypertensivemyocardialremodelingandrepresentsatargetforangiotensinIItype1receptorblockertreatment.AmJPathol.2008Aug;173(2):358-69.

342.43

C₁₇H₃₀N₂O₅

88321-09-9

RoomtemperatureincontinentalUS;mayvaryelsewhere

DMSO:≥23mg/mL

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

Purity:98.22%

SelectBatch:HY-100229-22435HY-100229-24213

DataSheet(124KB)SDS(389KB)

COA(92KB)HNMR(461KB)LCMS(135KB)

HandlingInstructions(1252KB)

• [1].Doh-UraK,etal.Lysosomotropicagentsandcysteineproteaseinhibitorsinhibitscrapie-associatedprionproteinaccumulation.JVirol.2000May;74(10):4894-7.

  [2].KonjarS,etal.HumanandmouseperforinareprocessedinpartthroughcleavagebythelysosomalcysteineproteinasecathepsinL.Immunology.2010Oct;131(2):257-67.

  [3].MullinsSR,etal.Three-dimensionalculturesmodelingpremalignantprogressionofhumanbreastepithelialcells:roleofcysteinecathepsins.BiolChem.2012Dec;393(12):1405-16.

  [4].HookG,etal.Thecysteineproteaseinhibitor,E64d,reducesbrainamyloid-βandimprovesmemorydeficitsinAlzheimer"sdiseaseanimalmodelsbyinhibitingcathepsinB,butnotBACE1,β-secretaseactivity.JAlzheimersDis.2011;26(2):387-408.

  [5].ChengXW,etal.Superoxide-dependentcathepsinactivationisassociatedwithhypertensivemyocardialremodelingandrepresentsatargetforangiotensinIItype1receptorblockertreatment.AmJPathol.2008Aug;173(2):358-69.

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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

公司介绍

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-

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