阿尔茨海默病治疗药物的研究进展(1)

学报JournalofChinaPharmaceuticalUniversity2010,41(5):395-400郭静静,廖红*(,210009)阿尔茨海默病(Alzheimersdisease,AD)是一种以严重的认知和记忆功能减退为临床表现的神经退行性病变目前美国FDA批准的治疗AD的临床药物以调节神经递质为主,虽然能缓解症状,但疗效有限,难以逆转疾病进展近年来,随着AD病理机制的进一步阐明,AD的药物研发取得了较大进展,并以开发能够有效延缓疾病进程及预防AD发生的药物为重点其中以淀粉样蛋白和tau蛋白为靶点开发的药物以及多种神经保护剂得到了广泛研究目前多种候选化合物已经进入临床试验,为AD的治疗带来新的希望根据药物作用靶点和机制,以上述几类药物为主,对目前AD的药物研究进展进行综述阿尔茨海默病;治疗药物;进展R971A1000-5048(2010)05-0395-06DevelopmentofdrugforAlzheimersdiseaseGUOJingjing,LIAOHong*CenterforDrugScreening,ChinaPharmaceuticalUniversity,Nanjing210009,ChinaAbstractAlzheimesdisease(AD)isaheterogeneousneurodegenerativedisease,whichischaracterizedbyseverememorydeficitsandcognitiveimpairmen.tCurrentFDAapproveddrugsforADaimatthecorrectionofneurotransmitterabnormalities.Theyproducelimitedsymptomaticeffectsbutdonotslowdiseaseprogression.Duringrecentyears,withthefurtherunderstandingofthemechanismsthatinitiateandperpetuateAD,greatprogresshasbeenmadeinthedevelopmentoftherapeuticdrugstoreversethediseasecourseandpreventitsinitiation.Particularly,drugstargetingamyloidandtauproteinaswellasneuroprotectivereagentshavebeenwidelystudied.Severalpromisingcandidatesarecurrentlyunderinvestigationinclinicaltrials,sheddingnewlightonadiseasemodifyingtherapyofAD.Inthispaper,thecurrentstatusofthedrugdevelopmentforADisreviewed,andtheabovementioneddrugsclassifiedaccordingtotheirtherapeutictargetsarediscussed.KeywordsAlzheimersdisease;therapeuticdrugs;developmentThisstudywassupportedbyChinaNationalKeyHiTechInnovationProjectfortheR&DofNovelDrugs(No.2009ZX09302);theNationalNaturalScienceFoundationofChina(No.30670793;No.30973608);andtheNaturalScienceFoundationofJiangsuProvince(No.BK2009296)(Alzheimersdisease,AD),,2006266AD,2050AD1/85[1]AD,ADFDANMDA(NmethylDasparticacid)[2],,,,AD,AD,395*20100901*Te:l025-83271043Emai:[e-mail]国家重大新药创制!科技重大专项资助项目(No.2009ZX09302);国家自然科学基金资助项目(No.30670793;No.30973608);江苏省自然科学基金资助项目(No.BK2009296)学报JournalofChinaPharmaceuticalUniversity41,tau,,ADAD1AD,5,AD,11改善中枢胆碱能神经系统的药物AD,AD,MN,ADFDAAD4:(tacrine)(rivastigmine)(donepezil)(galantamine)1,,,AD50%AD1[3]AD7(7nAchR),[4]EnVivo7nAchREVP6124,,∀[5]12调节谷氨酸水平的药物AD(memantine)NMDA,NMDA,NMDAAD,,AD[6]13作用于其他神经递质的药物,5(5HT)AD5HT,5HT1A5HT45HT6,AD5HT6,AD,5HT6[7]H3,5HT,[8]H3GSK189254(6[(3cyclobutyl2,3,4,5tetrahydro1H3benzazepin7yl)oxy]Nmethyl3pyridinecarboxamide),,AD[9]2(A)AD,(Amyloid,A),ADA,A(amyloidprecursorprotein,APP)APP:APP,APP(sAPP);APP38~43A42A(A42),,[10],A[11],A,A,A[12]A,,Ca2+,,AAAAA,AD21减少A产生AADAPP,A;A211分泌酶激活剂sAPPA,ADPKCPI3KMAPKPLC,3965:APP[13