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1、How to accelerate AD research,2019/3/2,2,Contents,Current situation of AD,1,What are big companies doing,2,Trends,3,Perspective,4,2019/3/2,3,1 Current situation of AD,Population：37 million Causes：too sophisticated Market drugs：Tarcrine，Donepezil，Rivastigmine，Galanthamine，Huperzine，Memantine Some soc
2、ial activities may correlate with AD，but cannot delay the progress of AD,2019/3/2,4,Nature Reviews.2010.7:387-398,2019/3/2,5,2 What are big companies doing,A big cake attracts a lot of big companies，attention，such as Pfizer，Elan，Merk，Novartis and so on,2019/3/2,6,BMC Medicine 2009, 7:7,2019/3/2,7,Tr
3、amiprosate,ALZHEMED（Neurochem Inc.） The Phase III trial did not show a beneficial effect on cognition or function，so the development program has been discontinued,2019/3/2,8,Vaccines and antibodies,AN-1792（Elan）the first-generation amyloid vaccine，Phase II trial was discontinued owing to the develop
4、ment of aseptic meningoencephalitis in 6% of the patients ACC-001（Elan）prevent the induction of a toxic cellular immune response，in a Phase II clinical trial Bapineuzumab (Elan/Wyeth) ：Phase III，monoclonal antibodies Immunoglobulin IgIV：Phase III，polyclonal antibodies,2019/3/2,9,2019/3/2,10,RAGE Inh
5、ibitor,Amyloid 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. PF-04494700 ：an orally bioavailable antagonist of RAGE，Phase II,2019/3/2,11,-secretase inhibit
6、ors,Tarenflurbil：the enantiomer of the non-steroidal anti-inflammatory drug flurbiprofen，modulates the activity of -secretase，failed in Phase III Semagacestat：reduction of amyloid peptide generation in blood and cerebrospinal fluid of patients with AD treated with tolerable doses， in Phase III,2019/
7、3/2,12,Tau aggregation inhibitor,Rember（Methylene blue）：a widely used histology dye, has been shown to interfere with tau aggregation. Entering Phase III,2019/3/2,13,2019/3/2,14,Microtubule stabilizer,NAP (AL-108)：derived from a natural neurotrophic protein, can be delivered to the central nervous s
8、ystem via intranasal administration. markedly reduces tau phosphorylation, and preliminary human studies have been encouraging.Now it is in Phase II trial.,2019/3/2,15,Dimebon-Pfizer,Phase III trial(Dimebon and Donepezil): failed，but Pfizer now is launching another Phase III trial about dimebon with
9、 other AD drugs.,2019/3/2,16,Phase III trials of Ginkgo biloba, NSAIDs, phenserine, statins, tarenflurbil, tramiprosate, and xaliproden have been completed, none of them demonstrating adequate efficacy. Phase II trials of dimebon, huperzine A, intravenous immunoglobulin, and methylthioninium chlorid
10、e were reported at 2008. Nineteen compounds are currently in Phase II trials, and 3 compounds (AN1792, lecozotan SR, and SGS742) failed at this stage of development.,2019/3/2,17,3 Trends,Multitarget Anti-Alzheimer Agents AD model further explore the causes coalition and cooperation,2019/3/2,18,Multi
11、target Anti-Alzheimer Agents,Novel Tacrine-8-Hydroxyquinoline Hybrids as Multifunctional Agents for the Treatment of Alzheimers Disease, with Neuroprotective, Cholinergic, Antioxidant, and Copper-Complexing Properties,2019/3/2,19,2019/3/2,20,Bivalent -Carbolines as Potential Multitarget Anti-Alzheim
12、er Agents,2019/3/2,21,AD model,A platform to perform pharmacological evaluation of animal models of Alzheimers disease In the future drug candidates may be directly used to animal models of Alzheimers disease,2019/3/2,22,Further explore the causes,The brain of AD patient likes a labyrinth,2019/3/2,2
13、3,Cooperation,While each of us is running into a stone wall with Alzheimers ，what will we do next？ Allow 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 m
14、oney developing drugs.,2019/3/2,24,4 Perspective,While it is not possible to predict the success of any individual program, one or more are likely to prove effective. Despite disappointing results from recently completed Phase III trials of several novel compounds, the extent and breadth of activity
15、 at all phases of clinical development suggest that new pharmacotherapeutic options for the treatment of AD will become available within the next decade. It seems reasonable to predict that in the not-too-distant future, a synergistic combination of agents will have the capacity to alter the neurode
16、generative cascade and reduce the global impact of this devastating disease.,Thank You !,2019/3/2,26,Reference,1 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
17、-Alzheimer Agents.J.Med.C.XXXX,Vol.XXX,NO.XX 3 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 Ray
18、mond 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,