cognitive enhancers (nootropics). part 3: drugs ... · 2 w. froestl et al. / cognitive enhancers...

Journal of Alzheimer’s Disease 34 (2013) 1–114DOI 10.3233/JAD-121729IOS Press

1

Review

Cognitive Enhancers (Nootropics). Part 3:Drugs Interacting with Targets other thanReceptors or Enzymes. Disease-modifyingDrugs

Wolfgang Froestl∗, Andrea Pfeifer and Andreas MuhsAC Immune SA, EPFL, Lausanne, Switzerland

Accepted 7 October 2012

Abstract. Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer’s disease,schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing,applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, andpsychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observedin clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. Toclassify the compounds, a concept is proposed assigning drugs to 19 categories according to their mechanism(s) of action, inparticular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants,metal chelators, and disease modifying drugs, meaning small molecules, vaccines, and monoclonal antibodies interacting withamyloid-� and tau. For drugs, whose mechanism of action is not known, they are either classified according to structure, e.g.,peptides, or their origin, e.g., natural products. The review covers the evolution of research in this field over the last 25 years.

Keywords: Amyloid-� aggregation inhibitors, antibodies, antioxidants, cognitive enhancers, metal chelators, natural products,peptides, psychostimulants, tau, vaccines

INTRODUCTION

As of September 30, 2012, there are 26,788 entriesin PubMed under the term cognitive enhancers, 26,781entries under the term nootropic, and 245 entries underthe term cognition enhancers. Scifinder lists 5,133references under the research topic nootropic, 541references under the term cognitive enhancer, and9,853 references for cognition enhancers. The Thom-son Reuters Pharma database lists 1,111 drugs as

∗Correspondence to: Dr. Wolfgang Froestl, AC Immune SA,EPFL Quartier de l’innovation building B, CH-1015 Lausanne,Switzerland. Tel.: +41 21 693 91 21; Fax: +41 21 693 91 20; E-mail:[email protected].

nootropic agents or cognition enhancers and gives zeroresults under the term cognitive enhancer. The termnootropics was coined by the father of piracetam Cor-neliu Giurgea in 1972/1973 [1, 2]: NOOS = mind andTROPEIN = toward.

Nootropics are drugs to treat cognition deficits,which are most commonly found in patients sufferingfrom Alzheimer’s disease (AD), schizophrenia, stroke,attention deficit hyperactivity disorder (ADHD), oraging. Mark J. Millan and 24 eminent researchers[3] presented an excellent overview on cognitivedysfunction in psychiatric disorders in the February2012 issue of Nature Reviews Drug Discovery anddefine cognition as “a suite of interrelated conscious

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2 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes

(and unconscious) mental activities, including pre-attentional sensory gating, attention, learning andmemory, problem solving, planning, reasoning andjudgment, understanding, knowing and represent-ing, creativity, intuition and insight, spontaneousthought, introspection, as well as mental time travel,self-awareness and meta cognition (thinking andknowledge about cognition)”.

Since a first review in 1989 on “Families of Cogni-tion Enhancers” by Froestl and Maıtre [4], substantialprogress has been made in the understanding ofthe mechanism(s) of cognitive enhancers. Therefore,we propose a new classification to assign cognitionenhancing drugs to 19 categories:

1. Drugs interacting with Receptors (Part 1)2. Drugs interacting with Enzymes (Part 2)3. Drugs interacting with Cytokines (Part 3)4. Drugs interacting with Gene Expression (Part 3)5. Drugs interacting with Heat Shock Proteins (Part

3)6. Drugs interacting with Hormones (Part 3)7. Drugs interacting with Ion Channels (non-

Receptors) (Part 3)8. Drugs interacting with Nerve Growth Factors

(Part 3)9. Drugs interacting with Re-uptake Transporters

(Part 3)10. Drugs interacting with Transcription Factors

(Part 3)11. Antioxidants (Part 3)12. Metal Chelators (Part 3)13. Natural Products (Part 3)14. Nootropics (“Drugs without mechanism”)

(Part 3)15. Peptides (Part 3)16. Drugs preventing amyloid-� aggregation (Part 3)

16.1. Ligands interacting with amyloid-�(Part 3)

16.2. Inhibitors of serum amyloid P compo-nent binding (Part 3)

16.3. Vaccines against amyloid-� (Part 3)16.4. Antibodies against amyloid-� (Part 3)

17. Drugs interacting with tau (Part 3)17.1. Small molecules preventing tau aggrega-

tion (Part 3)17.2. Ligands interacting with tau (Part 3)17.3. Vaccines against tau (Part 3)17.4. Antibodies against tau (Part 3)

18. Stem Cells (Part 3)19. Miscellaneous (Part 3)

In Part 1, drugs interacting with receptors weredescribed [5]. In Part 2, drugs interacting with enzymeswere described [1696]. Here, in Part 3, we give anoverview on drugs interacting with targets 3 to 10 andcompounds and preparations of categories 11 to 19.

Disease modifying drugs are aimed to counteract theprogression of a disease. In particular for AD, manyexcellent reviews discuss this subject (in chronolog-ical order) [6–27]. �-secretase activators and �- and�-secretase inhibitors (and modulators) were presentedin Part 2 of this review. Drugs interacting with amyloid-� (A�) and tau including immunotherapy are describedin Part 3.

DRUGS INTERACTING WITH CYTOKINES

There is abundant evidence that inflammatory mech-anisms within the central nervous system (CNS)contribute to cognitive impairment via cytokine-mediated interactions between neurons and glial cells.A current hypothesis is that an extracellular insultto neurons could trigger the production of inflam-matory cytokines by astrocytes and microglia [28].Conversely, A� has been shown to induce the expres-sion of interleukin (IL)-1�, tumor necrosis factor-�(TNF-�) and IL-6 in astrocytes and microglia in cul-ture [29]. One genome-wide analysis in 691 subjects ofmean age of 72.6 years showed that raised chemokine(C-C motif) receptor 2 (CCR2) expression was themost strongly associated transcript with lower Mini-Mental Status Exam scores and accelerated decline inscore over a period of 9 years [30]. Decline in scoreover a period of 9 years [30]. The expression profiles ofcytokines in the brains of Alzheimer’s disease patientswere compared to the brains of non-demented patients[1697]. Also see 11. Antioxidants, Also see 11. Antiox-idants, because inflammation is tightly connected withthe oxidative cascade.

TT-301 (MW01-6-189WH; MW-189; TransitionTherapeutics, Toronto following its acquisition of Neu-roMedix under license from Northwestern University)is an inhibitor of microglial cell activation and pro-inflammatory cytokine production for the potential i.v.treatment of CNS diseases including AD. Preclinicalcharacterization of the suppression of brain proinflam-matory cytokine upregulation was carried out [31]. Adouble-blind, randomized, placebo-controlled Phase Iclinical trial in healthy male subjects (n = 16) startedin the US in May 2011 (Thomson Reuters Pharma,update of September 14, 2012). The structure was notcommunicated.

W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes 3

Fig. 1. Drugs interacting with cytokines and with gene expression.

TT-302 (MW01-7-084WH, MW-084; TransitionTherapeutics, Toronto; Fig. 1) is an inhibitor of pro-inflammatory cytokine production by activated glia forthe potential oral treatment of CNS disorders includingAD, traumatic brain injury and inflammatory diseasessuch as arthritis [32]. Phase I clinical trials are expectedfor 2012 (Thomson Reuters Pharma, update of Septem-ber 29, 2012).

Minozac (MW01-2-151SRM, MW-151, TransitionTherapeutics, Toronto following its acquisition of Neu-roMedix, under license from Northwestern University)(Fig. 1) is an inhibitor of pro-inflammatory cytokineproduction by activated glia for the potential treatmentof CNS diseases including AD, Parkinson’s disease(PD), multiple sclerosis, and traumatic brain injury[33–36] (Thomson Reuters Pharma, update of August13, 2012).

AD-16 (Guangzhou Institutes of Biomedicine andHealth) is the thiophene analogue of Minozac. Itreduced amyloid-� induced spatial learning and mem-ory impairment as potently as donepezil in anAlzheimer’s mouse model [1698]. (Thomson ReutersPharma, update of October 19, 2012).

SEN-1176 (Senexis, Cambridge, UK) (Fig. 1) is apyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine, whichsuppresses A�42-induced macrophage production ofnitric oxide, TNF-�, IL-1�, and IL-6 in a dose-dependent fashion, an activity profile consistent with aneuroinflammation inhibitor [1711] (Thomson ReutersPharma, update of June 24, 2011).

Infliximab (Janssen Biotech, Horsham, PA),a launched monoclonal antibody against TNF-�,improved cognition after intrathecal administration ina woman with AD [38].

The University of Zurich is investigating an antibodyagainst the interleukin-12 subunit p40 for the poten-tial treatment of Alzheimer’s disease [1699] (ThomsonReuters Pharma, update of November 26, 2012).

The development of REN-1189 (formerly CPI-1189; Centaur Pharmaceuticals), a TNF-� releaseinhibitor, was terminated. Also the development ofSemapimod (CNI-1493; Cytokine PharmaSciences,CPSI, formerly Cytokine Networks), a cytokineinhibitor, which inhibited A� production, plaque for-mation, and cognitive deterioration in an animal modelof AD was suspended [39, 40].


DRUGS INTERACTING WITH GENEEXPRESSION

Gene therapy in AD, a potential for disease modi-fication, was discussed [1715]. An interesting reviewon genes and the parsing of cognitive processes wascommunicated [42]. Bi-phasic change in brain-derivedneurotropic factor (BDNF) gene expression follow-ing antidepressant drug treatment was described [43,44]. The modulation of Nur77 and Nor-1 expressionby dopaminergic drugs was elucidated [45]. The reg-ulation of GABAA receptor subunit expression bypharmacological agents was investigated [46]. Genetherapy in mouse models of Huntington’s disease (HD)was reviewed [47].

Beperminogene perplasmid (AMG-0001; DS-992; Collategene; AnGes MG, formerly MedGeneBioscience, Osaka, in collaboration with DaiichiSankyo) is a hepatocyte growth factor (HGF)plasmid-based gene therapy for i.m. injection. Itshowed nootropic properties with a potential for thetreatment of PD. In November 2011, a Phase III trialfor peripheral arterial disease was expected to be initi-ated in 2012. In April 2012, the Phase III studies werestill in preparation [48]. A long-term follow-up eval-uation of results from the clinical trial TREAT-HGFwas reported [49] (Thomson Reuters Pharma, updateof September 19, 2012).

RVX-208 (Resverlogix, Calgary) (Fig. 1) is anapolipoprotein A1 (ApoA1) gene expression stim-ulator for the potential prevention of A� plaqueaccumulation in AD. In January 2011, data from ananalysis of AD biomarkers in the Phase II ASSERTtrial in 299 patients showed that after 12 weeksof treatment with 150 mg/day, a positive effect onA�40 was seen. A compilation of data on RVX-208was published in Drugs in R & D [50]. The ratio-nale for the SUSTAIN study (172 patients) and theASSURE study (310 patients) was presented [51].Preclinical evaluations were reported [52, 53] andclinical data were provided [54–56]. RVX-208 sig-nificantly increased high-density lipoprotein (HDL)-C(p = 0.001), the primary endpoint of the SUSTAIN trial,a Phase 2b clinical study. SUSTAIN also successfullymet secondary endpoints, showed increases in levels ofApo-AI (p = 0.002) and large HDL particles (p = 0.02),both believed to be important factors in enhancingreverse cholesterol transport activity. In July 2012, thecompany was planning to initiate a Phase II trial ofRVX-208 in patients with mild cognitive impairment(MCI) in the second half of 2013 (Thomson ReutersPharma, update of September 27, 2012).

There are several drugs interacting with gene expres-sion in preclinical evaluation (in alphabetical order):

AAV-CYP46A1 (INSERM in collaboration withsanofi) is an adeno-associated virus (AAV) gene ther-apy encoding cholesterol 24-hydroxylase (CYP46A1gene) for the potential injectable treatment of AD.Reduced A� peptides, amyloid deposits, and trimericoligomers were observed in APP23 mice. Significantimprovements in cognitive function assessed by theMorris water maze were seen in Tau22 mice [57](Thomson Reuters Pharma, update of June 6, 2012).See also Part 2, Chapter 2.12. Drugs interacting withcholesterol 24-hydroxylase (CYP46A1).

AZ-AAV9 (RegenX Biosciences, Washington DC)is an AAV vector-9 that carries neuroprotective genesfor the potential injectable treatment of AD (ThomsonReuters Pharma, update of July 27, 2012).

HSD17B10 is a gene, which encodes HSD10, amitochondrial multifunctional enzyme that plays asignificant part in the metabolism of neuroactivesteroids and the degradation of isoleucine. Elevatedlevels of HSD10 were observed in the hippocampi ofAD patients [58].

PRO-289 (Prosensa Therapeutics, Leiden, theNetherlands) is the lead from a series of single-strandedRNA-based antisense oligonucleotide-based therapeu-tics to inhibit the CTG trinucleotide repeat expansionof the huntingtin gene (HTT) by preventing the cellu-lar production of aberrantly expanded HTT mRNA andmutant huntingtin protein (Thomson Reuters Pharma,update of February 10, 2012).

SynCav (Raft Therapeutics, San Diego CA) isa gene therapy that upregulates synaptic drivenCaveolin-1 to promote regeneration of neurons forthe potential treatment of neurodegenerative diseasessuch as AD, PD, HD, and amyotrophic lateral sclerosis(ALS) (Thomson Reuters Pharma, update of August10, 2012).

Intrahippocampal gene transfer of F-spondin, anactivator of the reelin pathway, improved spatial learn-ing/memory in the Morris water maze and increasedthe exploration of the novel object in the Novel ObjectRecognition test in wild-type mice [59].

lnventiva (Daix, Bourgogne, France) is investigat-ing compounds that increase expression of a target geneunder epigenetic control resulting in increased levels ofa secreted neuronal protein for the potential treatmentof Alzheimer’s disease. (Thomson Reuters Pharma,update of November 23, 2012). Structures were notcommunicated.

Neurologix under license from Keio University wasinvestigating colivelin, a hybrid peptide composed of


activity-dependent neurotrophic factor [60–64] and ahumanin derivative for the potential gene therapyof AD [65, 66]. The program was terminated. Thedevelopment of LX-6171 (Lexicon Pharmaceuticals,formerly Lexicon Genetics), a small molecule inhibitorof the SLC6A gene and the LG617 receptor, was dis-continued as well.

