Alzheimer's disease: new approaches to drug discovery

Available online at www.sciencedirect.com

Alzheimer’s disease: new approaches to drug discoveryMaria L Bolognesi, Riccardo Matera, Anna Minarini, Michela Rosini andCarlo Melchiorre

In this work, we review and comment upon the challenges and

the ‘quo vadis’ in Alzheimer’s disease drug discovery at the

beginning of the new millennium. We emphasize recent

approaches that, moving on from a target-centric approach,

have produced innovative molecular probes or drug

candidates. In particular, the discovery of endosome-targeted

BACE1 inhibitors and mitochondria-targeted antioxidants

represents a significant advance in Alzheimer’s research and

therapy. The case study of the development of rasagiline

provides an excellent example to support the validity of the

multitarget-designed ligand approach to the search for

effective medicines for combating Alzheimer’s disease.

Address

Department of Pharmaceutical Sciences, Alma Mater Studiorum,

University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy

Corresponding author: Melchiorre, Carlo ([email protected])

Current Opinion in Chemical Biology 2009, 13:303–308

This review comes from a themed issue on

Next-generation therapeutics

Edited by Karl-Heinz Altmann and Dario Neri

Available online 19th May 2009

1367-5931/$ – see front matter

# 2009 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.cbpa.2009.04.619

IntroductionAlzheimer’s disease (AD) represents one of the most

formidable challenges to the drug discovery community

[1]. Although a breakthrough treatment has been

promised repeatedly in the last 30 years, an effective

drug for AD has yet to arrive. We are all aware of its

socioeconomic and clinical burden. In developed

countries, AD is the fourth cause of death, and on the

basis of constant increase in life expectancy in western

societies, it is estimated that AD cases will triple by

2050. On the clinical front, AD is the most common form

of dementia, characterized by memory loss and impair-

ment in reasoning, judgment, and language. More and

more of us are experiencing the devastating effects of

having a close friend or family member with the con-

dition [2].

Today, medicinal chemistry projects rely mostly on

target-driven high-throughput approaches. This is

www.sciencedirect.com

because, since the early 1990s, drug discovery has gradu-

ally moved from an entirely human phenotype-based

endeavor to the so-called ‘reductionist approach’ [3].

This strategy attempts to reduce drug action to the level

of individual genes, single proteins, and one potential

modulating molecule, following the ‘one gene, one tar-

get, one drug’ paradigm [4]. Drug discovery in AD has

followed the same trend. Over the last 30 years, different

targets have been advocated as central players in AD

pathogenesis. Firstly, following the cholinergic hypoth-

esis [5], acetylcholinesterase (AChE) inhibition was vali-

dated as a therapeutic strategy, and a new generation of

centrally active AChE inhibitors (AChEIs) were regis-

tered for the treatment of mild to moderate AD. Later,

efforts to develop NMDA receptor antagonists as AD

drugs were stimulated by evidence that NMDA receptor-

mediated excitotoxicity is a central pathogenic event in

AD. The introduction of memantine in 2003 provided

patients with moderate to severe AD with a new thera-

peutic option [6].

However, owing to disappointing clinical results, the

effectiveness of these tools has been questioned [7],

and the search for real disease-modifying agents has

begun [8]. Previously, the question was: ‘Which is the

best target for preventing or curing AD?’. The answer

was in part determined by whether scientists saw b-

amyloid peptide (Ab) (also called BAP, among its many

other names) or hyperphosphorylated tau as the prime

culprit of the pathogenesis cascade leading to AD. This

dichotomy has been caricatured in the field as a reli-

gious war between the ‘baptists’ and the ‘tauists’ [9].

But, once again, attention was paid for developing

single target-directed ligands. A major group of drug

candidates in the pipeline works by diminishing the

concentration of Ab, while the other chief approach has

produced compounds targeting the protein tau. But

neither approach has thus far led to new medicines

to combat AD [10].

The medicinal chemist viewpoint has been profoundly

influenced by the reductionist approach. But, by think-

ing about drug discovery in a very different way, embra-

cing a system approach, one can look at the big picture

and complexity typical of the disease. The early signs of

this paradigm shift are now being registered, as AD is

now increasingly studied at multiple levels, and new

scientific advancements are providing insights into the

functioning of interacting biomolecules within cells or

organisms [11]. In this review, we highlight recent


mailto:[email protected]

http://dx.doi.org/10.1016/j.cbpa.2009.04.619

304 Next-generation therapeutics

examples of innovative molecules and drug candidates

that have been developed following a more holistic

approach, rather than being exclusively focused on a

single protein target.

