1、How to accelerate AD research 8/3/20222ContentsCurrent situation of AD1What are big companies doing 2Trends3Perspective48/3/202231 Current situation of ADvPopulation：37 million vCauses：too sophisticatedvMarket drugs：Tarcrine，Donepezil，Rivastigmine，Galanthamine，Huperzine，MemantinevSome social activit
2、ies may correlate with AD，but cannot delay the progress of AD8/3/20224Nature Reviews.2010.7:387-3988/3/202252 What are big companies doingvA big cake attracts a lot of big companies，attention，such as Pfizer，Elan，Merk，Novartis and so on8/3/20226BMC Medicine 2009,7:7 8/3/20227TramiprosatevALZHEMED（Neu
3、rochem Inc.）vThe Phase III trial did not show a beneficial effect on cognition or function，so the development program has been discontinued 8/3/20228Vaccines and antibodiesvAN-1792（Elan）the first-generation amyloid vaccine，Phase II trial was discontinued owing to the development of aseptic meningoen
4、cephalitis 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 antibodies8/3/202298/3/202210RAGE InhibitorvAmyloid is known to bind t
5、o 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 8/3/202211-secretase inhibitorsvTarenflurbil：the enantiomer of the
6、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 III8/3/202212Tau aggregation inhibitorvRember（Met
7、hylene blue）：a widely used histology dye,has been shown to interfere with tau aggregation.v Entering Phase III8/3/2022138/3/202214Microtubule stabilizervNAP(AL-108)：derived from a natural neurotrophic protein,can be delivered to the central nervous system via intranasal administration.vmarkedly redu
8、ces tau phosphorylation,and preliminary human studies have been encouraging.Now it is in Phase II trial.8/3/202215Dimebon-Pfizerv Phase III trial(Dimebon and Donepezil):failed，but Pfizer now is launching another Phase III trial about dimebon with other AD drugs.NNN8/3/202216vPhase III trials of Gink
9、go 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 Ph
10、ase II trials,and 3 compounds(AN1792,lecozotan SR,and SGS742)failed at this stage of development.8/3/2022173 TrendsvMultitarget Anti-Alzheimer AgentsvAD modelvfurther explore the causesvcoalition and cooperation8/3/202218Multitarget Anti-Alzheimer AgentsNovel Tacrine-8-Hydroxyquinoline Hybrids as Mu
11、ltifunctional Agents for the Treatment of Alzheimers Disease,with Neuroprotective,Cholinergic,Antioxidant,and Copper-Complexing Properties8/3/2022198/3/202220Bivalent-Carbolines as Potential Multitarget Anti-Alzheimer Agents8/3/202221AD modelvA platform to perform pharmacological evaluation of anima
12、l models of Alzheimers diseasevIn the future drug candidates may be directly used to animal models of Alzheimers disease8/3/202222Further explore the causesThe brain of AD patient likes a labyrinth 8/3/202223CooperationvWhile each of us is running into a stone wall with Alzheimers，what will we do ne
13、xt？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.8/3/2022244 PerspectivevWhile it is not possible to predict the success of
14、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
15、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.8/3/202226Reference1 Michae
16、l 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
17、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 neurodegenerati
18、ve 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