DRUGS INTERACTING WITH HEATSHOCK PROTEINS

Binding of heat shock protein 90 (HsP90) to taufacilitates a conformational change that results inits phosphorylation by glycogen synthase kinase 3�(GSK-3�) and its aggregation into filamentous struc-tures [67]. HsP90 regulates tau pathology throughco-chaperone complexes [68].

HsP90 inhibitors, such as PU-H71, PU-3, PU24FCl(Fig. 2) and PU-DZ8 of the purine class of HsP90inhibitors from the Memorial Sloan-Kettering Instituteof Cancer Research, New York caused an eliminationof aggregated tau [69–75].

PU-H71 is in Phase I clinical trials since July 2011(n = 40) in the US. The study was expected to be com-plete by July 2013 (Thomson Reuters Pharma, updateof April 24, 2012).

ALS Biopharma (Doylestown, PA) is investigatingsmall-molecule brain-penetrant modulators of HsP70for the potential treatment of neurological disordersincluding AD (Thomson Reuters Pharma update ofJanuary 17, 2012).

Conforma Therapeutics (San Diego, CA) presenteda new class of HsP90 inhibitors [76–78] and showedthat E102 (structure not disclosed) promoted selec-tive decrease of the P-tau species in a mouse modelof tauopathy.

KU-32 (University of Kansas, Fig. 2) is a novo-biocin derivative acting as an inhibitor of Hsp90 and aninducer of Hsp70 for the potential treatment of neuro-logical diseases. In transgenic mice expressing humanP301L-mutant tau KU-32 (10 mg/kg for 15 weeks)reduced cortical levels of CP13-Iabeled tau [1700].(Thomson Reuters Pharma, update of May 31, 2012).

Lundbeck follows up another series of HsP90inhibitors (Thomson Reuters Pharma update of March31, 2011).The structures were not disclosed.

Fig. 2. Heat shock protein 90 inhibitors and a thyrotropin-releasing hormone analogue.


A� accumulation decreased expression of the heatshock-protein 70-interacting protein (CHIP), whichfunctions as a tau ubiquitin ligase [79]. CHIP is akey molecular link between A� and tau patholo-gies. Increasing CHIP levels may have beneficialeffects to decrease tau pathology, because CHIP canpolyubiquitinate tau and may play a crucial role inpreventing accumulation of phospho-tau and neurofib-rillary tangles. Heat shock protein 70 prevented bothtau aggregation and the inhibitory effect of preexist-ing tau aggregates on fast axonal transport [80]. Anexchange of HsP70 for HsP90 is involved in tau degra-dation [1701].

Excellent reviews on heat shock proteins were pre-viously published [81, 82].

The development of AEG-33773 (Aegera Thera-peutics), an allosteric modulator of HsP90 leading toHsP70 upregulation, was terminated.

DRUGS INTERACTING WITH HORMONES

Sustained efforts went into the exploration of thecognition enhancing effects of thyrotropin-releasinghormone and its analogues since it had been recog-nized as an activator of brain cholinergic systems [83].Pilot studies of intravenous thyrotropin-releasing hor-mone in AD were undertaken [84, 85]. Improvement ofcognitive deficits in depressed patients were reported[86].

Taltirelin (Ceredist, TA-0910; Mitsubishi TanabePharma) (Fig. 2), an orally active synthetic thyrotropin-releasing hormone analogue, was launched in Japan in2000 for the treatment of neurodegenerative disease, inparticular spinocerebellar degeneration [87–89]. Thesales in 2011 were USD 226.8 million (ThomsonReuters Pharma, update of August 30, 2012).

KPS-0373 (Kissei under license from Shionogi)is a thyrotropin-releasing hormone derivative for thepotential oral treatment of spinocerebellar ataxia inPhase II clinical trials in Japan (Thomson ReutersPharma, update of July 31, 2012). The structure wasnot communicated.

Leuprolide acetate implant (VP-4896, Memryte;Curaxis Pharmaceuticals, Raleigh NC, formerly Voy-ager Pharmaceutical and DURECT) is a biodegradableimplant formulation of the gonadotropin-releasinghormone agonist 1-9-luteinizing hormone-releasingfactor-6D-leucine-9-(N-ethyl-L-prolinamide), a non-apeptide, for the treatment of AD in women. APhase IIb clinical study plan is currently evalu-ated. The effects of treatment with leuprolide acetate

depot on working memory in women were described[90]. Luteinizing hormone modulated the process-ing of amyloid-� protein precursor (A�PP) andA� deposition [91] and of cognition in transgenicmice [92]. Several reviews were published [93–96](Thomson Reuters Pharma, update of August 24,2012).

Tesamorelin (Egrifta; TH-9507; Theratechnolo-gies, Quebec and US commercialization partner EMDSerono and licensee Sanofi) is a stabilized, trun-cated growth hormone releasing factor (GRF1-44;ThGRF1-44). In a controlled study of 152 adults (66with MCI) participants self-administered daily subcu-taneous injections of tesamorelin or placebo for 20weeks, which had favorable effects on cognition in bothadults with MCI and healthy older adults [97] (Thom-son Reuters Pharma, update of August 15, 2012).

The development of azetirelin (YM-14673;Yamanouchi, now Astellas [98, 99]), of cal-citriol (Neurocalc; Apollo Biopharmaceuticals,now MitoKor), of JTP-2942 (Japan Tobacco[100–102]), of montirelin (CG-3703; CNK-602A;NS-3; Grunenthal [103]), of orotirelin (CG-3509;Grunenthal [104–106]), of posatirelin (RGH-2202;Gedeon Richter [107–109]), of protirelin (DN-1417;Takeda [110]), of thyrotropin-releasing hormoneanalogs (Roche), and of thymoliberin (RX-77368;Reckitt & Colman [111]) was terminated.

DRUGS INTERACTING WITH IONCHANNELS (NON-RECEPTORS)

Dysregulation of Ca2+ homeostasis plays a crucialrole in the pathogenesis of AD. In the pathogene-sis of AD [1702]. Oligomeric A� proteins directlyincorporated into neuronal membranes, formed cation-sensitive ion channels (“amyloid channels”) andcaused disruption of calcium homeostasis [112, 113].A� oligomers directly and dose-dependently mod-ulated P/Q-type calcium channels [114]. In tripletransgenic AD mice, upregulated ryanodine receptoractivity led to a reduction of long-term potentiation[115]. Mutations of presenilin can affect the intra-cellular calcium levels via the endoplasmic reticulumcalcium stores [116]. The levels of the calcium-sensingenzyme hippocalcin were elevated in AD brains [117].Interesting reviews were published [118–121].

Drug repositioning for the treatment of Alzheimer’sdisease was described recently [1703].

ARC-029 (Archer Pharmaceuticals, Roskamp Insti-tute, Sarasota FL) is a blood-brain barrier crossing


Fig. 3. Two ion channel blocker and three NGF and BDNF stimulators.

formulation of nilvadipine (Fig. 3), a blocker ofL-type voltage-gated calcium channels. The drug hasbeen approved for a multisite Phase III clinical trialenrolling more than 500 AD patients in Europe. InFebruary 2012, the study was expected to begin in thesecond half of 2012 (Thomson Reuters Pharma, updateof April 16, 2012).

Nilvadipine (FR-34235; Fujisawa; launched inJapan in 1989) was extensively characterized in vitroand in vivo for the potential treatment of AD. It facili-tated the clearance of A� across the blood-brain barrier[122, 123]. It prevented the impairment of spatial mem-ory induced by cerebral ischemia combined with A�in rats [124, 125]. It also antagonized A� vasoactiv-ity [126]. First positive clinical results on nilvadipinein AD patients were communicated. It was safe andprovided short-term cognitive benefits in AD patients[127–131].

ARC-031 and ARC-031-SR (Archer Pharmaceuti-cals; sustained release formulation) is a non-calciumchannel blocking and soluble A� reducing nilvadipinederivative in Phase I clinical trials (Thomson ReutersPharma, update of January 3, 2012). The structure wasnot communicated.

RNS-60 (Revalesio Corporation, Tacoma WA) actson voltage-gated ion channels. It is formulated as

an inhalant anti-inflammatory charge-stabilized nanos-tructure. The company investigates also the potentialtreatment in AD and PD. A Phase I/IIa asthma trialbegan in May 2010. In October 2011, data from themulti-dose stage of the Phase I study were reported.RNS-60 showed a therapeutic benefit and was safe atall doses (Thomson Reuters Pharma, update of April27, 2012). The structure was not communicated.

ZSET-1446 (ST-101, Sonexa Therapeutics, SanDiego CA under license from Zenyaku Kogyo) (Fig. 3)is in Phase II clinical trials for AD since February 2009.A second Phase II clinical trial for the treatment ofessential tremor was initiated in the US in May 2011.It was recognized that ZSET-1446 (ST-101) targetedT-type voltage-gated calcium channels in mediatingimproved cognition in the CNS [132]. In vivo data werepublished previously [133, 134] (Thomson ReutersPharma, update of July 17, 2012).

AD-N02 (Adamed, Mazowieckie, Poland) is asodium channel blocker and dopamine/5-HT stabilizerfor the potential treatment of schizophrenia and bipolardisorder (Thomson Reuters Pharma, update of August22, 2012). The structure was not communicated.

Isradipine (Novartis, launched in 1997) is aL-type voltage-gated calcium channel blocker pro-tecting MC65 neuroblastoma cells from A�PP


C-terminal fragment (A�PP-CTF)-induced neurotox-icity [135–137, 1704].

The development of many drugs interacting withion channels was terminated (in alphabetical order):DMP-543 (Bristol-Myers Squibb; an inhibitor of M-type K+ channels), enecadin (PAION under licensefrom Nippon Shinyaku; a sodium and calcium channelblocker), LB-101, LB-102, LB-217, LB-218, LB-253,LB-269, LB-301, and LB-302 (Lifelike Biomatic;modulators of two ionic channels, i.e., ionokines),linopirdine (DuP 996; Du Pont Merck, Bristol-MyersSquibb; an inhibitor of M-type K+ channels; despitepromising EEG brain mapping data [138] and anincrease of parietal regional cerebral blood flow inAD patients [139], the clinical results were disap-pointing [140]), MEM-1003 (BAY-Z-4406, MemoryPharmaceuticals under license from Bayer; a L-typevoltage-gated calcium channel [141]), nerispirdine(HP-184, Hoechst, now sanofi; an inhibitor of M-type K+ channels), nicardipine (YC-93, Yamanouchi[142]), nifedipine (BAY-A-1040, Adalat, Bayer[143]), nimodipine (BAY-E-9736, Nimotop, Bayer[144–152]), nitrendipine (BAY-E-5009; Bayotensin,Bayer; all L-type voltage-gated calcium channels[153, 154]), NP-34 (NP-04634; Noscira, formerlyNeuropharma; a dual calcium channel blocker andacetylcholinesterase inhibitor [155]), NS-649 (Neu-roSearch; a neuron-specific calcium channel blocker[156]), NSD-761 (NeuroSearch; a selective ion chan-nel modulator); RGH-2716 (TDN-345; a nootropicneuroselective ion channel blocker; Takeda in collab-oration with Gedeon Richter [157–159]), SNX-482(R-type calcium channel blocker of Neurex, nowElan Pharmaceuticals [160–162]), SPI-017 (Sucampo;selective type-2 chloride channel activator), tamo-larizine (NC-1100, calcium channel blocker, NipponChemiphar [163–165]), VRX-698 (Valeant Pharma-ceuticals International; a potassium channel opener),and XE-991 (Bristol-Myers Squibb; a KCNQ potas-sium channel blocker [166, 167]).

DRUGS INTERACTING WITH NERVEGROWTH FACTORS

The role of neurotrophic factors in AD was dis-cussed [168] as was a neurotrophic rationale forthe therapy of neurodegenerative diseases [169]. Thepotential therapeutic use of BDNF, a key regulatorfor protein-synthesis dependent long-term potentiationand long-term memory, in neurological and psychiatricdisorders was presented [170, 171], in particular for

AD [172, 173]. Interestingly, genetic knockdown ofBDNF in triple transgenic AD mice did not alter A�or tau pathology [174]. Nerve growth factor (NGF)-cholinergic dependency in brain aging, MCI, and ADwas discussed [175–181]. NGF treatment in demen-tia was described [182]. NGF and AD, new factsfor an old hypotheses were communicated recently[183]. Hippocampal ProNGF signaling pathways andamyloid-� levels in mild cognitive impairment andAlzheimer’s disease were elucidated [1705]. It wasclaimed that NGF promoted long-term memory for-mation by activating poly(ADP-ribose) polymerase-1(PARP-1) [184].

NeuroAid (MLC-601; Danqi Plantan Jiaonang;Moleac Pte Ltd, Singapore) is a BDNF stimulatorderived from Radix Astragali, Radix Salvia Miltior-rhizae, Radix Paeoniae Rubra, Rhizoma Chuanxiong,Radix Angelicae Sinensis, Carthamus Tinctorius,Prunus Persica, Radix Polygalae, Rhizoma AcoriTatarinowii, Buthus Martensii, Hirudo, EupolyphagaSeu Steleophaga, Calculus Bovis Synthetic or Arti-factus and Cornu Saigae Tataricae, for the potentialoral prevention of stroke including cerebral infarctionand ischemic stroke and for the potential treatmentof traumatic brain injury in a randomized, double-blind, placebo-controlled, multicenter, Phase III trial(n = 1100) since November 2007 in Singapore and thePhilippines. The study was expected to be completedin 2012 (Thomson Reuters Pharma, update of October3, 2012).

CERE-110 (AAV2-NGF; NeuroRescue AD; Cere-gene, San Diego CA) is an AAV2 vector based genedelivery system containing cDNA for NGF. A Phase IIclinical trial in mild-to-moderate AD patients (n = 50)started in May 2009 in the US. The therapeutic poten-tial of CERE-110 was described in detail [185, 186](Thomson Reuters Pharma, update of July 20, 2012).

GM-607 (Genervon Biopharmaceuticals, PasadenaCA) is a motoneuronotrophic factor analogue for thepotential treatment of ischemic stroke, spinal cordinjuries, ALS, AD, HD, and PD. By April 2011, aPhase II ischemic stroke trial was initiated. By Febru-ary 2012, further Phase II IND applications werebeing prepared for spinal cord injuries, ALS, PD, andAD (Thomson Reuters Pharma, update of August 28,2012).