Zooming out: from target proteins to targetorganellesBecause the amyloid hypothesis has been the prevailing

model of molecular pathogenesis in AD [12], most drug

discovery efforts have been concentrated on reducing/

modulating Ab production. Several strategies, which tar-

get different steps of the amyloid cascades from its

production (from amyloid precursor protein, APP) to its

deposition (antichelation therapies, vaccine) and its

inflammatory effects (anti-inflammatory drugs), have

been pursued [13].

The generation of Ab from APP occurs by sequential

proteolysis by b-secretase and g-secretase enzymes. In

this regard, the aspartic protease b-secretase (BACE1)

plays a key role, as its cleavage of APP is the limiting step

in Ab production. Thus, BACE1 has been considered an

ideal target for the reduction of Ab, and detailed knowl-

Figure 1

Illustration of the transition-state inhibitor linked to a sterol moiety targeting

releases the soluble APP (sAPPb) fragment. This generates a membrane-te

secretase to afford Ab (in red).


edge of its structure, localization, activity, and regulation

validated its role in the development of drugs for the

treatment of AD [14]. The crystal structure of BACE1 was

crucial for understanding the catalytic activity of the

enzyme and for structure-based design of inhibitors

[15]. Initially, several peptidic transition-state inhibitors

were designed, but they were too large to either penetrate

the blood–brain barrier or be useful as drug candidates.

Therefore, the late generation inhibitors are no longer

peptidic or peptidomimetic ligands, but relatively small

molecules [16–18]. For some of them, such as GRL-8234,

the ability to penetrate membranes and to inhibit Ab

production is well demonstrated in transgenic mice [19].

In 2007, a compound named CTS-21166, belonging to

small-molecule transition-state analog, began Phase I of

clinical trials (see CoMentis announcement at http://

www.athenagen.com/index.php?/athenagen/press_re-

leases/48). However, many of the BACE1 inhibitors

developed so far inhibit APP binding to the active site,

but underestimate the fact that the main location of

enzyme activity is in endosomes. This might explain

the poor results obtained with some inhibitors in cellular

assays [20].

the active BACE1 found in endosomes. Cleavage of APP by BACE1

thered C-terminal fragment (bCTF) that is subsequently cleaved by g-


http://www.athenagen.com/index.php?/athenagen/press_releases/48



Anti-Alzheimer leads and drug candidates Bolognesi et al. 305

Figure 2

Illustration of MitoQ targeting mitochondrion.

In fact, although ubiquitously expressed, BACE1 mRNA

has the highest expression levels in the mammalian brain,

and is found in acidic organelles of the endosomes and

trans-Golgi network [21]. This is consistent with the

discovery that BACE1 cleavage of APP occurs predomi-

nantly in endosomes, and that endocytosis of APP and

BACE1 is essential for Ab production. BACE1 activity

and access to substrates are regulated by the composition

of lipid raft domains in the membrane bilayer. Endo-

somes have high lipid raft and cholesterol content, critical

in regulating APP endocytosis with increased amyloido-

genic processing. In order to overcome this crucial issue,

an innovative approach was recently reported, consisting

of targeting inhibition to the subcellular compartment

where the enzyme is active. A membrane-anchored b-

secretase transition-state inhibitor was synthesized by

coupling via a poly(ethylene glycol) linker the inhibitor

to a sterol moiety (Figure 1) [22��]. This inhibitor effi-

ciently targeted b-secretase in endosomes via endocyto-

sis, significantly enhancing the inhibitor efficacy, both in

cell culture and in fly and mouse models of AD. Although

it is too early to say whether this approach will lead to a

functional drug therapy, the authors postulate that this

membrane-tethering strategy might also be useful for

designing inhibitors against other disease-associated

membrane proteins.

Another emerging player in AD pathogenesis is the

organelle mitochondrion [23��,24]. Multiple lines of evi-

dence suggest that mitochondrial dysfunction plays a

crucial role in the pathogenesis of AD [25]. This evidence

comes from impaired activities of the three key enzymes

of the respiratory chain complexes I, III, and IV found in

AD patients and postmortem in AD brain tissues. In

addition to a direct mitochondrial respiratory chain

defect, increased autophagic degradation of mitochondria

has also been detected in AD [26]. Moreover, mitochon-

dria are among the major intracellular targets of soluble

Ab oligomers [27]. The accumulation of Ab in mitochon-

dria precedes extracellular amyloid deposition and

increases with age. Soluble Ab localizes to mitochondria

and interferes with their normal functioning, disrupting

the electron-transport chain, causing ROS overproduc-

tion, and contributing to synaptic damage [28]. The

increased oxidative stress exhibited by synaptic mito-

chondria might damage several biomolecules, including

lipids, proteins, and nucleic acids, and, in a vicious

manner, reinforces Ab production [29].

