早老性癡呆藥物研究進(jìn)展 ppt課件

1、How to accelerate AD research ContentsCurrent situation of AD1What are big companies doing 2Trends3Perspective41 Current situation of ADvPopulation：37 million vCauses：too sophisticatedvMarket drugs：Tarcrine，Donepezil，Rivastigmine，Galanthamine，Huperzine，MemantinevSome social activities may correlate

2、with AD，but cannot delay the progress of ADNature Reviews.2019.7:387-3982 What are big companies doingvA big cake attracts a lot of big companies，attention，such as Pfizer，Elan，Merk，Novartis and so onBMC Medicine 2021, 7:7 TramiprosatevALZHEMEDNeurochem Inc.v vThe Phase III trial did not show a benef

3、icial effect on cognition or function，so the development program has been discontinued Vaccines and antibodiesvAN-1792Elanthe first-generation amyloid vaccine，Phase II trial was discontinued owing to the development of aseptic meningoencephalitis in 6% of the patientsvACC-001Elanprevent the inductio

4、n of a toxic cellular immune response，in a Phase II clinical trialvBapineuzumab (Elan/Wyeth) ：Phase III，monoclonal antibodiesvImmunoglobulin IgIV：Phase III，polyclonal antibodiesRAGE InhibitorvAmyloid is known to bind to receptors for advanced glycated endproducts (RAGE) on the surface of cells andv

5、at the blood-brain barrier； this binding may contribute tov inflammation and neuronal death.vPF-04494700 ：an orally bioavailable antagonist of RAGE，Phase IIv v -secretase inhibitorsvTarenflurbil：the enantiomer of the non-steroidal anti-inflammatory drug flurbiprofen，modulates the activity of -secret

6、ase，failed in Phase III vSemagacestat：reduction of amyloid peptidev generation in blood and cerebrospinal fluid of patients with AD treated with tolerable doses，v in Phase IIITau aggregation inhibitorvRemberMethylene blue：a widely used histology dye, has been shown to interfere with tau aggregation.

7、v Entering Phase IIIMicrotubule 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.Dim

8、ebon-Pfizerv Phase III trial(Dimebon and Donepezil): failed，but Pfizer now is launching another Phase III trial about dimebon with other AD drugs.NNNvPhase III trials of Ginkgo biloba, NSAIDs, phenserine, statins, tarenflurbil, tramiprosate, and xaliproden have been completed, none of them demonstra

9、ting adequate efficacy.vPhase II trials of dimebon, huperzine A, intravenous immunoglobulin, and methylthioninium chloride were reported at 2019. vNineteen compounds are currently in Phase II trials, and 3 compounds (AN1792, lecozotan SR, and SGS742) failed at this stage of development.3 TrendsvMult

10、itarget Anti-Alzheimer AgentsvAD modelvfurther explore the causesvcoalition and cooperationMultitarget Anti-Alzheimer AgentsNovel Tacrine-8-Hydroxyquinoline Hybrids as Multifunctional Agents for the Treatment of Alzheimers Disease, with Neuroprotective, Cholinergic, Antioxidant, and Copper-Complexin

11、g PropertiesBivalent -Carbolines as Potential Multitarget Anti-Alzheimer AgentsAD 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 diseaseFurther explore the causesThe brain

12、 of AD patient likes a labyrinth CooperationvWhile 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 mo

13、dels that could save time and money developing drugs.4 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 b

14、readth 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 t

15、o alter the neurodegenerative cascade and reduce the global impact of this devastating disease.Reference1 Michael S Rafii and Paul S Aisen.Recent developments in Alzheimers disease therapeutics.BMC Medicine 2021, 7:7 ,1741-7-15.2 Yvonne Rook.Bivalent -Carbolines as Potential Multitarget Anti-Alzheim

16、er 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 (2021) 202:1536.5 Marwa