](muscarinicacetylcholinereceptor,mAchR)[14],M1AF102B[Cevimelin,(#)cis2methylspiro(1,3oxathiolane5,3)quinuclidine]A[15]PLC5HT4ADsAPP[16]212分泌酶抑制剂APPA,A,AD[17],:∃,,;%,,[18],CTS21166&[19]213分泌酶抑制剂,,,Notch[20]EliLillySemagacestat[(2S)2hydroxy3methylN((1S)1methyl2{[(1S)3methyl2oxo2,3,4,5tetrahydro1H3benzazepin1yl]amino}2oxoethyl)butanamide]ADA,ADA,∀ADA4050%,,∋[21]22促进A清除A,ADAAA221A免疫疗法A:A,A,A,AN1792A,6%,T,ATh2Th1,A2,[22]A,,AD[22]∋,bapineuzumabsolanezumad[23]IvIg,IvIg,A,A[24]∀IvIgAD,IvIg∋[25]10,A,A,AD,,,AAD,AD[26]222促进A降解A,(neprilysin)(IDE)(ACE)(MMP),neprilysinIDEAADA[27],ADIDE[17]A,A,223调节A跨血脑脊液屏障转运,AAAAD(LRP)A,(RAGE)A[28]LRP(LRP()A,AD[29];ARAGE397学报JournalofChinaPharmaceuticalUniversity41A,RAGEPF04494700(TTP488)∀[30]23抑制A寡聚化A,AA,AA,Tramiprostae(Homotaurine,3aminopropane1sulfonicacid)Cyclohexanehexol(AZD103,cis1,2,3,5trans4,6cyclohexanehexol)(DHA)(melatonin)(curcumine)A,[17]Bush[31]A,ADAEDTAA,,A,3tautauAD,tau,,;,,,tau,AD[32]31tau蛋白过度磷酸化抑制剂tau,3(GSK3)tauGSK3,GSK3tau,GSK3tautau,GSK3tau[23]GSK3SB415286(3[(3chloro4hydroxyphenyl)amino]4(2nitrophenyl)1Hpyrrole2,5dione)NAP(HAsnAlaProValSerIleProGlnOH),[33]32微管蛋白稳定剂,tau,AD∀,[34]4AD,,AD(NGF)[35],,(ROS),,,MedivationPfizerDimebon(2,3,4,5tetrahydro2,8dimethyl5(2(6methyl3pyridyl)ethyl)1Hpyrido(4,3b)indole)∀,∋,,DimebonAD[36]5AD,,AD,3985::∃,;%AD,,;),bapineuzumabApoE4[26],∋,;∗,AD,AD,AD;+AD,,AD[1]BrookmeyerR,JohnsonE,ZieglerGrahamK,etal.ForecastingtheglobalburdenofAlzheimersdisease[J].AlzheimersDement,2007,3(3):186-191[2]NeugroschlJ,SanoM.CurrenttreatmentandrecentclinicalresearchinAlzheimersdisease[J].MtSinaiJMed,2010,77(1):3-16[3]GiacobiniE.LongtermstabilizingeffectofcholinesteraseinhibitorsinthetherapyofAlzheimerdisease[J].JNeuralTransmSuppl,2002,(62):181-187[4]NieoullonA.AcetylcholinesteraseinhibitorsinAlzheimersdisease:furthercommentsontheirmechanismsofactionandtherapeuticconsequences[J].PsycholNeuropsychiatrVieil,2010,8(2):123-131[5]MangialascheF,SolomonA,WinbladB,etal.Alzheimersdisease:clinicaltrialsanddrugdevelopment[J].LancetNeurol,2010,9(7):702-716[6]ThomasSJ,GrossbergGT.Memantine:areviewofstudiesintoitssafetyandefficacyintreatingAlzheimersdiseaseandotherdementias[J].ClinIntervAging,2009,4:367-377[7]GeldenhuysWJ,VanderSchyfCJ.Theserotonin5HT6receptor:aviabledrugtargetfortreatingcognitivedeficitsinAlzheimersdisease[J].ExpertRevNeurother,2009,9(7):1073-1085[8]LeursR,BakkerRA,TimmermanH,etal.ThehistamineH3receptor:fromgenecloningtoH3receptordrugs[J].NatRevDrugDiscov,2005,4(2):107-120[9]MedhurstAD,AtkinsAR,BeresfordIJ,etal.G