On the basis of the consideration that mitochondria are a

major source of ROS and are particularly vulnerable to

oxidative stress, one would predict that antioxidants that

alleviate mitochondrial dysfunction could be beneficial in

AD. This prompted researchers to deliver the antioxidant

therapy to this organelle specifically, through the devel-

opment of purposely designed mitochondria-targeted

antioxidants [26,30]. This might overcome the apparent


clinical inefficiency of antioxidants that do not target

oxidative stress in this organelle specifically [31]. At

the forefront of this approach, MitoQ is an orally active

antioxidant currently in development by Antipodean

Pharmaceuticals Inc, now undergoing Phase II clinical

trials for the potential treatment of several diseases in

which mitochondrial oxidative damage is implicated,

including neurodegenerative diseases [32].

MitoQ comprises a ubiquinone moiety, the antioxidant

component of the respiratory chain constituent coenzyme

Q10 (CoQ10), covalently linked by an aliphatic 10-carbon

chain to the lipophilic cation triphenylphosphonium, that

drives its selective uptake into mitochondria in a mem-

brane potential-dependent manner (Figure 2). Once

internalized by mitochondria, it adsorbs in the phospho-

lipid bilayers, where it is readily reduced to the active

ubiquinol form MitoQH2, which exerts its antioxidant

properties [33].

MitoQ is a promising antioxidant candidate for treating

AD patients [31]. Penetrating into mitochondria several

hundred-fold more than natural antioxidants do, it rapidly

neutralizes free radicals at their source and before they

reach their targets, with an improved therapeutic poten-

tial [34].

Multiple targets are better than one: the casestudy of ladostigilAD is currently recognized as a complex neurodegenera-

tive disorder with a multifaceted pathogenesis. This may

explain why the currently available drugs, developed

according to the reductionist paradigm of ‘one-mol-



Figure 3

Pathways leading to the discovery of new medications: (a) target-driven drug discovery approach, that is, the application of the current one-molecule-

one-target paradigm. Although this approach has led to many effective drugs able to hit a single target, it is now well-documented that these drugs

may represent the exception rather than the rule. (b) MTDLs approach to drug discovery. A drug could recognize (in principle, with comparable

affinities) different targets involved in the cascade of pathological events leading to a given disease. Thus, such a medication would be highly effective

for treating multifactorial diseases, such as AD. The design of such a drug may not be easy because it could also bind targets that are not involved with

the disease and could be responsible (although not necessarily) for side effects. Adapted from Ref. [36].

Figure 4

The design strategy leading to the anti-Alzheimer MTDL ladostigil.

ecule-one-target,’ have turned out to be palliative rather

than curative. In light of this, drug combinations that can

act at different levels of the neurotoxic cascade offer new

hopes toward curing AD and other neurodegenerative

diseases [35]. In parallel, a new strategy is emerging —

that is the development of single chemical entities able to

modulate multiple targets simultaneously, with superior

efficacy and safety profiles. This approach has led to a

new paradigm in medicinal chemistry, the ‘multitarget-

directed ligand’ (MTDL) design strategy (Figure 3),

which has been successfully exploited at both academic

and industrial levels in the fields of AD [36,37] and

similarly complex diseases [38�,39�]. The main criticism

is that this approach is resource hungry, because the

rational design of MTDLs has to deal with the critical

issues of affinity balancing and pharmacokinetics. How-

ever, as proof of principle, and to support the view that

MTDLs are destined to become the mainstream of AD

therapeutics in the years to come, we briefly discuss the

biological profile of ladostigil (TV-3326), an MTDL

developed by Youdim [40], which is currently in Phase

II clinical trials for AD.

