早老性痴呆药物研究进展.ppt

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1、早老性痴呆药物研究进展 Still waters run deep.流静水深流静水深,人静心深人静心深 Where there is life,there is hope。有生命必有希望。有生命必有希望ContentsCurrent situation of AD1What are big companies doing 2Trends3Perspective42022/12/321 Current situation of ADvPopulation：37 million vCauses：too sophisticatedvMarket drugs：Tarcrine，Donepezil，Ri

2、vastigmine，Galanthamine，Huperzine，MemantinevSome social activities may correlate with AD，but cannot delay the progress of AD2022/12/33Nature Reviews.2010.7:387-3982022/12/342 What are big companies doingvA big cake attracts a lot of big companies，attention，such as Pfizer，Elan，Merk，Novartis and so on

3、2022/12/35BMC Medicine 2009,7:7 2022/12/36TramiprosatevALZHEMED（Neurochem Inc.）vThe Phase III trial did not show a beneficial effect on cognition or function，so the development program has been discontinued 2022/12/37Vaccines and antibodiesvAN-1792（Elan）the first-generation amyloid vaccine，Phase II

4、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 an

5、tibodies2022/12/382022/12/39RAGE 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 I

6、I 2022/12/310-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 tole

7、rable doses，in Phase III2022/12/311Tau aggregation inhibitorvRember（Methylene blue）：a widely used histology dye,has been shown to interfere with tau aggregation.v Entering Phase III2022/12/3122022/12/313Microtubule stabilizervNAP(AL-108)：derived from a natural neurotrophic protein,can be delivered t

8、o 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.2022/12/314Dimebon-Pfizerv Phase III trial(Dimebon and Donepezil):failed，but Pfizer now is launching another Phase III tria

9、l about dimebon with other AD drugs.2022/12/315vPhase 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 methylthioniniu

10、m 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.2022/12/3163 TrendsvMultitarget Anti-Alzheimer AgentsvAD modelvfurther explore the causesvcoalition and cooperation2022/12/317Multi

11、target Anti-Alzheimer AgentsNovel Tacrine-8-Hydroxyquinoline Hybrids as Multifunctional Agents for the Treatment of Alzheimers Disease,with Neuroprotective,Cholinergic,Antioxidant,and Copper-Complexing Properties2022/12/3182022/12/319Bivalent-Carbolines as Potential Multitarget Anti-Alzheimer Agents

12、2022/12/320AD 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 disease2022/12/321Further explore the causesThe brain of AD patient likes a labyrinth 2022/12/322CooperationvW

13、hile 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 dr

14、ugs.2022/12/3234 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 clin

15、ical 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

16、reduce the global impact of this devastating disease.2022/12/324Reference1 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.

17、XX3MaraIsabelFernandez-Bachiller.NovelTacrine-8-HydroxyquinolineHybrids 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 treat

18、ment 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 2022/12/326