MIM-D3 (Mimetogen Pharmaceutics, Quebec,Fig. 3) is a small molecule NGF peptidomimetic forthe treatment of AD and dry eye (xerophthalmia). APhase II trial for dry eye was initiated in November2010 [187] (Thomson Reuters Pharma, update of May17, 2012).


PYM-50028 (Cogane, P58, P63; Phytopharm, UK)(Fig. 3), a steroidal saponin, stimulated BDNFrelease and may be beneficial for the treatmentof PD, AD, glaucoma, and ALS. PYM-50028reversed neuronal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MTPT) in a mousemodel of PD [188]. In July 2011, FDA grantedPYM-50028 orphan drug status for ALS. In Novem-ber 2010, recruitment of patients (n = 400) beganin the randomized, double-blind, proof-of-concept,placebo-controlled, dose-ranging Phase II studyCONFIDENT-PD (Thomson Reuters Pharma, updateof August 16, 2012).

T-817MA (Toyama Chemical, Fujifilm Holding)(Fig. 3) is a neurotrophic small molecule in PhaseII clinical trials for AD in the US since April 2008.T-817MA attenuated cognitive impairments in P301Ltau transgenic mice [189], prevented memory deficitscaused by i.c.v. A� administration [190, 191], andattenuated A�-induced neurotoxicity [192] (ThomsonReuters Pharma, update of July 30, 2012).

NsG-0202 (ECB-AD, ECT-AD, NsGene A/s, Den-mark) is an encapsulated cell biodelivery system todeliver cells expressing NGF. A Phase Ib trial startedin December 2007 in Sweden. First clinical data werepresented in July 2011. In January 2012, the trial wasexpected to be completed in 2012 [193] (ThomsonReuters Pharma, update of January 17, 2012).

There are several drugs interacting with neu-rotrophic factors in preclinical evaluation (in alpha-betical order):

AL-209 (ADNF-9, SAL; Allon Therapeutics, Van-couver) is an activity-dependent neurotrophic factorderived nine amino acid sequence peptide and tubulin-binding agent that stimulated PARP-1 for the potentialtreatment of CNS and ocular disorders (ThomsonReuters Pharma, update of March 6, 2012).

AL-309 (Allon Therapeutics, Vancouver) is ananalogue of AL-209 and PARP stimulator for oral,intranasal and s.c. administration. By October 2012preclinical development had been completed (Thom-son Reuters Pharma, update of October 17, 2012).

AMRS-001 (CNS-001; Amarantus BioSciences,Sunnyvale CA, formerly CNS Protein Therapeuticshaving acquired the relevant IP from Prescient Neu-ropharma) is a program of therapeutics based onmesencephalic astrocyte-derived neurotrophic factor[194], which promoted the survival of dopaminergicneurons for the potential treatment of PD, AD, andbrain injury. It also protected the heart from ischemicdamage [195] (Thomson Reuters Pharma, update ofOctober 2, 2012).

Catecholamine derivatives (Emory University,Atlanta, GA) acted like BDNF to activate the tyrosinekinase B (TrkB) receptor. They have a potential for thetreatment of neurological diseases such as ALS, PD,and AD (Thomson Reuters Pharma, update of July 27,2012). Structures were not communicated.

CB-1, CB-2, and CB-3 (Molcode, Tartu, Estonia)are BDNF mimetics, which activated the TrkB recep-tor leading to its phosphorylation (Thomson ReutersPharma, update of December 27, 2011). The structureswere not communicated.

7,8-Dihydroxy-flavone, a TrkB receptor agonistand BDNF mimic, reversed memory deficits in a mousemodel of AD [196]. The compound and derivativesthereof are also evaluated at Emory University in col-laboration with the University of Wisconsin [197–199](Thomson Reuters Pharma, update of August 10,2012).

FC29 peptide (University of Queensland, Brisbane,Australia) is a fragment of the p75 neurotophin recep-tor that inhibited p75NTR-mediated neuronal deathvia regulation of the Trk receptor function for thepotential treatment of AD, PD, and motor neuron dis-ease (Thomson Reuters Pharma, update of May 17,2012).

Gambogic amine and gambogic amide (EmoryUniversity, Atlanta GA), TrkA receptor agonists withrobust neurotrophic activity, prevented neuronal celldeath [200] (Thomson Reuters Pharma, update ofAugust 28, 2012).

Gedunin (Emory University, Atlanta GA) and itsderivatives including deoxygedunin are TrkB receptoragonists for the potential treatment of PD, HD, AD,HIV-related dementia, ALS, stroke, and multiple scle-rosis [201] (Thomson Reuters Pharma, update of April26, 2012).

JRP-655 (Prous Institute for Biomedical Research,Barcelona) is a BDNF secretagogue and neuroplastic-ity modulator (Thomson Reuters Pharma, update ofSeptember 5, 2012). The structure was not communi-cated.

4-methylcatechol, which increased BDNF contentand stimulated BDNF mRNA expression and synthe-sis, effectively improved spatial learning and memoryin rats [202, 203].

NeuroAiD II (MLC-901, Moleac Pte Ltd., Singa-pore), a BDNF stimulator, is a derivative of NeuroAiDfor the potential treatment of global ischemia inpreclinical development (Thomson Reuters Pharma,update of September 2, 2011).

ND-602 (Neurodyn, Charlottetown, Canada) is aneuroprotective progranulin (PC cell-growth factor)-


expressing lentiviral vector for the potential treatmentof PD, AD, and ALS. ND-602 was found to increaseactivity of neprilysin and significantly reduced A� andplaque burden in the hippocampus and entorhinal cor-tex of Tg2576 mice (Thomson Reuters, update of May25, 2012).

The development of many drugs interacting withneurotrophic factors was terminated. The mostadvanced drug, xaliproden (SR-57746A, Xaprila;sanofi), a 5-HT1A agonist and stimulator of endoge-nous neurotrophin synthesis, did not meet the cognitionendpoints in Phase III trials in AD patients, whichapplies also to paliroden (SR-57667B; with a biphenylinstead of the �-naphtyl in xaliproden; sanofi, [204]).The lessons learnt from the xaliproden clinical trialswere discussed [205]. The biological characterizationwas reviewed [206].

Also the development of other drugs inter-acting with neurotrophic factors (in alphabeticalorder) was terminated: ABS-200 (American Bio-genetic Sciences), ADNF-14 (NIH, activity-dependentneurotrophic factor-14), AGT-120, and AGT-140(ArmaGen Technologies); AK-30-NGF (a mono-clonal antibody as carrier for the delivery of NGF;Alkermes), arundic acid (MK-0724, ONO-2506, Aro-cyte, Ono Pharmaceuticals [207–210]), beta NGF(tethered to a molecular shuttle; Apollo Life Sci-ences), CEP-427 (a neurotrophic factor enhancingsmall molecule; Cephalon, now Teva), coleneuramide(MCC-257; Mitsubishi Tanabe Pharma), CX-438(Cortex Pharmaceuticals), dekafin-1 (a fibroblastgrowth factor receptor, agonist and tyrosine kinasemodulator; Enkam Pharmaceuticals); dFGF (dimer-ized fibroblast growth factor; Massachusetts Instituteof Technology (MIT)/ViaCell Inc.), GDF-1 (CreativeBiomolecules, now Curis; a growth and differen-tiation factor-1 agonist), glial maturation factor(Rhone-Poulenc/Regeneron), huIM-13 (a humanizedmonoclonal antibody that binds to the TrkA receptor,Lay Line Genomics), inosine (an NGF, Alseres Phar-maceuticals, formerly Boston Life Sciences (BLSI),under license from the Children’s Hospital of Boston),KP-66, KP-447, and KP-546 (Krenitsky), leteprinim(AIT-082; SPI-205, Neotrofin; Spectrum Pharmaceu-ticals, formerly NeoTherapeutics), which induced theexpression of NGF, neurotrophin-3, and of basicfibroblast growth factor [211–216], LM11A-31 (a p75neurotrophin receptor ligand; Elan), nerve growthfactor agonists (Chiron), neuregulin-2 (cerebellum-derived growth factor, NRG2; Acorda Therapeuticsunder license from CeNeS and Harvard Univer-sity), NGF therapy (Lay Line Genomics), NP-901

(Noscira), NS-521 (NeuroSearch), p75 NGF recep-tor antagonist (Circadian Technologies under licensefrom the Walter & Eliza Hall Institute), NT-3 (Genen-tech and StemCells), ReN-1820 (ReNeuron underlicense from the University of Bristol), ST-857 (acetyl-L-carnitine arginine amide; Sigma-Tau [217–219]),T-588 (Toyama [220–227]), and trofexin (a peptideneurotrophic factor; Protarga).

DRUGS INTERACTING WITH RE-UPTAKETRANSPORTERS (PSYCHOSTIMULANTS)

Psychostimulants exert behavioral-calming andcognition-enhancing actions in the treatment of ADHD[228]. Cognition-enhancing doses of psychostimulantsexert regionally restricted actions elevating extra-cellular catecholamine levels and enhancing neuralsignal processing preferentially in the prefrontal cor-tex. Additional evidence suggests a prominent role ofprefrontal cortex �2 and D1 receptors in the behav-ioral and electrophysiological actions of low-dosepsychostimulants [229, 230]. Excellent reviews onattention-modulating effects of cognitive enhancerswere published [231–236]. An analysis of studentuse (and abuse) of cognitive enhancers was presented[237]. A review on glycine transporter type 1 (GlyT1)inhibitors was disclosed [238].

Methylphenidate (Ritalin, Ciba, now Novar-tis, launched 1956) is a psychostimulant drug,which increased the levels of dopamine and nora-drenaline in the brain through re-uptake inhibition ofthe monoamine transporters [239]. Methylphenidatepreferentially increased catecholamine neurotrans-mission within the prefrontal cortex at low dosesthat enhance cognitive functions [240]. Cognition-enhancing doses of methylphenidate preferentiallyincreased prefrontal cortex neuronal responsiveness[241]. Methylphenidate decreased the amount of glu-cose needed by the brain to perform a cognitive task[242]. The improvement of memory functions bymethylphenidate (and modafinil) in healthy individualswas described [243].

Most of these experiments were made withthe mixture of erythro and threo stereoisomers.The active principle of methylphenidate is the(+)-(�R,2R)-threo-methylphenidate hydrochloride(Dexmethylphenidate, Ritadex; Novartis Pharmaunder license from Celgene launched 2002) (Fig. 4),also available as an extended-release oral formulationFocalin XR [244]. The spheroidal oral drug absorp-tion system dexmethylphenidate was described [245](Thomson Reuters Pharma, update of July 27, 2012).


Fig. 4. Psychostimulant cognition enhancers.

Modafinil (Provigil, Lafon Laboratories, laterCephalon, now Teva, launched 1998) is an inhibitor ofdopamine, noradrenaline, and serotonin re-uptake andan �1 adrenoceptor agonist [246]. Modafinil showedimprovement of cognition and attention in patientswith chronic schizophrenia ADHD [247, 248], in par-ticular in the first episode of psychosis [249, 250]. Theneuronal mechanism by which modafinil affects cog-nitive and emotional function in schizophrenic patients

was reviewed [251]. Experiments using BOLD func-tional magnetic resonance imaging (fMRI) in healthyvolunteers showed that modafinil enhanced the effi-ciency of prefrontal cortical cognitive informationprocessing, while dampening reactivity to threateningstimuli in the amygdala, the brain area implicated inanxiety [252]. Modafinil improved attention in well-rested individuals [243]. Modafinil reliably enhancedperformance on several cognitive tests of planning


and working memory, but did not improve learningand delayed recall performance in healthy volunteers[253]. It may be useful in the treatment of substanceabuse [254]. It improved working memory and sus-tained attention in cocaine users [255].

The active principle of modafinil is the (R)-enantiomer Armodafinil (Nuvigil; CEP-10953;Cephalon, now Teva launched 2009) (Fig. 4). Thesales of armodafinil in 2011 amounted to USD 266mil (Thomson Reuters Pharma, update of September21, 2012).

Atomoxetine (tomoxetine, Strattera, LY-139603;Lilly; launched 2003) (Fig. 4) is a selective nora-drenaline re-uptake inhibitor for the treatment ofADHD in children and adults [256]. Atomoxetineinhibited noradrenaline and serotonin transporters withKi values of 2.6 and 48 nM, respectively [257]. Ato-moxetine improved response inhibition in ADHDpatients and in healthy volunteers via increased acti-vation in the right frontal gyrus measured via fMRI[258, 259]. Sales in 2011 were USD 620 million(Thomson Reuters Pharma, update of September 26,2012).

Lisdexamfetamine (Vyvanse; Shire Pharmaceuti-cals and New River Pharmaceuticals, launched 2007)(Fig. 4) is a drug for the treatment of ADHD inchildren, adolescents, and adults [260]. Lisdexam-fetamine itself is inactive and acts as a prodrug todextroamphetamine upon cleavage of the lysine por-tion of the molecule. Dextroamphetamine inhibitednoradrenaline, serotonin and dopamine transporterswith respective Ki values of 39, 3,830, and 34 nM[261]. The use of lisdexamfetamine in patients withdementia was described [231]. Sales in 2011 wereUSD 805 million (Thomson Reuters Pharma, updateof September 28, 2012).

Indeloxazine (YM-08054; Elen, Noin,Yamanouchi, Schering-Plough, now Merck andJeil Pharmaceuticals, launched in China and SouthKorea) (Fig. 4) blocked the reuptake of noradrenalinewith IC50 of 3.2 �M and of serotonin with IC50 of0.71 �M. It is also a MAO inhibitor. It showed learningand memory improving effects in many animal tests[262–267].

NS-2359 (NeuroSearch, Fig. 4) is a blocker ofdopamine, noradrenaline, and serotonin re-uptake cur-rently in Phase I clinical trials in Denmark forthe potential treatment of CNS diseases. GSK waspreviously developing NS-2359 for the treatmentfor depression but discontinued the development(Thomson Reuters Pharma, update of September 26,2012).

There are several drugs interacting with re-uptaketransporters in preclinical evaluation (in alphabeticalorder):

AM-285 (Cyclocreatine, CincY; Lumos Pharma,Austin TX based on University of Cincinnati technol-ogy) (Fig. 4) is evaluated for the potential treatmentof creatine transporter deficiency, an X-linked autismspectrum disorder characterized by severe cognitiveimpairment [268]. In June 2012, the FDA awardedcyclocreatine Orphan designation for the treatmentof creatine transporter deficiency (Thomson ReutersPharma, update of August 24, 2012).

