早老性痴呆药物研究进展.ppt

HowtoaccelerateADresearch,2019/12/6,2,Contents,CurrentsituationofAD,1,Whatarebigcompaniesdoing,2,Trends,3,Perspective,4,2019/12/6,3,1CurrentsituationofAD,Population：37millionCauses：toosophisticatedMarketdrugs：Tarcrine，Donepezil，Rivastigmine，Galanthamine，Huperzine，MemantineSomesocialactivitiesmaycorrelatewithAD，butcannotdelaytheprogressofAD,2019/12/6,4,NatureReviews.2019.7:387-398,2019/12/6,5,2Whatarebigcompaniesdoing,Abigcakeattractsalotofbigcompanies，attention，suchasPfizer，Elan，Merk，Novartisandsoon,2019/12/6,6,BMCMedicine2009,7:7,2019/12/6,7,Tramiprosate,ALZHEMED（NeurochemInc.）ThePhaseIIItrialdidnotshowabeneficialeffectoncognitionorfunction，sothedevelopmentprogramhasbeendiscontinued,2019/12/6,8,Vaccinesandantibodies,AN-1792（Elan）thefirst-generationamyloidvaccine，PhaseIItrialwasdiscontinuedowingtothedevelopmentofasepticmeningoencephalitisin6%ofthepatientsACC-001（Elan）preventtheinductionofatoxiccellularimmuneresponse，inaPhaseIIclinicaltrialBapineuzumab(Elan/Wyeth)：PhaseIII，monoclonalantibodiesImmunoglobulinIgIV：PhaseIII，polyclonalantibodies,2019/12/6,9,2019/12/6,10,RAGEInhibitor,Amyloidisknowntobindtoreceptorsforadvancedglycatedendproducts(RAGE)onthesurfaceofcellsandattheblood-brainbarrier；thisbindingmaycontributetoinflammationandneuronaldeath.PF-04494700：anorallybioavailableantagonistofRAGE，PhaseII,2019/12/6,11,-secretaseinhibitors,Tarenflurbil：theenantiomerofthenon-steroidalanti-inflammatorydrugflurbiprofen，modulatestheactivityof-secretase，failedinPhaseIIISemagacestat：reductionofamyloidpeptidegenerationinbloodandcerebrospinalfluidofpatientswithADtreatedwithtolerabledoses，inPhaseIII,2019/12/6,12,Tauaggregationinhibitor,Rember（Methyleneblue）：awidelyusedhistologydye,hasbeenshowntointerferewithtauaggregation.EnteringPhaseIII,2019/12/6,13,2019/12/6,14,Microtubulestabilizer,NAP(AL-108)：derivedfromanaturalneurotrophicprotein,canbedeliveredtothecentralnervoussystemviaintranasaladministration.markedlyreducestauphosphorylation,andpreliminaryhumanstudieshavebeenencouraging.NowitisinPhaseIItrial.,2019/12/6,15,Dimebon-Pfizer,PhaseIIItrial(DimebonandDonepezil):failed，butPfizernowislaunchinganotherPhaseIIItrialaboutdimebonwithotherADdrugs.,2019/12/6,16,PhaseIIItrialsofGinkgobiloba,NSAIDs,phenserine,statins,tarenflurbil,tramiprosate,andxaliprodenhavebeencompleted,noneofthemdemonstratingadequateefficacy.PhaseIItrialsofdimebon,huperzineA,intravenousimmunoglobulin,andmethylthioniniumchloridewerereportedat2019.NineteencompoundsarecurrentlyinPhaseIItrials,and3compounds(AN1792,lecozotanSR,andSGS742)failedatthisstageofdevelopment.,2019/12/6,17,3Trends,MultitargetAnti-AlzheimerAgentsADmodelfurtherexplorethecausescoalitionandcooperation,2019/12/6,18,MultitargetAnti-AlzheimerAgents,NovelTacrine-8-HydroxyquinolineHybridsasMultifunctionalAgentsfortheTreatmentofAlzheimersDisease,withNeuroprotective,Cholinergic,Antioxidant,andCopper-ComplexingProperties,2019/12/6,19,2019/12/6,20,Bivalent-CarbolinesasPotentialMultitargetAnti-AlzheimerAgents,2019/12/6,21,ADmodel,AplatformtoperformpharmacologicalevaluationofanimalmodelsofAlzheimersdiseaseInthefuturedrugcandidatesmaybedirectlyusedtoanimalmodelsofAlzheimersdisease,2019/12/6,22,Furtherexplorethecauses,ThebrainofADpatientlikesalabyrinth,2019/12/6,23,Cooperation,WhileeachofusisrunningintoastonewallwithAlzheimers，whatwillwedonext？Allowresearcherstostudyalargerpoolofpatientswillhelpusseehowthediseaseprogresses,identifysubgroups,andhopefullydevelopmoresophisticatedcomputermodelsthatcouldsavetimeandmoneydevelopingdrugs.,2019/12/6,24,4Perspective,Whileitisnotpossibletopredictthesuccessofanyindividualprogram,oneormorearelikelytoproveeffective.DespitedisappointingresultsfromrecentlycompletedPhaseIIItrialsofseveralnovelcompounds,theextentandbreadthofactivityatallphasesofclinicaldevelopmentsuggestthatnewpharmacotherapeuticoptionsforthetreatmentofADwillbecomeavailablewithinthenextdecade.Itseemsreasonabletopredictthatinthenot-too-distantfuture,asynergisticcombinationofagentswillhavethecapacitytoaltertheneurodegenerativecascadeandreducetheglobalimpactofthisdevastatingdisease.,ThankYou!,2019/12/6,26,Reference,1MichaelSRafiiandPaulSAisen.RecentdevelopmentsinAlzheimersdiseasetherapeutics.BMCMedicine2009,7:7,1741-7-15.2YvonneRook.Bivalent-CarbolinesasPotentialMultitargetAnti-AlzheimerAgents.J.Med.C.XXXX,Vol.XXX,NO.XX3MaraIsabelFernandez-Bachiller.NovelTacrine-8-HydroxyquinolineHybridsasMultifunctionalAgentsfortheTreatmentofAlzheimersDisease,withNeuroprotective,Cholinergic,Antioxidant,andCopper-ComplexingProperties.J.Med.C.XXXX,XXX,000-000.4RaymondT.Bartus&ReginaldL.DeanIII.PharmaceuticaltreatmentforcognitivedeficitsinAlzheimersdiseaseandotherneurodegenerativeconditions:exploringnewterritoryusingtraditionaltoolsandestablishedmaps.Psychopharmacology(2009)202