The design of MTDLs is based on the combination of

two or more pharmacophores acting on different AD

targets. In particular, ladostigil was designed by merging

the structures of rivastigmine, an AChEI, and rasagiline,

a selective MAO-B inhibitor (Figure 4). Thanks to these

chemical features, ladostigil showed the ability to inhi-

bit both cholinesterases (AChE and butyrylcholinester-

ase) and brain monoamine oxidases (MAO-A and MAO-

B). The block of MAOs avoids hydrogen peroxide

generation, thus preventing the Fenton reaction and


the formation of neurotoxic free radical species. In

addition, MAOs’ inhibition confers potential anti-

depressant activity by increasing the levels of dopamine,

noradrenaline, and serotonin in the central nervous

system [41��]. Interestingly, in addition to its ability


Anti-Alzheimer leads and drug candidates Bolognesi et al. 307

to inhibit MAOs and AChE, ladostigil also showed other

supplementary neuroprotective actions, such as APP

processing regulation via mitogen-activated protein

kinase-signaling pathways, and mitochondrial mem-

brane potential stabilization [42,43]. Furthermore,

ladostigil was a protective agent against oxidative

stress-induced neuronal apoptosis, increasing the anti-

oxidant enzymes’ expression and catalase activity [44].

Ladostigil increased the brain-derived nerve factor

(BDNF) mRNA expression, leading to an improved

the production of BDNF and to a consequent enhanced

neuroprotective activity [45]. Thanks to this wide

MTDL profile, ladostigil can be considered a very

promising drug for the treatment of AD.

ConclusionsThe classical physics reductionist approach in drug dis-

covery aims to examine the smallest units to gain insight

into the larger ones. This has resulted in target-centric

efforts and a recent generation of single-targeted drugs

that have not delivered the promised efficiencies. This is

because, in contrast to physics, the path from biological

particles to functional biology is often highly nonlinear

and nonpredictable, because of the many post-targeted

complex interactions that occur at the level of genes,

proteins, organelles, cells, organs, and whole bodies.

From animal models to protein models via cellular

models, there has been a decrease in complexity and a

concomitant decrease of relevance to human conditions

[46]. Conversely, many of the most severe pathologies

afflicting mankind, such as neurodegenerative diseases,

are multifactorial, where the disease phenotype arises

from the dysregulation of multiple genes, pathways,

and proteins. This complexity allows us to describe them

as ‘network diseases’ [47]. Therefore, it is conceivable

that the classical biological approaches have only enabled

us to achieve a partial understanding of their etiopatho-

genic complexities.

Currently, AD is best characterized as a multidysfunc-

tional molecular condition, where interrelated molecular

events result in amyloid formation, tau abnormalities,

amyloid accumulations, and loss of acetylcholine modu-

lation of cortical neuro-transmission [48]. Currently avail-

able drugs and most of the drugs under development for

AD treatment target one of these mechanisms, suggesting

that an MTDL is a more adequate therapeutic tool to

confront this complexity [49,50].

It is only with the new millennium that drug designers are

moving away from target-centric strategies. A system

biology approach offers an integrated and deeper inves-

tigation into the functioning of organelle and cellular

structures in a network context. These investigations,

coupled with the advancement already made in the

molecular pathways involved, may help medicinal che-

mists to design new chemical entities able to understand,


and hopefully modify, the disease course for this devas-

tating neurodegenerative disorder.

Conflict of interestThe authors declare no financial or other potential con-

flicts of interest.

AcknowledgementsThe authors would like to thank Prof V Tumiatti for useful discussions andto apologize for not mentioning some important publications because ofspace limits. This work was supported by a grant from MIUR (PRIN n.20073EWPF9_003) and the University of Bologna.

References and recommended readingPapers of particular interest, published within the period of the review,have been highlighted as:

� of special interest�� of outstanding interest

1. Popescu BO: Still debating a cause and diagnostic criteria forAlzheimer’s disease. J Cell Mol Med 2007, 11:1225-1226.

2. Abbott A: Neuroscience: the plaque plan. Nature 2008, 456:161-164.

3. Lansbury PT Jr: Back to the future: the ‘old-fashioned’ way tonew medications for neurodegeneration. Nat Med 2004, 10Suppl:S51-S57.

4. Hopkins AL: Network pharmacology: the next paradigm in drugdiscovery. Nat Chem Biol 2008, 4:682-690.

5. Bartus RT, Dean RL III, Beer B, Lippa AS: The cholinergichypothesis of geriatric memory dysfunction. Science 1982,217:408-414.

6. Witt A, Macdonald N, Kirkpatrick P: Memantine hydrochloride.Nat Rev Drug Discov 2004, 3:109-110.

7. Terry AV Jr, Buccafusco JJ: The cholinergic hypothesis of ageand Alzheimer’s disease-related cognitive deficits: recentchallenges and their implications for novel drug development.J Pharmacol Exp Ther 2003, 306:821-827.

8. Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J: Therapeuticapproaches to Alzheimer’s disease. Brain 2006, 129:2840-2855.

9. Mudher A, Lovestone S: Alzheimer’s disease-do tauists andbaptists finally shake hands? Trends Neurosci 2002, 25:22-26.

10. Gura T: Hope in Alzheimer’s fight emerges from unexpectedplaces. Nat Med 2008, 14:894.

11. Noorbakhsh F, Overall CM, Power C: Deciphering complexmechanisms in neurodegenerative diseases: the advent ofsystems biology. Trends Neurosci 2009, 22:88-100.

12. Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer’sdisease: progress and problems on the road to therapeutics.Science 2002, 297:353-356.

13. Citron M: Strategies for disease modification in Alzheimer’sdisease. Nat Rev Neurosci 2004, 5:677-685.

14. Stockley JH, O’Neill C: Understanding BACE1: essentialprotease for amyloid-beta production in Alzheimer’s disease.Cell Mol Life Sci 2008, 65:3265-3289.

15. Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK, Zhang XC,Tang J: Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science 2000, 290:150-153.

16. Evin G, Kenche VB: BACE inhibitors as potential therapeuticsfor Alzheimer’s disease. Recent Patent CNS Drug Discov 2007,2:188-199.

17. Durham TB, Shepherd TA: Progress toward the discovery anddevelopment of efficacious BACE inhibitors. Curr Opin DrugDiscov Dev 2006, 9:776-791.



18. Ghosh AK, Kumaragurubaran N, Hong L, Koelsh G, Tang J:Memapsin 2 (beta-secretase) inhibitors: drug development.Curr Alzheimer Res 2008, 5:121-131.

19. Ghosh AK, Gemma S, Tang J: Beta-secretase as a therapeutictarget for Alzheimer’s disease. Neurotherapeutics 2008, 5:399-408.

20. Hoyos Flight M: Neurodegenerative disease: Inhibiting beta-secretase where it matters. Nat Rev Neurosci 2008, 9:414-415.

21. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA,Denis P, Teplow DB, Ross S, Amarante P, Loeloff R et al.: Beta-secretase cleavage of Alzheimer’s amyloid precursor proteinby the transmembrane aspartic protease BACE. Science 1999,286:735-741.

22.��

Rajendran L, Schneider A, Schlechtingen G, Weidlich S, Ries J,Braxmeier T, Schwille P, Schulz JB, Schroeder C, Simons M et al.:Efficient inhibition of the Alzheimer’s disease beta-secretaseby membrane targeting. Science 2008, 320:520-523.

This work describes a very elegant approach for targeting BACE1 inhibitorsto endosome and presents the proof of principle of subcellular targeting.

23.��

Lin MT, Beal MF: Mitochondrial dysfunction and oxidativestress in neurodegenerative diseases. Nature 2006, 443:787-795.

This is an excellent review article that provides the rational basis fortherapies targeting mitochondrial processes.

24. Armstrong JS: Mitochondrial medicine: pharmacologicaltargeting of mitochondria in disease. Br J Pharmacol 2007,151:1154-1165.

25. Starkov AA, Beal FM: Portal to Alzheimer’s disease. Nat Med2008, 14:1020-1021.

26. Chaturvedi RK, Beal MF: Mitochondrial approaches forneuroprotection. Ann N Y Acad Sci 2008, 1147:395-412.

27. Lin MT, Beal MF: Alzheimer’s APP mangles mitochondria. NatMed 2006, 12:1241-1243.

28. Reddy PH, Beal MF: Amyloid beta, mitochondrial dysfunctionand synaptic damage: implications for cognitive decline inaging and Alzheimer’s disease. Trends Mol Med 2008, 14:45-53.

29. Mancuso M, Coppede F, Murri L, Siciliano G: Mitochondrialcascade hypothesis of Alzheimer’s disease: myth or reality?Antioxid Redox Signal 2007, 9:1631-1646.

30. Smith RA, Adlam VJ, Blaikie FH, Manas AR, Porteous CM,James AM, Ross MF, Logan A, Cocheme HM, Trnka J et al.:Mitochondria-targeted antioxidants in the treatment ofdisease. Ann N Y Acad Sci 2008, 1147:105-111.