AS-1522489-00 (Astellas Pharma) is a glycinetransporter-1 inhibitor, a 1,2,4-triazole derivative, ofwhich only the (S)-atropisomer is biologically active[269, 270] (Thomson Reuters Pharma, update of Jan-uary 27, 2012). The structure was not communicated.

Lu-AA42202 (Lundbeck) (Fig. 4) is a tripledopamine, noradrenaline, and serotonin re-uptakeinhibitor for the potential treatment of major depres-sive disorders and ADHD (Thomson Reuters Pharma,update of December 1, 2010).

MLR-1017 (mesocarb, sydnocarb, sidnocarb,Melior Pharmaceuticals, Exton, PA) (Fig. 4) isa dopamine transporter inhibitor for the potentialtreatment of ADHD and levodopa-induced side effectsin PD. The drug was previously launched in Russia[271, 272] (Thomson Reuters Pharma, update of April12, 2012).

PD-2005 (P2D Bioscience, Cincinnati, OH, identi-cal with AHN 2-005, National Institute of Drug Abuseand US Naval Medical Research Center) (Fig. 4) is aninhibitor of the dopamine transporter for the potentialtreatment of ADHD and for cognitive impairments intraumatic brain injury. It dose-dependently improvedperformance of rats in a delayed-alternation task ofspatial working memory [273] (Thomson ReutersPharma, update of June 12, 2012).

RO-4543338 (Roche) is a well-tolerated glycinetransporter inhibitor, which facilitated drug cue extinc-tion [274, 275]. The structure was not communicated.

Selective Serotonin Re-uptake Inhibitors (SSRIs)showed cognitive enhancing effects [276]. Patientstreated with citalopram showed significant improve-ments on a cognitive subscale. Paroxetine and fluoxe-tine improved most of the tested cognitive functions ina study of 242 depressed patients during one year [277].Other studies with citalopram, fluoxetine, sertraline,and zimelidine did not report improvement of memoryand/or reaction time in demented patients [278].

Thiethylperazine (Torecan) (Fig. 4), a drugapproved by the FDA to relieve nausea and vomiting,


Fig. 5. VMAT2 and DA-reuptake PET ligands.

is an activator of ABCC1 transporters. In a mousemodel of AD expressing the ABCC1 transporter, amarkedly reduced load of A� was measured. Defi-ciency of ABCC1 transporter substantially increasedcerebral A� levels [279] (Thomson Reuters Pharma,update of April 26, 2012).

The development of ASP-2535 (Astellas; aglycine transporter-1 inhibitor [280]), coluracetam(BCI-540, MKC-231; BrainCells Inc. under licensefrom Mitsubishi Tanabe Pharma; an enhancer ofhigh-affinity choline uptake and K+-induced releaseof acetylcholine [281–288]), CP-101 (CogniPharm,an i.v. formulation of modafinil), D-serine re-uptakeinhibitors (Memory Pharmaceuticals, now Roche),flufenoxina (FAES Farma; a dual serotonin and nore-pinephrine re-uptake inhibitor), glycine transporter-1inhibitors (Helicon Therapeutics), JNJ-17305600(NFPS; NPS Allelix; a glycine transporter inhibitor[289]), PD-2007 (P2D Bioscience, a dopamine trans-porter inhibitor), SCH-900435 (Org-25935; Organon,Schering-Plough, now Merck, a glycine transporter-1inhibitor), SSR-103800 [290–292]) and SSR-504734(both sanofi; both glycine transporter-1 inhibitors[293–297]), teniloxazine (sufoxazine, Lucelan,

Metatone, Y-8894, Yoshitomi, Mitsubishi Pharma, anoradrenaline uptake inhibitor [298],[299–301]), andtesofensine (NS-2330, NeuroSearch, a monoaminere-uptake inhibitors of serotonin, dopamine, and nora-drenaline [302]) was terminated. The developmentof tesofensine for the once-daily oral treatment ofobesity in Phase II trials was also suspended [303].

The vesicular monoamine transporter 2(VMAT2) located on the membrane of vesiclesis responsible for storing and packaging neuro-transmitters into monoamine vesicles or granules.Imaging VMAT2 in the brain provides a measurementreflecting the integrity of dopaminergic, noradrenergicand serotonergic neurons [304]. Positron emissiontomography (PET) ligands for the VMAT2 havebecome valuable diagnostic tools.

(+)-[11C]-dihydrotetrabenazine (DTBZ) (Fig. 5)allows the determination of the striatal monoaminergicpresynaptic terminal density. In a study enrolling 20patients with dementia with Lewy bodies (DLB), 25AD patients, 7 patients with frontotemporal dementia,and 19 elderly controls clinicians could accuratelydifferentiate between the different forms of dementia[305–307]. The uptake of (+)-11C-DTBZ in the stria-


tum of AD patients mainly reflecting the presynapticdopaminergic system was unchanged compared tocontrols. The striatal uptake in DLB and PD patientswas significantly decreased [308].

18F-Florbenazine (18F-AV-133; 18F-FP-DTBZ;Avid Radiopharmaceuticals, Philadelphia PA, a sub-sidiary of Lilly, under license from University ofMichigan) (Fig. 5) is in Phase III clinical evaluation.In May 2012, an open-label, single-blind, Phase II/IIIstudy (NCT01550484; 18F-AV-133-B04) was initi-ated in patients with undiagnosed movement disorders(n = 150) in the US to assess the safety and efficacyof florbenazine in differentiating PD. At that time, thestudy was scheduled to complete in September 2014.For the synthesis, see [309]; for the binding character-istics in rat striatum and hypothalamus homogenates(Kd = 0.19 and 0.25 nM, respectively), see [310, 311].The whole body biodistribution was studied [312].18F-AV-133 was used for noninvasive assessment ofthe vesicular monoamine transporter type 2 in 17 PDpatients and 6 healthy controls. VMAT2 binding poten-tial was decreased by 81% in the posterior putamen,70% in the anterior putamen, and 48% in the caudatenucleus of PD patients [313].

This ligand is a valid measure of dopaminergicneuron integrity. The in vivo assessment in patientswith DLB and AD was reported [314]. The optimalscanning time window was elucidated [315]. For PETimaging in a MPTP-induced mouse model of PD, see[316] (Thomson Reuters Pharma, update of August 7,2012).

11C-�-CFT and 18F-�-CFT (Fig. 5) proved tobe valuable PET ligands due to their high affinityinteraction with dopamine re-uptake sites. AD patientsshowed a reduction of 11C-�-CFT in putamen and cau-date of about 20%. Thus the putamen and the caudatenucleus were equally affected in contrast to PD, whichshowed predominantly putaminal reduction [317]. InPD, the mean uptake of 18F-�-CFT in the contralat-eral putamen was reduced to 31% and in the ipsilatralputamen to 45%. In the caudate nucleus, the uptakewas reduced contralaterally to 67% and ipsilaterally to77% [318]. For an exhaustive review, see [319].

123I-Ioflupane (123I-FP-CIT; Amersham, now GEHealthcare) (Fig. 5) is a SPECT ligand launched in2000. It is the ligand of choice to differentiate betweenAD and DLB patients [320, 321]. It is valuable forthe diagnosis of Parkinsonian syndromes [322]. SERTdependent 123I-ioflupane uptake allows a more com-prehensive assessment of neurochemical disturbancesin degenerative Parkinsonism [323–325] (ThomsonReuters Pharma, update of August 14, 2012).

DRUGS INTERACTING WITHTRANSCRIPTION FACTORS

cAMP response element-binding (CREB) proteinand the discovery of cognitive enhancers was reviewed[326–328]. CREB phosphorylation as a mechanis-tic marker in the development of memory enhancingAD therapeutics was described [329]. The currentknowledge of key calcium signal-regulated transcrip-tion factors, namely CREB, nuclear factor of activatedT-cells, and downstream regulatory element antago-nist modulator (DREAM) and memory formation wassummarized [330]. A� disrupted activity-dependentgene transcription required for memory through theCREB-regulated transcription co-activators CRTC1[331]. The GABAB receptor antagonist SGS742improved spatial memory and reduced protein bind-ing to CREB2 in the hippocampus [332] (see Part1, Chapter 1.10.2 GABAB receptors). CREB anti-sense oligonucleotide administration into the dorsalhippocampal CA3 region impaired long- but not short-term spatial memory in mice [333].

The lack of DREAM protein enhanced learning andmemory and slowed brain aging [334].

SRF/MYOCD inhibitors (Socratech LLC,Rochester NY) are small molecule inhibitors againstserum response factor and myocardin, which areinteractive transcription factors in vascular smoothmuscle cells for the potential treatment of AD[335]. For a review on the imbalance of vascularmolecules in AD, see [336] (Thomson ReutersPharma, update of February 15, 2012). Structureswere not communicated.

The development of CREB modulators (HeliconTherapeutics) and of EPAC inhibitors (exchange pro-tein directly activated by cAMP, a guanine nucleotide-exchange factor; Scottish Biomedical [337]) wasterminated.

ANTIOXIDANTS

Soluble A� oligomers localize to mitochondriaand interfere with their normal functioning caus-ing an overproduction of reactive oxygen species(ROS), inhibiting respiration and ATP production anddamaging the structure of mitochondria [338–340].Some authors, however, claim that the early impair-ments of mitochondrial dysfunction and oxidativestress may precede A� overproduction and depo-sition [341–343]. Excellent reviews were presentedover years [344–347]. Possibilities of intervention ofantioxidant pathways in AD were discussed [348, 349].


Fig. 6. Mitochondria-targeting antioxidants.

Also see Chapter 3. Cytokines, as inflammation istightly connected with the oxidative cascade.

Over the years, clinicians have explored treatmentof AD patients with antioxidants. Free radicals canbe scavenged by dietary means. Compounds such asacetyl-L-carnitine, curcumin [350], Gingko bilobaextracts such as EGb 716, (R)-α-lipoic acid, mela-tonin, morin, trolox, vitamin C [351], and vitamin E[352–355] were tested in clinical trials in AD patients.The results were disappointing [356–372]. As a conse-quence of a landmark study, clinicians even advise ADpatients not to take large doses of vitamin E or �-lipoicacid [373].

Many clinical trials were also carried out withsynthetic antioxidants such as edaravone (MCI-186,Mitsubishi [374],[375–377]), idebenone (CV-2619,Avan, Catena, Noben, Sovrima; Takeda [378–380]),and the derivatives of 21-aminosteroids (Upjohn’slazaroids, such as tirilazad or U-74006F, U-74389G,U-74500A, U-75412E, U-78518F, and U-83836E[381–384]). None of these compounds produced statis-tically significant therapeutic benefits for AD patients.

MitoQ (redox mixture of mitoquinone and mito-quinol; Antipodean Pharmaceuticals, Menlo Park

CA, under license from the University of Otago;Fig. 6 shows the oxidized form) is a brain penetrat-ing mitochondria-targeting antioxidant [385–388]. Itselectively blocked mitochondrial oxidative damageand prevented cell death [389–394]. It is evaluated inPhase II clinical trials for the treatment of PD and liverdamage. Clinical trials for the treatment of Friedreich’sataxia and sunburn were abandoned (Thomson ReutersPharma, update of June 18, 2012).

A potential follow-up compound is MitoVitE(Fig. 6) [395, 396]. The development of MitoPBN(Antipodean Pharmaceuticals, Menlo Park CA)(Fig. 6) consisting of the spin trapping agent �-phenyl-N-tert.-butyl-nitrone [397, 398] conjugated totriphenyl-phosphonium bromide was terminated [399](Thomson Reuters Pharma, update of June 18, 2012).

MTP-131 (Bendavia, SS-31, Szeto-Schiller pep-tide; Stealth Peptides Inc., Newton Centre MA) (Fig. 7)is a cell-permeable mitochondria-targeting antioxidanttetrapeptide (NH2-D-Arg-Dmt-Lys-Phe-NH2), whichis in Phase II clinical trials for ischemia reperfusioninjury since September. 2010 (EMBRACE–STEMItrial). It will further be investigated for the treatmentof eye, neurological, mitochondrial, and metabolic


Fig. 7. The Szeto-Schiller peptide, a manganoporphyrin antioxidant and CNB-001.

diseases [400–402],[403] (Thomson Reuters Pharma,update of June 15, 2012).

VP-20629 (OX1; IN-OX1; OX1; OXIGON, Indole-3-propionic acid; ViroPharma, Exton PA, under licensefrom Intellect Neurosciences, New York Universityand Mindset BioPharmaceuticals) is an antioxidant andA� aggregation/deposition inhibitor. The prevention ofA� induced neurotoxicity by indole-3-propionic acidwas described [404]. The rationale behind the selectionof OXIGON as a potential disease-modifying therapyfor Alzheimer’s disease was presented [1706]. Pre-liminary data from a multiple-dose Phase Ib trial forAD were reported in October 2010. It appears thatViroPharma wants to pursue the drug for the indicationFriedreich’s ataxia only (Thomson Reuters Pharma,update of August 17, 2012).

There are several antioxidants in preclinical evalua-tion (in alphabetical order):

Catalytic manganoporphyrine antioxidants, suchas AEOL-10113, AEOL-10150, AEOL-10201 andAEOL-11207 (Aeolus Pharmaceuticals, MissionViejo CA; Fig. 7) may be promising for the treatment of

PD and ALS [405–407] and ischemic stroke [408–412](Thomson Reuters Pharma, update of April 23, 2012).

CNB-001 (The Salk Institute for Biological Studies)(Fig. 7) is a curcumin derivative for potential treatmentof traumatic brain injury and stroke (Thomson ReutersPharma, update of November 9, 2011).

DL-3-n-butylphtalide (NBP, Hebei, China) is a nat-ural antioxidant extracted from seeds of Apium anda powerful free radical scavenger [413]. It protecteddopamine neurons in a rotenone model for PD [414].

FRP-0924 (gemifloxacin, Neuron BioPharma,Granada, Spain) is an antioxidant and neuroprotectantfor the potential treatment of neurodegenerative dis-eases including AD. FRP-924 crossed the blood-brainbarrier and prevented neuronal death. As fluoro-quinolones are generally well tolerated with most sideeffects being mild and serious adverse effects beingrare, it is expected that the drug will enter Phase IIrapidly (Thomson Reuters Pharma, update of August14, 2012).

IAC (Cerebricon, Finland and Medestea Research,Torino, Italy) (Fig. 8) is a novel radical scavenger react-


Fig. 8. Antioxidants in preclinical evaluation.

ing with most carbon-, nitrogen-, and oxygen-centeredradicals of biological interest [415–418]. Daily treat-ment with IAC (3–30 mg/kg i.p.) decreased mortality,enhanced cognitive functions in the water maze, andreduced the A� plaque burden in hA�PP transgenicmice [419].

