早老性痴呆药物研究进展.pptx

2024/8/22 周四1ContentsCurrent situation of AD1What are big companies doing 2Trends3Perspective42024/8/22 周四21 Current situation of ADvPopulation：37 million vCauses：too sophisticatedvMarket drugs：Tarcrine，Donepezil，Rivastigmine，Galanthamine，Huperzine，MemantinevSome social activities may correlate with AD，but cannot delay the progress of AD2024/8/22 周四3Nature Reviews.2010.7:387-3982024/8/22 周四42 What are big companies doingvA big cake attracts a lot of big companies，attention，such as Pfizer，Elan，Merk，Novartis and so on2024/8/22 周四5BMC Medicine 2009,7:7 2024/8/22 周四6TramiprosatevALZHEMED（Neurochem Inc.）vThe Phase III trial did not show a beneficial effect on cognition or function，so the development program has been discontinued 2024/8/22 周四7Vaccines and antibodiesvAN-1792（Elan）the first-generation amyloid vaccine，Phase II trial was discontinued owing to the development of aseptic meningoencephalitis in 6%of the patientsvACC-001（Elan）prevent the induction of a toxic cellular immune response，in a Phase II clinical trialvBapineuzumab(Elan/Wyeth)：Phase III，monoclonal antibodiesvImmunoglobulin IgIV：Phase III，polyclonal antibodies2024/8/22 周四82024/8/22 周四9RAGE InhibitorvAmyloid is known to bind to receptors for advanced glycated endproducts(RAGE)on the surface of cells and at the blood-brain barrier；this binding may contribute to inflammation and neuronal death.vPF-04494700：an orally bioavailable antagonist of RAGE，Phase II 2024/8/22 周四10-secretase inhibitorsvTarenflurbil：the enantiomer of the non-steroidal anti-inflammatory drug flurbiprofen，modulates the activity of-secretase，failed in Phase III vSemagacestat：reduction of amyloid peptide generation in blood and cerebrospinal fluid of patients with AD treated with tolerable doses，in Phase III2024/8/22 周四11Tau aggregation inhibitorvRember（Methylene blue）：a widely used histology dye,has been shown to interfere with tau aggregation.v Entering Phase III2024/8/22 周四122024/8/22 周四13Microtubule stabilizervNAP(AL-108)：derived from a natural neurotrophic protein,can be delivered to the central nervous system via intranasal administration.vmarkedly reduces tau phosphorylation,and preliminary human studies have been encouraging.Now it is in Phase II trial.2024/8/22 周四14Dimebon-Pfizerv Phase III trial(Dimebon and Donepezil):failed，but Pfizer now is launching another Phase III trial about dimebon with other AD drugs.2024/8/22 周四15vPhase III trials of Ginkgo biloba,NSAIDs,phenserine,statins,tarenflurbil,tramiprosate,and xaliproden have been completed,none of them demonstrating adequate efficacy.vPhase II trials of dimebon,huperzine A,intravenous immunoglobulin,and methylthioninium chloride were reported at 2008.vNineteen compounds are currently in Phase II trials,and 3 compounds(AN1792,lecozotan SR,and SGS742)failed at this stage of development.2024/8/22 周四163 TrendsvMultitarget Anti-Alzheimer AgentsvAD modelvfurther explore the causesvcoalition and cooperation2024/8/22 周四17Multitarget Anti-Alzheimer AgentsNovel Tacrine-8-Hydroxyquinoline Hybrids as Multifunctional Agents for the Treatment of Alzheimers Disease,with Neuroprotective,Cholinergic,Antioxidant,and Copper-Complexing Properties2024/8/22 周四182024/8/22 周四19Bivalent-Carbolines as Potential Multitarget Anti-Alzheimer Agents2024/8/22 周四20AD modelvA platform to perform pharmacological evaluation of animal models of Alzheimers diseasevIn the future drug candidates may be directly used to animal models of Alzheimers disease2024/8/22 周四21Further explore the causesThe brain of AD patient likes a labyrinth 2024/8/22 周四22CooperationvWhile each of us is running into a stone wall with Alzheimers，what will we do next？vAllow researchers to study a larger pool of patients will help us see how the disease progresses,identify subgroups,and hopefully develop more sophisticated computer models that could save time and money developing drugs.2024/8/22 周四234 PerspectivevWhile it is not possible to predict the success of any individual program,one or more are likely to prove effective.vDespite disappointing results from recently completed Phase III trials of several novel compounds,the extent and breadth of activity at all phases of clinical development suggest that new pharmacotherapeutic options for the treatment of AD will become available within the next decade.vIt seems reasonable to predict that in the not-too-distant future,a synergistic combination of agents will have the capacity to alter the neurodegenerative cascade and reduce the global impact of this devastating disease.2024/8/22 周四25Reference1 Michael S Rafii and Paul S Aisen.Recent developments in Alzheimers disease therapeutics.BMC Medicine 2009,7:7,1741-7-15.2 Yvonne Rook.Bivalent-Carbolines as Potential Multitarget Anti-Alzheimer Agents.J.Med.C.XXXX,Vol.XXX,NO.XX3 Mara Isabel Fern andez-Bachiller.Novel Tacrine-8-Hydroxyquinoline Hybrids as Multifunctional Agents for the Treatment of Alzheimers Disease,with Neuroprotective,Cholinergic,Antioxidant,and Copper-Complexing Properties.J.Med.C.XXXX,XXX,000-000.4 Raymond T.Bartus&Reginald L.Dean III.Pharmaceutical treatment for cognitive deficits in Alzheimers disease and other neurodegenerative conditions:exploring new territory using traditional tools and established maps.Psychopharmacology(2009)202:1536.5 Marwan N.Sabbagh.Drug Development for Alzheimers Disease:Where Are We Now and Where Are We Headed?.The American Journal of Geriatric Pharmacotherapy 2009,7(3):167-185.6 Martin Citron.Alzheimers disease:strategies for disease modification.Nature Reviews.2010.7:387-398