31. Pratico D: Evidence of oxidative stress in Alzheimer’s diseasebrain and antioxidant therapy: lights and shadows. Ann N YAcad Sci 2008, 1147:70-78.

32. Tauskela JS: MitoQ — a mitochondria-targeted antioxidant.IDrugs 2007, 10:399-412.

33. Ross MF, Prime TA, Abakumova I, James AM, Porteous CM,Smith RA, Murphy MP: Rapid and extensive uptake andactivation of hydrophobic triphenylphosphonium cationswithin cells. Biochem J 2008, 411:633-645.

34. Azzi A: Oxidative stress: a dead end or a laboratoryhypothesis? Biochem Biophys Res Commun 2007, 362:230-232.

35. Schmitt B, Bernhardt T, Moeller HJ, Heuser I, Frolich L:Combination therapy in Alzheimer’s disease: a review ofcurrent evidence. CNS Drugs 2004, 18:827-844.


36. Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V,Recanatini M, Melchiorre C: Multi-target-directed ligands tocombat neurodegenerative diseases. J Med Chem 2008,51:347-372.

37. Zhang HY: One-compound-multiple-targets strategy tocombat Alzheimer’s disease. FEBS Lett 2005, 579:5260-5264.

38.�

Millan MJ: Dual- and triple-acting agents for treating core andco-morbid symptoms of major depression: novel concepts,new drugs. Neurotherapeutics 2009, 6:53-77.

This timely review describes the network approach concepts applied tothe discovery of multitarget antidepressants.

39.�

Morphy R, Rankovic Z: Designing multiple ligands — medicinalchemistry strategies and challenges. Curr Pharm Des 2009,15:587-600.

This is a critical review of several MTDLs examples from a medicinalchemistry perspective.

40. Youdim MB: The path from anti Parkinson drug selegiline andrasagiline to multifunctional neuroprotective anti Alzheimerdrugs ladostigil and m30. Curr Alzheimer Res 2006,3:541-550.

41.��

Youdim MB, Buccafusco JJ: Multi-functional drugs for variousCNS targets in the treatment of neurodegenerative disorders.Trends Pharmacol Sci 2005, 26:27-35.

The first article that addresses in a systematic manner the MTDLapproach for combating neurodegenerative diseases.

42. Bar-Am O, Weinreb O, Amit T, Youdim MB: The novelcholinesterase-monoamine oxidase inhibitor and antioxidant,ladostigil, confers neuroprotection in neuroblastoma cells andaged rats. J Mol Neurosci 2009, 37:135-145.

43. Weinreb O, Amit T, Bar-Am O, Yogev-Falach M, Youdim MB: Theneuroprotective mechanism of action of the multimodal drugladostigil. Front Biosci 2008, 13:5131-5137.

44. Weinreb O, Bar-Am O, Amit T, Drigues N, Sagi Y, Youdim MB: Theneuroprotective effect of ladostigil against hydrogenperoxide-mediated cytotoxicity. Chem Biol Interact 2008,175:318-326.

45. Van der Schyf CJ, Mandel S, Geldenhuys WJ, Amit T,Avramovich Y, Zheng H, Fridkin M, Gal S, Weinreb O, Bar Am Oet al.: Novel multifunctional anti-Alzheimer drugs with variousCNS neurotransmitter targets and neuroprotective moieties.Curr Alzheimer Res 2007, 4:522-536.

46. Barrett TD, Maurice DH, Guppy RJ: Functional pharmacology:the drug discovery bottleneck? Drug Discov Today: Targets2004, 3:208-215.

47. Korcsmaros T, Szalay MS, Bode C, Kovacs IA, Csermely P: Howto design multi-target drugs: target search options in cellularnetworks. Expert Opin Drug Discov 2007, 2:1-10.

48. Becker RE, Greig NH: Alzheimer’s disease drug development in2008 and beyond: problems and opportunities. Curr AlzheimerRes 2008, 5:346-357.

49. Bolognesi ML, Rosini M, Andrisano V, Bartolini M, Minarini A,Tumiatti V, Melchiorre C: MTDL design strategy in the context ofAlzheimer’s disease: from lipocrine to memoquin and beyond.Curr Pharm Des 2009, 15:601-613.

50. Bolognesi ML, Cavalli A, Melchiorre C: Memoquin: a multi-target-directed ligand as an innovative therapeuticopportunity for Alzheimer’s disease. Neurotherapeutics 2009,6:152-162.


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Alzheimer's disease: new approaches to drug discovery