Lipid soluble antioxidants (OXIS International,Beverley Hills CA) mimic the activity of the body’snatural cell membrane-protecting antioxidant vitaminE for the potential treatment of cardiovascular diseases,diabetes, AD, and PD (Thomson Reuters Pharma,update of June 12, 2012). The structures were notcommunicated.

Lipocrine and Memoquin, dual acetylcholines-terase inhibitors and antioxidants (University ofBologna), were described in Part 2, Chapter 2.1.1.3.(formulae in Part 2 in Fig. 6).

NPS-0155 (Neuron BioPharma, Granada, Spain) isan antioxidant and neuroprotective compound for thepotential treatment of AD and other neurodegenerativediseases (Thomson Reuters Pharma, update of April27, 2012). The structure was not communicated.

PAN-811 (3-AP; NSC-663249; OCX-191; Triapine,Panacea Pharmaceuticals, Gaithersburg MD) (Fig. 8) isa ribonucleotide reductase inhibitor, calcium ion chela-tor, and radical scavenger for the potential treatmentof AD and ischemia [420, 421] (Thomson ReutersPharma, update of February 25, 2011).

S-52 (Shanghai Institute of Materia Medica) (Fig. 8)is a sinomenine derivative, an active natural product

from the Chinese herb Sinomenum acutum. It is a scav-enger of free radicals. It attenuated the toxicity of A�to energy metabolism, mitochondrial membrane struc-ture, and key enzymes in the electron transport chain[422].

There are numerous preclinical reports of drugsand natural products, which, in addition to their radi-cal scavenging properties, also prevented A�-inducedneurotoxicity, such as peoniflorin [423], 2,2′-pyridoin[424], quetiapine [425]), stemazole (Fig. 8) [426], andzeatin (Fig. 8) [427].

Dual free radical scavengers and A� binding lig-ands were described [428, 429].

The development of many antioxidants was ter-minated (in alphabetical order) of AN-808 (AthenaNeurosciences, now Elan Pharmaceuticals), AO-2 andAO-3 antioxidants (Antoxis), CNSB-002 (AM-36;Relevare; AMRAD, formerly Zenyth Therapeutics[430] [431, 432]), CPI-1189 (Centaur [433, 434]), dis-ufenton sodium (Cerovive, NXY-059, AstraZeneca,which was in Phase III clinical trials for the treatmentof acute ischemic stroke [435–445]), FR-210575 (Fuji-sawa [446]), MDL-101002 (Hoechst Marion Roussel,now sanofi [447, 448]), and raxofelast (IRFI-016,Biomedica Foscama Industria [449–452]).

METAL CHELATORS

The metallobiology of AD was investigated in greatdetail over the last fifteen years. Excellent reviews were


published (in chronological order) 2001: [453], 2002:[454], 2003: [455], 2006: [456], 2007: [457–459],2008: [460–462], 2009: [463–467], 2010: [468–472],2011: [473–478], 2012: [479–485], 2012: [1707].

DP-b99 (D-Pharm, Rehovot, Israel) (Fig. 9) is ani.v. prodrug of the calcium and zinc chelator BAPTAfor the potential treatment of stroke and traumaticbrain injury. It is in Phase III clinical trials for strokesince October 2009. First reports on clinical resultswere communicated [486–488]. Also preclincial datawere disclosed [489–491] (Thomson Reuters Pharma,update of February 3, 2012).

PBT-2 (Prana Biotechnology, Parkville, Australia)(Fig. 9) is an oral zinc ionophore metal-protein attenu-ating compound that reduced levels of soluble A� andtau hyperphosphorylation [492]. A Phase IIa study inAD patients (n = 78), started in December 2006 withdaily doses of 50 or 250 mg or placebo over threemonths, was completed in January 2008. A signifi-cant reduction of A�42 levels in the cerebrospinal fluid(CSF) was seen in the 250 mg group. This dose alsosignificantly improved executive function performancein the category fluency and the trail making cogni-tive tests compared to placebo [493, 494]. In January2012, the FDA approved an IND to initiate a random-ized, multicenter, double-blind, placebo-controlled,parallel-group, safety, tolerability, and efficacy PhaseIIa trial in early- to mid-stage HD patients (n = 100) inthe US and Australia. In April 2012, the first patientwas dosed in this trial. By June 2012 the trial hadbeen initiated in Australia. Data are expected in thesecond half of 2013. The compound was extensivelycharacterized in preclinical studies [495–497] (Thom-son Reuters Pharma, update of October 2, 2012). Seealso Chapter 17.1. Small molecules preventing tauaggregation.

AEN-100 (Synthetic Biologics, formerly AdeonaPharmaceuticals, Ann Arbor, MI) is a once-daily, gas-troretentive, sustained-release, oral tablet formulationof zinc acetate for the potential treatment of ALS andAD. By November 2011, a Phase I study for ALSpatients was underway (Thomson Reuters Pharma,update of September 19, 2012).

Other metal chelators are currently in preclinicalevaluation (in alphabetical order):

Aom-0937 (Hangzhou Adamerck Pharmlabs,China) is a prodrug of DP-b99 (Thomson ReutersPharma, update of July 28, 2011). The structure wasnot communicated.

DP-460 (D-Pharm, Rehovot Israel) (Fig. 9) is amembrane active chelator derivative of the calcium-specific chelator BAPTA that modulates copper and

zinc homeostasis to inhibit oxygen radicals and plaqueformation. It is in preclinical evaluation for the poten-tial oral treatment of AD and ALS (Thomson ReutersPharma, update of November 1, 2011). It appears thatDP-460 was preferred to DP-109 [498]. Both com-pounds have been evaluated as neuroprotectants ina transgenic mouse model of ALS [499] (ThomsonReuters Pharma, update of August 7, 2012).

Deferoxamine (SAN-121; Sanomune, a subsidiaryof DiaMedica under license from HealthPartnersResearch Foundation, Winnipeg, Canada) (Fig. 10) is anasally-delivered iron chelator improving performancein a radial arm water maze in P3301L tau trans-genic mice [500] (Thomson Reuters Pharma, updateof December 23, 2011).

HLA20A (Technion Haifa) (Fig. 10) is a com-bination of an 8-hydroxy-quinoline metal chelator,which was carbamoylated at the 8-hydroxy functionto interact with acetylcholinesterase as in rivastigmine[501, 502]. See Part 2, Chapter 2.1.1.10. Dual acetyl-cholinesterase inhibitors and metal chelators.

PA-1637 (Palumed, France) is an A� plaqueproduction-inhibiting copper chelating agent (Thom-son Reuters Pharma, update of May 28, 2012). Thestructure was not communicated.

PBT-3 and PBT-4 (Prana Biotechnology, Parkville,Australia) are non-8-hydroxyquinoline metal pro-tein attenuating compounds, potential follow-ups ofPBT-2. (For both Thomson Reuters Pharma, updateof November 2, 2011). The structures were notcommunicated.

Triazole-pyridine derivatives as inhibitors ofmetal-induced A� aggregation were described [503].

VAR-10200 (HLA-20; Varinel, West Chester, PA)(Fig. 10) is a dual iron-chelating agent and MAO-Binhibitor for the potential treatment of age-related mac-ular degeneration [501] (Thomson Reuters Pharma,update of February 24, 2012). See Part 2, Chapter 2.26.Drugs interacting with Monoamine Oxidase.

VAR-10300 (M-30; Varinel, West Chester, PA,Technion and the Weizmann Institute) (Fig. 10)combines the iron-chelating properties of 8-hydroxy-quinoline with the MAO inhibitor moiety of rasaglinine[504–517] (Thomson Reuters Pharma, update ofSeptember 24, 2012). See also Part 2, Chapter 2.26.Drugs interacting with Monoamine Oxidase.

The development of many metal chelators wasterminated (in alphabetical order): desferrioxam-ine [518–520], Gero-46 (clioquinol, Gerolymatos);NG-1 and PBT-1 (clioquinol, Prana Biotechnol-ogy [521, 522]); phanquinone (PN Gerolymatos);tetrathiomolybdate (a copper chelating agent of


Fig. 9. Metal chelators.

Fig. 10. Metal chelators II.

Adeona Pharmaceuticals, formerly Pipex under licensefrom the University of Michigan); the iron chelatorVAR-10100 (VK-28) [523–526] and VK-11 and VK-12 (Prana Biotechnology).

NATURAL PRODUCTS

Excellent reviews on naturally occurring phyto-chemicals for the prevention and treatment of AD have


been presented [527–532]. An overview on “naturalsubstances and AD: from preclinical studies to evi-dence based medicine” was published recently [533].

Mentat (BR-16A; Himalaya Drug Co.) is a stan-dardized mixture of herbal extracts, which has beenlaunched in India and the US (as MindCare) inNovember 2000 for the treatment of cognitive deficits(Thomson Reuters Pharma, update of November 6,2000).

YY-280 (Yucrid; Yuyu, South Korea) is a combi-nation therapy of ticlopidine and EGb-761 (tanamin,a Ginkgo biloba extract) administered as a tabletfor the treatment of apoplexy and myocardial infarc-tion. The drug was registered in Korea in May 2008[534] (Thomson Reuters Pharma, update of April 11,2012).

SK-PC-B70M (SK Chemicals Life Science, SouthKorea) is derived from the dried root of Pulsatellakoreana (baekduong). A randomized, double-blind,placebo-controlled Phase III clinical trial for the treat-ment of mild-to-moderate AD patients (n = 256) wasinitiated in November 2010 in South Korea. SK-PC-B70M improved scopolamine-induced impairments ofmemory consolidation in rats [535, 536]. It had antiox-idant activity and reduced A� levels in the brains ofTg2576 mice [537, 538]. It alleviated the neurologicsymptoms in G93A-SOD1 ALS mice [538] (ThomsonReuters Pharma, update of February 28, 2012).

Circadin (KI-1001, NSC-56423; Neurim Phar-maceuticals, Tel Aviv) is an oral controlled-releaseformulation of melatonin (i.e., melatonin acetamide)and was launched in 2007 for the treatment of primaryinsomnia. A Phase II clinical trial was initiated in Israelin patients with MCI (n = 50) in October 2007. AnotherPhase II clinical trial was initiated in the US, UK, andIsrael in patients with mild-to-moderate AD (n = 140)treated with an acetylcholinesterase inhibitor to evalu-ate the effects of add-on Circadin (2 mg) on decline incognitive skills, global functioning, and daytime som-nolence in September 2009 (Thomson Reuters Pharma,update of September 26, 2012).

KD-501 (Kwang Dong Pharmaceutical Co., Seoul)is an extract from the Scrophulariae radix. The drug isin Phase II clinical trials for AD since March 2009(Thomson Reuters Pharma, update of February 11,2011).

PPLs (NatureWise Biotech, Taipeh, Taiwan) areprenylflavanone compounds extracted from Taiwanesepropolis in Phase II clinical trials. A pilot AD programof PPLs in combination with Aricept was initiated inNovember 2010 (Thomson Reuters Pharma, update ofJuly 10, 2012).

PTX-200 (Phytrix, Munich, Germany) is a plant-derived neuroprotectant for the potential treatment ofPD. A Phase I/IIa clinical evaluation in the UK wassuccessfully completed (Thomson Reuters Pharma,update of February 1, 2012).

Resveratrol is a natural phyto compound, whichactivated Sirtuin-1 [539–544]. It reduced A� accu-mulation [545–548]. It remodeled soluble oligomersand fibrils of A� into off-pathway conformers [549].Resveratrol is not a direct activator of SIRT1 enzymeactivity [550]. Resveratrol improved memory deficitsin mice fed a high-fat diet [551]. Subchronic oraltoxicity and cardiovascular safety pharmacology stud-ies were carried out [552]. The biosynthesis ofresveratrol in yeast and in mammalian cells wasachieved [553]. The Georgetown University MedicalCenter in Washington DC started at Phase II, ran-domized, double-blind, placebo-controlled study inpatients with mild-to-moderate AD (n = 120) in the USin May 2012 (NCT01504854). A novel application inHD was discussed recently [554]. See also in Part 2,Chapter 2.40, Drugs interacting with Sirtuin, formulain Part 2, Fig. 23 (Thomson Reuters Pharma, update ofJune 22, 2012).

RPh-201 (Regenera Pharma, Rehovot, Israel) is asubcutaneous formulation of an agent derived froma traditional medicinal plant. A Phase I/IIa random-ized, double-blind, placebo-controlled trial in healthyvolunteers and adults with AD (n = 56) started in Jan-uary 2012 in Canada. A topical formulation is currentlyevaluated in a Phase II study in patients with chroniculcerated wounds (n = 15) in Israel (both ThomsonReuters Pharma, update of January 31, 2012).

VR-040 (apomorphine as dry powder inhaledformulation, Vectura, Chippenham, UK) is beingdeveloped in Phase II clinical trials for the potentialtreatment of PD since June 2006 (Thomson ReutersPharma, update of October 3, 2012).

Exebryl-1 (ProteoTech, Kirkland, WA and Chineselicensee Tasly Pharmaceuticals) is a synthetic com-pound with molecular weight of about 300 Da, one ofthe components of an Amazonian vine Uncaria tomen-tosa extract, which reduced aggregation of both A�and tau. A Phase I clinical trial for AD was initiated inJuly 2008 (Thomson Reuters Pharma, update of June8, 2012).

Taisi (Beijing SL Pharmaceutical under license fromXuanwu Hospital of Capital Medical University), acapsule formulation of a stilbene analogue isolatedfrom an unspecified organism, is in clinical studies inChina since February 2011 (Thomson Reuters Pharma,update of June 29, 2012).


There are many natural products in preclinical eval-uation as potential drugs for the treatment of AD (inalphabetical order):

Alpha-mangostin, a polyphenolic xanthone deriva-tive from mangosteen, concentration-dependentlyattenuated neurotoxicity induced by A�1-40 or A�1-42oligomers (EC50 = 3.89 nM and 4.14 nM, respectively)[555].

Anatabine (Star Scientific, Glen Allen VI throughits subsidiary Rock Creek Pharmaceuticals in col-laboration with the Roskamp Institute) reduced A�when applied to cells [556] (Thomson Reuters Pharma,update of January 3, 2012).

Andrographis paniculata leaves extract showedcerebroprotective and nootropic activities in rats [557].

