Drugs in Clinical Trials for Alzheimer's Disease: The Major Trends

被引:248
作者
Bachurin, Sergey O. [1 ]
Bovina, Elena V. [1 ]
Ustyugov, Aleksey A. [1 ]
机构
[1] Russian Acad Sci, Inst Physiol Act Cpds, Severny Proezd 1, Chernogolovka 142432, Moscow Region, Russia
基金
俄罗斯科学基金会;
关键词
neurodegenerative disease; Alzheimer's disease; multitargeting compounds; disease-modifying drugs; repositioning of old drugs; clinical trial; AD treatment; amyloid-beta; Tauopathy; proteinopathy; MILD COGNITIVE IMPAIRMENT; AMYLOID PRECURSOR PROTEIN; PLACEBO-CONTROLLED TRIAL; PAIRED HELICAL FILAMENT; LONG-TERM TREATMENT; DOUBLE-BLIND; MOUSE MODEL; A-BETA; CHOLINESTERASE-INHIBITORS; BAPINEUZUMAB PHASE-3;
D O I
10.1002/med.21434
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Alzheimer's disease (AD) is characterized by a chronic and progressive neurodegenerative process resulting from the intracellular and extracellular accumulation of fibrillary proteins: beta-amyloid and hyperphosphorylated Tau. Overaccumulation of these aggregates leads to synaptic dysfunction and subsequent neuronal loss. The precise molecular mechanisms of AD are still not fully understood but it is clear that AD is a multifactorial disorder and that advanced age is the main risk factor. Over the last decade, more than 50 drug candidates have successfully passed phase II clinical trials, but none has passed phase III. Here, we summarize data on current "anti-Alzheimer's" agents currently in clinical trials based on findings available in the Thomson Reuters "Integrity" database, on the public website www.clinicaltrials.gov, and on database of the website Alzforum.org. As a result, it was possible to outline some major trends in AD drug discovery: (i) the development of compounds acting on the main stages of the pathogenesis of the disease (the so-called "disease-modifying agents")-these drugs could potentially slow the development of structural and functional abnormalities in the central nervous system providing sustainable improvements of cognitive functions, which persist even after drug withdrawal; (ii) focused design of multitargeted drugs acting on multiple molecular targets involved in the pathogenesis of the disease; (3) finally, the repositioning of old drugs for new (anti-Alzheimer's) application offers a very attractive approach to facilitate the completion of clinical trials. (C) 2017 Wiley Periodicals, Inc. Med. Res. Rev., 37, No. 5, 1186-1225, 2017
引用
收藏
页码:1186 / 1225
页数:40
相关论文
共 189 条
[1]   An Effector-Reduced Anti-β-Amyloid (Aβ) Antibody with Unique Aβ Binding Properties Promotes Neuroprotection and Glial Engulfment of Aβ [J].
Adolfsson, Oskar ;
Pihlgren, Maria ;
Toni, Nicolas ;
Varisco, Yvan ;
Buccarello, Anna Lucia ;
Antoniello, Katia ;
Lohmann, Sophie ;
Piorkowska, Kasia ;
Gafner, Valerie ;
Atwal, Jasvinder K. ;
Maloney, Janice ;
Chen, Mark ;
Gogineni, Alvin ;
Weimer, Robby M. ;
Mortensen, Deborah L. ;
Friesenhahn, Michel ;
Ho, Carole ;
Paul, Robert ;
Pfeifer, Andrea ;
Muhs, Andreas ;
Watts, Ryan J. .
JOURNAL OF NEUROSCIENCE, 2012, 32 (28) :9677-9689
[2]   Selective Brain-Targeted Antagonism of p38 MAPKα Reduces Hippocampal IL-1β Levels and Improves Morris Water Maze Performance in Aged Rats [J].
Alam, John J. .
JOURNAL OF ALZHEIMERS DISEASE, 2015, 48 (01) :219-227
[3]   AZD3293 A NOVEL BACE1 INHIBITOR: SAFETY, TOLERABILITY, AND EFFECTS ON PLASMA AND CSF Aβ PEPTIDES FOLLOWING SINGLE- AND MULTIPLE-DOSE ADMINISTRATION [J].
Alexander, Robert ;
Budd, S. ;
Russell, M. ;
Kugler, A. ;
Cebers, G. ;
Ye, N. ;
Olsson, T. ;
Burdette, D. ;
Maltby, J. ;
Paraskos, J. ;
Elsby, K. ;
Han, D. ;
Goldwater, R. ;
Ereshefsky, L. .
NEUROBIOLOGY OF AGING, 2014, 35 :S2-S2
[4]   Tolerability, safety and pharmacokinetics of the FGLL peptide, a novel mimetic of neural cell adhesion molecule, following intranasal administration in healthy volunteers [J].
Anand, Ravi ;
Seiberling, Michael ;
Kamtchoua, Thierry ;
Pokorny, Rolf .
CLINICAL PHARMACOKINETICS, 2007, 46 (04) :351-358
[5]  
[Anonymous], 2006, DRUG DATA REP, V28, P1006
[6]  
[Anonymous], 2014, PSYCHOPHARMACOLOGY, DOI [DOI 10.1176/appi.focus.12.2.152, 10.1176/appi.focus.12.2.152, DOI 10.1176/APPI.FOCUS.12.2.152]
[7]   What causes Alzheimer's disease? [J].
Armstrong, Richard A. .
FOLIA NEUROPATHOLOGICA, 2013, 51 (03) :169-188
[8]   Complex Disposition of Methylthioninium Redox Forms Determines Efficacy in Tau Aggregation Inhibitor Therapy for Alzheimer's Disease [J].
Baddeley, Thomas C. ;
McCaffrey, Jennifer ;
Storey, John M. D. ;
Cheung, John K. S. ;
Melis, Valeria ;
Horsley, David ;
Harrington, Charles R. ;
Wischik, Claude M. .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2015, 352 (01) :110-118
[9]   Biliverdin reductase-A: a novel drug target for atorvastatin in a dog pre-clinical model of Alzheimer disease [J].
Barone, Eugenio ;
Mancuso, Cesare ;
Di Domenico, Fabio ;
Sultana, Rukhsana ;
Murphy, M. Paul ;
Head, Elizabeth ;
Butterfield, D. Allan .
JOURNAL OF NEUROCHEMISTRY, 2012, 120 (01) :135-146
[10]  
Begley S., 2016, ALZHEIMERS RES SEETH