Apomorphine is an inhibitor of A� fibril formation[558]. Apomorphine treatment of AD mice promotedA� degradation [559]. Roles of apomorphine for reg-ulated �-cleavage, autophagy, and antioxidation werediscussed [560].

AX-00111 (Axonal Consultoria Tecnologica Ltda,Sao Paulo Brazil) is a plant-derived compound for thepotential treatment of AD (Thomson Reuters Pharma,update of June 1, 2012).

Axona (Accera Inc., Broomfield, CO) is a newmedical food therapy for AD patients [561, 562].It contains the proprietary formulation of medium-chain triglycerides, mostly caprylic triglyceride. Therationale for the use of Axona is based on the find-ing that the cerebral hypometabolism (i.e., impairedglucose metabolism) is an early sign of AD. Medium-chain triglycerides are metabolized in the liverresulting in the production of the ketone body beta-hydroxybutyrate, which is transported to the brainto provide an alternative fuel source for cerebralmetabolism [563, 564]. See also [565].

Bacopa monnieri has shown memory free recallenhancing effects in adult humans [566]. Neuroprotec-tive effects in experimental models of dementia weredescribed [567].

Baicalein (5,6,7-trihydroxyflavone) protected corti-cal neurons from A�25-35-induced toxicity [568] andin a one dose pre-treatment at 5 and 10 mg/kg i.p.attenuated A�25-35-induced amnesia in mice in a step-through passive avoidance paradigm. Post-treatmentfor 7 or 13 days (10–15 mg/kg i.p.) also attenuatedA�25-35-induced amnesia [569]. Baicalin preventedthe production of hydrogen peroxide and oxidativestress induced by A� aggregation in SH-SY5Y cells[570]. Apigenin (4′,5,7-trihydroxyflavone), baicalein,and nordihydroguaiaretic acid were potent inhibitorsof liposome permeabilization by A�42 oligomers

[571]. Baicalein inhibited the formation of �-synucleinoligomers within living cells and prevented A� peptidefibrillization and oligomerization [572].

Beta-asarone improved cognitive functions in ratsafter injection of A� into the hippocampus [573] prob-ably via JNK signaling and modulation of bcl-2 familyproteins [574] and attenuation of neuronal apoptosis[575, 1708].

BT-11 is an extract of the dried root of Poly-gala tenuifolia (Willdenow) and effectively enhancedcognitive functions in elderly humans [576–578].

BV-7003 (Bioved Pharmaceuticals) is a naturalproduct for the potential treatment of memory loss(Thomson Reuters Pharma, update of September 11,2012). The structure was not communicated.

Cabernet Sauvignon attenuated A� neuropathol-ogy in a mouse model of AD [579].

Carvacrol showed cognition enhancing activity intwo rat models of dementia [580].

Catechins showed potent anti-amyloidogenic andfibril-destabilizing effects in vitro [581–583].

Celastrol, a triterpenoid antioxidant compound iso-lated from the Chinese Thunder of God vine (T.wilfordii) reduced A� pathology in a transgenic mousemodel of AD [584].

Celastrus paniculatus seeds showed nootropicactivity [585].

Chelerythrine showed promising cholinesteraseinhibition, good inhibition of amyloid-� aggregationand the ability to disaggregate preformed amyloid-�aggregates [1709].

Cinnamon extract reduced A� oligomerization andcorrected cognitive impairment in animal models ofAD [586].

Coumarins are naturally occurring �-secretaseinhibitors [587] and acetylcholinesterase inhibitors[588].

Cryptotanshinone (CTS), an active componentof the medicinal herb Salvia miltiorrhiza, inhibitedA� aggregation and protected SH-SY5Y cells fromdamage by A� [589]. It upregulated �-secretase byactivation PI3K pathway in cortical neurons [590].

Curcumin showed potent anti-amyloidogeniceffects for AD A� fibrils in vitro and in vivo [591–605].Clinical trials in AD patients showed disappointingresults [350, 600, 606]. A novel nanoparticle for-mulation of curcumin (NanoCurc) was developed atthe Indiana University School of Medicine [607].For curcumin-decorated nanoliposomes see [608].Structure-activity relationships of A� aggregationinhibitors based on the curcumin scaffold were pre-sented [609–611].


DL-3-n-butylphtalide (NBP Pharmaceuticals,Hebei China) is a natural antioxidant extracted fromseeds of Apium and a powerful free radical scavenger[413]. It protected dopamine neurons in a rotenonemodel for PD [414].

DX-9386 is a traditional Chinese medicinalprescription, which improved thymectomy-inducedimpairment of learning behaviors in mice [612].

Ecdysterones, steroidal hormones in insects andterrestrial plants, inhibited A� aggregation, disaggre-gated preformed fibrils, and inhibited A�42-inducedcytotoxicity [613].

(-)-Epigallocatechin-3-gallate (EGCG; Sunphe-non) present in green tea reduced A�-mediatedcognitive impairment presumably via flavonoid-mediated presenilin-1 phosphorylation, whichreduced A� production [614–616]. EGCG preventedlipopolysaccharide-induced elevation of A� gener-ation [617]. EGCG remodeled mature �-synucleinand A� fibrils and reduced cellular toxicity [618].The cell signaling pathways and iron chelation weredescribed [582, 619–624]. Also ERK and NF- κBpathways are involved [617]. The structural propertiesof EGCG-induced, nontoxic AD A� oligomers weredescribed [625]. EGCG functions through estrogenreceptor mediated activation of ADAM10 in thepromotion of non-amyloidogenic processing of A�PP[626, 627]). A special formulation of EGCG innanolipidic particles to improve its bioavailability waspresented [628]. See also Part 1, Chapter 1.9. Drugsinteracting with estrogen receptors and Part 1, Fig. 10.

ESP-102, a standardized combined extract ofAngelica gigas, Saururus chinensis, and Schizandrachinenis, significantly improved scopolamine-inducedmemory impairment [629] and A�1-42-induced mem-ory impairment in mice [630].

An aqueous extract of Eucommia ulmoidesOliv. Bark (EUE) showed beneficial effects on learn-ing and memory impairments in mice [631].

Flavonoids in AD and neuroinflammation werediscussed in depth [621, 632–635]. Some act as acetyl-cholinesterase inhibitors [636]. Biflavanoids weresuperior to monoflavonoids in inhibiting A� toxicity[637].

Fortasyn Connect is a multi-nutrient diet com-prising docosahexanoic acid (DHA), eicosapentenoicacid, uridine-mono-phosphate, choline, phospholipids,folic acid, vitamins B6, B12, C, and E and sele-nium. It reduced AD-like pathology in young adultA�PPSWE/PS1dE9 mice [638].

Fulvic acid inhibited aggregation and promoted dis-assembly of tau fibrils associated with AD [639].

Gallic acid from grape seed polyphenol extract maybe useful for the treatment of AD [583].

Garlic extract attenuated the cytotoxicity of A� onundifferentiated PC12 cells [640] and suppressed lipidperoxidation induced by A� in PC12 cells [641]. Itprotected against A�-induced apoptosis [642]. Garlicextract inhibited A� fibril formation and defibrillatedA� preformed fibrils [643]. Aged garlic extract ame-liorated the early cognitive deficits in Tg2576 mice[644, 645]. A review on the “aged garlic extract” waspublished [646].

Gastrodin protected primary cultured rat hip-pocampal neurons against amyloid-� peptide-inducedneurotoxicity via ERK1/2-Nrf2 pathway [1710].

Ginger root extracts (Zingiber officinale, Cog-nition Therapeutics) effected inhibition of A�42aggregation (Thomson Reuters Pharma, update of May23, 2012).

Gingko biloba (EGb 761, Tanakan, Tanamin) treat-ment prevented age-related spatial memory deficits ina transgenic mouse model of AD [647]. It enhancedadult hippocampal neurogenesis and phosphorylationof CREB [648]. For reviews on Ginkgo biloba extractand CNS functions, see [649, 650]. For results of clin-ical studies, see (in chronological order) [651–665].

Grape-derived polyphenolics from Vitis viniferagrape seeds attenuated cognitive deterioration in amouse model of AD [666]. Ultrastructural alterationsof AD paired helical filaments by grape seed-derivedpolyphenols was studied [667].

Guanosine protected human neuroblastoma cellsfrom oxidative stress and toxicity induced by A� pep-tide oligomers [668].

Hederacolchidide-E from Pulsatilla koreanashowed cognition-enhancing and neuroprotectiveeffects by reversing scopolamine-induced cognitiveimpairments in rats. It increased viability of humanneuroblastoma SK-N-SH cells incubated with A�42[536].

Heme prevented A�1-40 aggregation and its cyto-toxicity [669].

Hopeahainol A attenuated memory deficits by tar-geting amyloid-� in APP/PS1 transgenic mice [1711].

HSH-971 (Ocean University of China, Shandong)is a marine sulfated oligosaccharide for the potentialtreatment of AD [670]. (Thomson Reuters Pharma,update of November 7, 2011).

HX-106 (HX-106N; ViroMed Co., Seoul) is anatural product inhibiting acetyl-cholinesterase forthe potential treatment of AD (Thomson ReutersPharma, update of June 13, 2012). The structure wasnot disclosed.


Hyperoside protected primary rat cortical neu-rons from neurotoxicity induced by A� via thePI3K/Akt/Bad/Bcl(XL)-regulated mitochondrialapoptotic pathway [671].

IB-10C179(Instituto Biomar, Leon, Spain) is acompound derived from marine organisms which pro-tected primary neurons from apoptosis and reducedfree radical production (Thomson Reuters Pharma,update of March 7, 2012). The structure was notcommunicated.

Icariin is a flavonoid isolated from Epimediiherba. It inhibited A�25-35 induced expression of�-secretase in rat hippocampus [672]. It attenuatedA�-induced neurotoxicity by inhibition of tau pro-tein hyperphosphorylation in PC12 cells [673]. Itattenuated lipopolysaccharide-induced microglial acti-vation and resultant death of neurons by inhibitingTAK1/IKK/NF-κB and JNK/p38 MAPK pathways[674]. It improved memory impairment in AD modelmice and attenuated A�-induced neurite atrophy [675].There seems to be a synergistic effect to improve learn-ing and memory deficits in rats by co-administrationof Icariin and Panax notoginseng saponins [676].

IDN-5706, a hyperforin derivative, decreased thecontent of acetylcholinesterase associated with dif-ferent types of A� plaques in 7-month-old doubleA�PPSWE/PS1 transgenic mice after treatment withIDN 5706 for 10 weeks [677].

Kaempferol protected PC12 and T47D cells fromA� toxicity [581, 678, 679].

Loganin isolated from Cornus officinalis showedcognitive-enhancing activity in scopolamine-inducedamnesic mice [680].

Luteolin exerted ameliorating effects on A�-induced impairment of water maze performance andpassive avoidance in rats [681–684].

Medical Food Cocktail consisting of the dietarysupplements curcumin, piperine, epigallocatechin gal-late, �-lipoic acid, N-acetylcysteine, B vitamins,vitamin C, and folate administered for 6 months toTg2576 mice resulted in improvement of cognitivefunctioning [685].

Melatonin inhibited AD �-fibrillogenesis[686–689]. The neuro-protective activities ofmelatonin against the A� are not mediated by mela-tonin membrane receptors. The role of melatonin inAD-like neurodegeneration was described [690–693].Melatonin facilitated short-term memory [694].

Menthol exerted a protective effect on A�-inducedcognitive deficits in mice [695].

Morin destabilized A�42 protofibrils [696]. It inhib-ited the early stages of A� aggregation [697]. It

attenuated tau hyperphosphorylation by inhibitingGSK-3� [698].

Myrcetin is a naturally occurring regulator of metal-induced A� aggregation and neurotoxicity [699, 700].

Naringin showed memory enhancing activity inmice [701].

NeurocentRX Pharma is investigating a naturalproduct-based compound for the treatment of cognitivediseases (Thomson Reuters Pharma, update of Febru-ary 17, 2012).

Nordihydroguaiaretic acid inhibited growth aris-ing from direct A� protofibril association [599, 702,703].

O4 (an orcein-related small molecule) was able toconvert toxic A� oligomers to nontoxic �-sheet-richamyloid fibrils [704].

Obovatol, a biphenolic compound isolated fromMagnolia obovata, attenuated scopolamine-inducedcognitive dysfunctions [705], improved cognitivefunctions in animal models of AD [706], andattenuated LPS-induced memory impairments in micevia inhibition of NF-κB signaling pathway [707, 708].

Oleuropein and derivatives from olives were recog-nized as tau aggregation inhibitors [709].

Oren-gedoku-to exerts its potential use for thetreatment of AD as a weak, reversible inhibitor ofindoleamine-2,3-dioxygenase [710].

Oroxylin A is a flavonoid compound that is found inthe root of Scutellaria baicalensis Georgi. It attenuatedthe memory impairment induced by transient bilateralcommon carotid artery occlusion in mice [711].

1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranoseis the active constituent of the traditional medicinalherb Paeonia suffruticosa. It showed potent A�anti-aggregation effects in vitro and in vivo [712].

Piceatannol showed protective effects against A�-induced neuronal cell death [713].

Pinocembrin, a flavonoid abundant in propolis, pro-tected against A�-induced toxicity in neurons [714].

Polyphenol derivatives (Pharma Eight, Nagoya)probably interacted with A� through � – � stackinginteractions via the aromatic amino acids of A� [715].For a review, see [716] (Thomson Reuters Pharma,update of January 13, 2011).

Procyanidins extracted from the lotus seedpodreversed memory impairment in cognitively impairedaged rats associated with decreased hippocampalCREB phosphorylation [717, 718].

Prosopis cineraria (L.) Druce (Leguminosae), aplant of the Thar Desert of India and Pakistan, is usedtraditionally by local people for the treatment of mem-ory disorders and to arrest wandering of the mind.


The extract exerted significant nootropic activity in theMorris water maze test, which may be attributed to theinhibition of brain acetylcholinesterase [719].

Puerarin, a phytoestrogen isolated from Puerarialobata, attenuated A�-induced cognitive impairment[720–723, 1712].

Quercetin-O-glucuronide significantly reduced thegeneration of amyloid-� peptide [1713].

Pycnogenol protected neurons from A�-inducedapoptosis [724].

Quercetin showed protective effects against A�42in primary neurons [586, 725]).

Rosmarinic acid protected PC12 cells fromA�-induced neurotoxicity [599, 726]. Subchronicadministration of rosmarinic acid, a natural prolyloligopeptidase inhibitor, enhanced cognitive perfor-mance [727].

Rutin inhibited A� aggregation and cytotoxicity,attenuated oxidative stress, and decreased the produc-tion of nitric oxide and proinflammatory cytokines[728].

Saffron from Crocus sativus had an inhibitory effecton A� aggregation [729, 730]. It was administeredto 46 patients with probable AD in a 16-week dou-ble blind study (15 mg twice a day). Saffron was safeand effective [731]. A 22 week study corroborated thefirst results [732]. Saffron may be a source of novelacetylcholinesterase inhibitors [733].

Salidroside showed neuroprotective effects againstA�-induced oxidative stress in SH-SY5Y human neu-roblastoma cells [734].

S-allyl-L-cysteine, the main constituent of garlic,protected against A�-induced apoptosis and attenuatedcaspase-3 activation, DNA fragmentation and PARPcleavage [648]. It exerted protective effects on A�-induced cell death in NGF-differentiated PC12 cells[735] and protected against A�-induced neurotoxic-ity in organotypic hippocampal cultures [736]. For areview on garlic extract and one of its active ingredi-ents, S-allyl-L-cysteine, see [646].

Silibinin, a flavonoid derived from Silybum mar-ianum, prevented memory impairment induced byA�25-35 in the Y-maze and novel object recognitiontests in mice [737].

Sinapic acid is a phenylpropanoid compound withanti-inflammatory and neuroprotective effects in amouse model of A�1-42 protein-induced AD [738].

Souvenaid (Nutricia, Chatel-St-Denis, Switzer-land) is a mix of nutrients including the omega-3fatty acid docosahexanoic acid, uridine monophos-phate, and choline, dietary precursors for the synthesisof phospholipids. Two clinical trials, Souvenir I, which

lasted 12 weeks, and Souvenir II, which lasted 24weeks, were concluded [739–741].

Substance P, the tachykinin undecapeptide, pro-tected cerebellar granule cells against A�-inducedapoptosis [742].

Syringin from the dried stem barks of Fraxinusrhynchophylla protected against A�-induced toxicityin neuronal cells [743].

Tannic acid destabilized A� fibrils in vitro [744,745]. It is a natural �-secretase inhibitor [746].

�-Tocopherol quinone inhibited A� aggregationand cytotoxicity, disaggregated preformed fibrils anddecreased the production of ROS, nitric oxide, andinflammatory cytokines [747].

Thymol showed cognitive-enhancing activity in tworat models of dementia [580].

Total coptis alkaloids produced a protective effecton A�25-35-induced learning and memory dysfunctionin rats [748].

Ursolic acid attenuated A�-induced apoptosis in adose dependent manner [749].

Vitamin A has anti-oligomerization effects on A�in vitro [750].

Vitamin B12 deficieny is associated with cognitiveimpairment [1714]. Vitamin B12 supplements admin-istered orally or parenterally at high dose (1 mg daily)were effective in correcting biochemical defiency, butimproved cognition only in patients with pre-existingvitamin B12 deficiency [1715].

Vitamin D defiency is associated with increasedodds of cognitive impairment [1716–1718].

Withania somnifera (also known as Ashwagandha,an Indian ginseng) is a nootropic agent promotingcognition including memory [751]). W. somniferaadministered once daily over 30 days reversed behav-ioral deficits, plaque pathology, accumulation of A�peptides and oligomers in the brains of middle-agedand old A�PP/PS1 AD mice. Enhanced expression oflow-density lipoprotein receptor-related protein (LRP)in brain microvessels and the A� degrading proteaseneprilysin occurred 14–21 days after a substantialdecrease in brain A� levels [752].

Wuzi Yanzong Granule improved memory func-tions in patients with MCI [753].

Yokukansan (TJ-54), a traditional Japanese herbalmedicine, was tested in clinics for potential anti-dementia effects [754]. Spatial memory in a rat modelof early AD was improved [755].

Zokumei-to (ZMT) attenuated A�25-35-inducedmemory impairment [756].

The Central Drug Research Institute (India) wasdeveloping bacosides A and B, which are saponin


nootropic agents. The compounds were in Phase IIclinical evaluation, but it appears that the developmentwas terminated. Also the development of CBNU-06 (Chungbuk University), DCB-AD1 (DevelopmentCenter for Biotechnology), dysiherbaine (DaiichiSuntory Biomedical Research Co., a compound iso-lated from the Micronesian sponge Dysidea herbacea[757]), of the nordihydroguaiaretic acid derivativeEM-4232 (Eromos Pharmaceutical LLC), HSS-808, HSS-818, HSS-838, HSS-848 and HSS-888(HerbalScienceLLC Singapore; standardized turmericcurcuma longa extracts), of LHM-123 (Mazal PlantPharmaceuticals), MDF-004 and MDF-005 (NeuronBioPharma), and of YY-1224 and YY-1824 (Yuyu;orally available terpene trilactones extracted fromGinkgo biloba [758]) was terminated.

NOOTROPICS (“DRUGS WITHOUTMECHANISM”)

In this chapter compounds are described, whosemechanism(s) of action are unknown. Initiation of clin-ical trials was based on positive effects on impairedbrain functions in experimental animals after proof ofgood tolerability.

LSL-001 (Laboratoire S. Lasnier, Etaules, France)is a nootropic compound in Phase II clinical trials sinceJune 2011 for the potential treatment of AD (ThomsonReuters Pharma, update of June 5, 2012). The structurewas not disclosed.

N-251 (Neurokos Inc., Palo Alto, CA) is a com-pound of an undisclosed mechanism of action forthe potential treatment of AD. Phase II clinical trialsstarted in May 2009 (Thomson Reuters Pharma, updateof January 16, 2012). The structure of N-251 was notcommunicated.

PF-03049423 (Pfizer) is a neurorestorative com-pound for the potential treatment of neurologicaldisorders including stroke recovery. In December2010, a randomized, double-blind, placebo-controlledPhase II trial was initiated in the US and in South Korea(n = 240) (Thomson Reuters Pharma, update of August13, 2012). The structure was not communicated.

TPM-189 (Teikoku Pharma USA, San Jose, CA) isa transdermal formulation of a small molecule ther-apeutic for the potential treatment of AD in PhaseII development (Thomson Reuters Pharma, update ofMay 17, 2012). The structure was not communicated.

VI-1121 (VIVUS Inc., Mountain View, CA) is anootropic agent in Phase II clinical trials (n = 50) sinceAugust 2011 in the US (NCT01428362) (Thomson

Reuters Pharma, update of September 9, 2011). Thestructure of VI-1121 was not communicated.

ASP-0777 (Astellas Pharma) is in Phase I clini-cal trials since May 2009 (Thomson Reuters Pharma,update of September 19, 2012). The structure was notdisclosed.

Lilly is developing a small molecule for the treat-ment of cognitive impairment in schizophrenia inPhase I clinical trials since July 2012. (ThomsonReuters Pharma, update of November 13, 2012). Thestructure was not disclosed.

RO-5508887 (Roche) is a nootropic agent inPhase I clinical trials in healthy male volunteers inFrance since October 2011 (Thomson Reuters Pharma,update of August 16, 2012). The structure was notdisclosed.

SEP-363856 (Sunovion Pharmaceuticals, Marlbor-ough MA and Sumitomo Chemical) is an orally activecompound with novel mechanism of action for thetreatment of schizophrenia. The drug is in Phase I in theUS. (Thomson Reuters Pharma, update of November5, 2012). The structure was not disclosed.

TAK-357 (Takeda) is a cognitive enhancer withunspecified drug target in Phase I clinical development(Thomson Reuters Pharma, update of July 30, 2012).The structure was not communicated.

There are currently many nootropic agents in pre-clinical evaluation (in alphabetical order):

AC-0523 (Neuera, a subsidiary of Accera, Broom-field, CO) (Fig. 11) is indicated for the treatmentof mitochondrial dysfunction-related HD (ThomsonReuters Pharma, update of February 15, 2012).

AFX-929 (Afecta Pharmaceuticals; Irvine, CA) is anootropic agent in preclinical development (ThomsonReuters Pharma, update of November 10, 2011). Thestructure was not disclosed.

Alzheimer’s disease therapeutics (Berg Pharma,Nashville TN) are nootropic compounds for the poten-tial treatment of AD (Thomson Reuters Pharma,update of April 17, 2012). The structures were notdisclosed.

Alzheimer’s disease therapeutics (SienaBiotech/Roche) are neuroprotectant compounds for the poten-tial treatment of AD (Thomson Reuters Pharma,update of February 8, 2012). The structures were notdisclosed.

Alzheimer’s disease therapy (Reyon Pharmaceu-ticals, Seoul) is a therapeutic program for the potentialtreatment of AD (Thomson Reuters Pharma, update ofJune 20, 2012). The structures were not disclosed.

AVN-457, AVN-458, and AVN-492 (Avineuro Phar-maceuticals, San Francisco, CA) are nootropic agents


Fig. 11. Nootropics and one peptide.

in preclinical development (All three drugs in Thom-son Reuters Pharma, update of August 19, 2011). Thestructures were not disclosed.

CPC-001 (Chase Pharmaceuticals, Washington,DC) is a compound for the palliative treatment of AD(Thomson Reuters Pharma, update of July 12, 2012).The structure was not communicated.

CWF-0804 (JW Pharmaceutical Corp., ChoongwaeHoldings, Seoul) is a nootropic agent in develop-ment for the Korean and Japanese markets (ThomsonReuters Pharma, update of May 11, 2012). The struc-ture was not disclosed.

D-130 (Envoy Therapeutics, Jupiter, FL) is a com-pound targeting the cortex region of the brain usingbacTRAP technology for the potential treatment ofcognition deficits (Thomson Reuters Pharma, updateof June 1, 2012). The structure was not disclosed.

D-180 (Envoy Therapeutics, Jupiter, FL) is a com-pound targeting the striatum region of the brain usingbacTRAP technology for the potential oral treatmentof PD (Thomson Reuters Pharma, update of September12, 2012). The structure was not disclosed.

GSK-2647544 (GSK) is a neuroprotectant for thepotential treatment of Alzheimer’s disease. In October2012, a single-blind, randomized, placebo-controlled,Phase I trial was expected to begin later that month inAustralia in healthy male subjects (expected n = 16). Atthat time, the trial was expected to complete in April

2013 (Thomson Reuters Pharma, update of November20, 2012). The structure was not disclosed.

J-147 (Salk Institute for Biological Studies)(Fig. 11) is a drug that improved memory in normalrodents and prevented cognitive decline in transgenicmice of AD (Thomson Reuters Pharma, update ofDecember 22, 2011).

JAY 2-22-33 (Medical College of Georgia) (Fig. 11)significantly reduced A� toxicity and improved cogni-tive performances in transgenic AD mice [759].

JWB1-84-1 (Medical College of Georgia) (Fig. 11)is a tertiary amine analogue of choline from the labora-tory of the late Prof. Jerry J. Buccafusco. It produced adose-dependent decrease in the number of errors madeby well-trained AD-transgenic mice in the radial armwater maze test [759, 760].

KD-901 (Kwang Dong Pharmaceutical Co., Seoul)is a nootropic drug in preclinical evaluation (Thom-son Reuters Pharma, update of March 1, 2011). Thestructure was not disclosed.

KU-046 (Kareus Therapeutics and Connexios LifeSciences, Atlanta, GA) is a combination drug, whichdemonstrated significant improvement of cognition(Thomson Reuters Pharma, update of May 29, 2012).The structure was not disclosed.

LNK-3186 and LNK-3248 (AstraZeneca after itsacquisition of Link Medicine Corp., Waltham, MA)are nootropic compounds (For both Thomson Reuters


Pharma, update of July 13, 2012). The structures werenot disclosed.

Maltoyl p-coumarate attenuated cognitive deficitsin rats treated with scopolamine or with A�42 [761].

MeN061016-1 (Lijun International Pharmaceuti-cal, Hong Kong) is a small molecule neuroprotectant(Thomson Reuters Pharma, update of June 26, 2012).The structure was not disclosed.

MPP-26 (M et P Pharma, formerly Mattern Pharma-ceuticals, Emmetten, Switzerland) is an intranasal gelformulation of pregnenolone for the potential enhance-ment of memory (Thomson Reuters Pharma, update ofJanuary 27, 2012).

NNZ-2591 (Neuren Pharmaceuticals, Auckland,NZ) (Fig. 11) is an orally active neuroprotectant dike-topiperazine derivative for the treatment of brain injuryand PD [762] (Thomson Reuters Pharma, update ofAugust 31, 2012).

NXD-9062 (Nymox Pharmaceutical Corp., Quebec)is a neuroprotectant for the potential treatment of AD(Thomson Reuters Pharma, update of February 22,2012). The structure was not disclosed.

NXT-182 (Inception Sciences Inc., San Diego) isa novel small molecule neuroprotectant for the poten-tial treatment of CNS disorders, including Alzheimer’sdisease, Parkinson’s disease and age-related cognitivedecline (Thomson Reuters Pharma, update of October29, 2012). The structure was not disclosed.

OG-635 (Oryzon Genomics, Barcelona) is anootropic agent for the potential treatment of AD andPD (Thomson Reuters Pharma, update of May 31,2012). The structure was not disclosed.

Pentylenetetrazole (Balance Therapeutics, Hills-borough, CA) is investigated for the potential treatmentof cognitive impairment in Down’s syndrome (Thom-son Reuters Pharma, update of September 4, 2012).

PNB-03, PNB-04, and PNB-05 (PharmaNeuro-Boost NV, Limburg, Belgium) are nootropic agents forthe potential treatment of PD (PNB-03), AD (PNB-04),and obsessive compulsive disorders (PNB-05) (Thom-son Reuters Pharma, update of February 1, 2012). Thestructures were not communicated.

PTI-125 (Pain Therapeutics Inc., Austin, TX)reduced A�-related AD pathogenesis by targeting fil-amin A [763] (Thomson Reuters Pharma, update ofAugust 3, 2012). The structure was not communicated.

RP-4000 (Reviva Pharmaceuticals, San Jose, CA)is a small molecule nootropic agent (Thomson ReutersPharma, update of December 27, 2011). The structurewas not communicated.

SEL-103 (Selvita Life Sciences Solutions, Krakow,Poland and Orion, Espoo, FL) is a program inves-

tigating small molecule nootropic agents (ThomsonReuters Pharma, update of July 4, 2012). Structureswere not communicated.

SKL-A4R (SK Biopharmaceuticals, formerly SKLife Science, Fair Lawn, NJ) is a small moleculenootropic agent (Thomson Reuters Pharma, update ofMarch 19, 2012). The structure was not communicated.

TYP-1 (NOBEL ILAC, Istanbul, Turkey) is a smallmolecule neuroprotectant (Thomson Reuters Pharma,update of July 30, 2011). The structure was not com-municated.

The development of ABIO-08-01 (BTG-1640;Abiogen under license from British TechnologyGroup, BTG), ADS-8703 (Adamas Pharmaceuticals),AIP-002 (American Home Products, Wyeth, nowPfizer), AIT-034 (Spectrum Pharmaceuticals, formerlyNeoTherapeutics), Alzheimer’s disease therapeutics(DuPont/Scios), ALE-26015 (Allelix Pharm-Eco LP),aloracetam (Hoechst, now sanofi), Alzene (Bar IlanUniversity and Ivax); AQW-051 (Novartis; Phase IItrials for treatment of schizophrenia and PD are ongo-ing), ASP-2535 and ASP-2905 (Astellas), AVN-397(Avineuro Pharmaceuticals; in Phase II trials for thetreatment of anxiety), AWD-52-39 (Alzneimittel-werke Dresden, elbion), AZD-2858 (AstraZeneca),BCE-001 (4-chloro-phenoxy-acetic acid-1,3-bis(dimethylamino)-2-propylester [764–766]), BD-1054(Russian Academy of Medical Science), BGC-20-0406 (RS-0406; SEN-1269 [767]; Senexis underlicense from BTG under license from Sankyo), BGC-20-0466 (BTG), BGC-20-1178 (Senexis under licensefrom BTG under license from Sankyo), BGC-20-1259(BTG under license from Sankyo), BMS-181168(BMY-21502; Bristol-Myers Squibb [768–770]),BTG-4247 (BTG), BW-394-U (GSK), CG-301338(CrystalGenomics), CL-287663 (KE-748; LederleLaboratories, now Pfizer), of CLL-502 (CLL Pharma),CM-2433 (Cenomed, a subsidiary of Abraxis Bio-Science in collaboration with Medical College ofGeorgia), CX-417, CX-423 and CX-438 (CortexPharmaceuticals), DW-514 and DW-0811 (DaewonPharm), DWJ-209 (Daewoong Pharmaceutical Co.),of the coumarin derivative ensaculin (KA-672;Dr. Willmar Schwabe [771–777]), ETX-6765 (e-Therapeutics), F-94517 (Pierre Fabre), gedocarnil(Bayer Schering Pharma), GM-1416 (GliaMed Inc.),GT-4035 and GT-4054 (Gliatech), HL-026 (HanAllBiopharma), HMR-2420 (Hoechst Marion Roussel,now sanofi), HSB-13 (EncephRx, a spin-out of theSouthern Methodist University and the University ofTexas [1719]), HTC-867 (Wyeth, now Pfizer), IQ200and IQ-201 (Immune Network under license from


the University of British Columbia), JNJ-39393406(Janssen Pharmaceutica), LX-104 (Laxdale, AmarinCorp.), of the MBARC program (EnVivo Phar-maceuticals), MK-0249 (Merck & Co), MK-5757(Merck & Co), MG-19649 (Molecular Geriatrics,now Applied Neuro Solutions), MP-100 (AddictionTherapeutix), MR-708 (Medea Research), NDD-094(Novartis [778]), NeoEA-1001 (neoCodex), nooglutil(Russian Academy of Medical Sciences [779]), NSA-789 (Wyeth, now Pfizer), OF-5858 and OF-6145 (AllRussian Research Institute of Pharmaceutical Chem-istry), Oligotropin (HF-0420; Loyola University ofChicago), Org-31433 (Organon Biosciences, nowMSD OSS BV), PF-05297909 (Pfizer), Prisotinol(CGS-5649B; Ciba-Geigy, Novartis [780–783]), pro-caine hydrochloride (Samaritan Pharmaceuticals),PRX-4001 and PRX-4006 (Proximagen), R-641 andRo-40-1641 (both Roche), RU-47067 and RU-52583(Roussel-Uclaf, now sanofi), sabeluzole (JanssenPharmaceutica NV, Johnson & Johnson [784–789]),SCH-54388 (Schering-Plough, now Merck; a metabo-lite of felbamate), sibopirdine (EXP921; Du PontMerck [790]), silicon-containing pyridylsubstitutedisoxazoles (Latvian Institute of Organic Synthesis),SLV-351 (Solvay Pharmaceuticals, now AbbottLaboratories), SN-104 (Sention), SNK-882 (SanwaKagaku Kenkyusho), SPPI-339 (SPI-339, NEO-339;Spectrum Pharmaceuticals, formerly NeoThera-peutics), SRA-997 (Novartis), ST-587 (BoehringerIngelheim), T-9021 and T-9022 (QRxPharma), TAK-065 (Takeda), tenilsetam (Hoechst Marion Roussel,now sanofi [791, 792]) trifusal (Grupo Uriach),V-0191 (Pierre Fabre) and of Z-4105 (Zambon) wasterminated.

PEPTIDES

Cerebrolysin (Ebewe Pharmaceuticals, Vienna,Austria, launched, available in 1 ml, 5 ml, and 10 mlampoules and in vials of 30 ml and 50 ml for intramus-cular or intravenous injection or intravenous infusion)is “derived through a biotechnological procedure fromhighly purified porcine brain proteins and is com-prised of free amino acids and biologically active,short chain peptides” [793]. Cerebrolysin acted asa presynaptic GABAB receptor agonist [794]. Thenootropic effects of cerebrolysin were investigated indepth [795–799]. Cerebrolysin protected neurons fromischemia-induced loss of microtubule-associated pro-tein 2 [800]. Effects of cerebrolysin on A� depositionin transgenic mice were studied extensively [801–807].

The pharmacology of neurotrophic treatment withcerebrolysin was reviewed [808]. Clinical data werepublished (in chronological order) [793, 809–823].First clinical results of a combination treatment of cere-brolysin and donepezil were reported [824]. Data ofcerebrolysin in AD were compiled [825]. The safetyprofile of cerebrolysin in dementia and stroke trials wasdescribed [826].

Cortexin (Geropharm, St. Peterburg, Russia)is a launched polypeptide with neuroprotective,nootropic and antioxidant properties, for the intra-muscular treatment of central nervous system injurycaused by cerebrovascular accidents, encephalitis,encephalopathies, epilepsy and trauma (ThomsonReuters Pharma, update of October 05, 2012). Thestructure was not communicated.

Davunetide (intranasal, AL-108, NAP, Allon Ther-apeutics, Vancouver) is an 8-amino acid peptide(NAPVSIPQ) derived from the activity-dependentneuroprotective protein. A Phase III clinical trial wasinitiated for the treatment of patients with progres-sive supranuclear palsy in December 2010. A PhaseII clinical trial in AD patients started in January 2007(Thomson Reuters Pharma, update of July 17, 2012).Allon Therapeutics is also developing injectable intra-venous and subcutaneous formulations of davunetide.

There are numerous publications on the extensivepreclinical characterization of davunetide describ-ing protection of the brain against ischemic injuryin rats [827], inhibition of the aggregation of A�[828], decrease of anxiety-like behavior in aging mice[829], reduction of the severity of traumatic headinjury [830], reduction of accumulation of A� andof tau hyperphosphorylation [831–833], stimulationof microtubule assembly [834, 835], enhancementof cognitive behavior in transgenic mice [836]),and improvement in motor function and reductionof �-synuclein inclusions in mice overexpressing�-synuclein [837]. Reviews on davunetide werepublished [838–847]. The effects of davunetide on cog-nition and functional capacity in schizophrenia weredescribed [848] (Thomson Reuters Pharma, update ofSeptember 21, 2012).

AM-111 (XG-102, D-JNKI-1; Auris Medical andXigen, a spin off from the Centre Hospitalier Uni-versitaire Vaudois and the University of Lausanne) isan injectable protease-resistant peptidic derivative ofthe JNK-inhibiting protein IB-1 for the i.v. treatmentof acute sensorineural hearing loss, stroke, and AD[849–852]. A Phase IIb trial for acute sensorineuralhearing loss was initiated in January 2009 (n = 210) andresults are expected in autumn of 2012. Auris Medical


is also investigating a topical gel formulation of AM-111 (Thomson Reuters Pharma, update of August 31,2012).

Etanercept (ENBREL, NK-001; Neurokine Phar-maceuticals, Vancouver) is a recombinant fusionprotein of 934 amino acids (mol. weight: 150 kDa)composed of a dimer of the extracellular portion ofhuman TNFR-2 fused to the Fc fragment of humanIgG1 [853, 854]. A rapid cognitive improvementfollowing perispinal etanercept administration to 15probable-AD patients treated once weekly for 6 monthswas reported [855–857]. See also the commentary[858]. In December 2010, the drug was in Phase IIdevelopment for the potential treatment of neurocogni-tive impairment following coronary artery bypass graftsurgery (Thomson Reuters Pharma, update of July 9,2012).

FGL (ENKAM Pharmaceuticals, Copenhagen,Denmark) is a peptide neural cell adhesion moleculemimetic for the potential treatment of AD and stroke.In December 2011, clinical studies including threePhase I studies, one proof-of-concept Phase IIa studyin AD, and a pilot study in patients recovering fromstroke was planned to begin in 2012 (Thomson ReutersPharma, update of April 23, 2012). Enkam was previ-ously developing FGLL, a peptide neural cell adhesionmolecule mimetic, for the potential intranasal treat-ment of AD and stroke. In May 2005, the drug wasshown to be safe and well tolerated in a Phase I studyfor AD. By December 2011, the drug was no longerbeing developed due to the lack of flexibility for theroute of administration.

Glypromate (Gly-Pro-Glu) is naturally cleavedfrom the N-terminal sequence of IGF-I and displayedneuroprotective actions in vitro and in vivo [859–861].It protected against A�-induced somatostatin depletionin rat cortex [862, 863].

NNZ-2566 (Neuren Pharmaceuticals, Auckland,NZ) (Fig. 11) is an analogue of glypromate withan additional �-methyl-group on the proline moiety,which resulted in an improved half-life and betteroral bioavailability. In March 2012, a randomized,double-blind, placebo-controlled Phase I study wasinitiated in healthy volunteers (n = 32) in Australia.Potential indications are mild traumatic brain injury,Rett syndrome, PD, and AD [864– 867]. Excellent syn-thetic organic chemistry was described [868–871]. InNovember 2012 the IND was filed for a Phase II trial.At that time an application was submitted to the TexasChildren’s Hospital IRB and enrollment was expectedto begin pending approval by the FDA and the TexasChildren’s Hospital IRB. (Thomson Reuters Pharma,

update of November 23, 2012). (Thomson ReutersPharma, update of August 31, 2012). Neuren is alsodeveloping a formulation for intravenous infusion.

There are many peptides in preclinical evaluation forthe potential treatment of AD (in alphabetical order):

AL-408 (Allon Therapeutics, Vancouver) is theorally active D-amino acid derivative of davune-tide (AL-108) and an active element of the PARP-1activating activity-dependent neuroprotective protein(Thomson Reuters Pharma, update of November 9,2011).

Alzimag (IMAGENIUM, Paris, France) is a peptidefor the potential treatment of AD (Thomson ReutersPharma, update of December 22, 2011). The structureof the compound were not communicated.

C3bot peptides (Charite Medical School Berlin andHannover Medical School) are short neuron-specificneuritogenic peptides derived from the C3 exoenzymeof Clostridium botulinum, which transiently activatedRhoA for the potential treatment of neurodegenera-tive disorders including AD, PD, Huntington’s chorea,spinal cord and traumatic brain injury [872–875](Thomson Reuters Pharma, update of June 7, 2012).

COG-112, COG-133, and COG-1410 (CognosciInc., Research Triangle Park, NC) are apoE-mimeticpeptides that showed consistent reduction of both A�deposition and of tau hyperphosphorylation in three tautransgenic mouse models and in two A�PP transgenicmouse models [876, 877] (Thomson Reuters Pharma,update of June 5, 2012 for COG-112 and of September11, 2012 for COG-133 and COG-1410).

G-79 (BN-201; Bionure, Barcelona) is a peptide forthe potential treatment of multiple sclerosis, ALS, AD,PD, and glaucoma (Thomson Reuters Pharma, updateof July 4, 2012).

KIBRA pathway modulators (Amnestix Inc., awholly owned subsidiary of SYGNIS Pharma; Heidel-berg, Germany) offer a new genetic link to cognitionthat may benefit patients suffering from AD. For theassociation of KIBRA and late onset AD, see [878];for enhancement of cognition in anxiety disorders[879] (Thomson Reuters Pharma, update of August14, 2012).

Leptin reduced the accumulation of A� and phos-phorylated tau in rabbit organotypic slices [880–882].The company Neurotez (Bridgewater, NJ) is inves-tigating leptin as an A� synthesis inhibitor for thepotential treatment of AD. The company planned tofile an IND in 2012. Effects of leptin on memoryprocessing were described [883–885]. Leptin inducedproliferation of neuronal progenitor cells [886] (Thom-son Reuters Pharma, update of August 24, 2012).


MT-007 (MT-007-LRPIV; recombinant LRP frag-ments; Socratech LLC, Rochester NY) is produced bystable transfected baby hamster kidney cells express-ing LRP-IV. The preparation improved cerebral bloodflow, learning and memory in a mouse model of AD(Thomson Reuters Pharma, update of April 23, 2012).

Netrin-1 (BioMarin Pharmaceuticals, Novato, CA,under license from the Buck Institute) interacted withA�PP and regulated A� production [887, 888]. Netrin-1 increased soluble A�PP� and decreased A�1-40and A�1-42 levels in a J20 mouse model of AD.An intranasal delivery is planned (Thomson ReutersPharma, update of July 20, 2012).

NNZ-4921 and NNZ-4945 (NRP-2945, an 11-mer;CuroNZ under license from Neuren Pharmaceuticals,Auckland, NZ) are neuronal regeneration peptides forthe potential treatment of multiple sclerosis and motorneuron disease, respectively [889] (Thomson ReutersPharma, updates of June 18, 2012 and September 7,2012, respectively).

NRG-101 (Mind-NRG, Geneva, Switzerland underlicense from ProteoSys, Mainz, Germany) is aninjectable neuregulin peptide for the potential treat-ment of PD, AD, and schizophrenia (Thomson ReutersPharma, update of July 6, 2012).

NT-1 and NT-2 (Neurotez, Bridgewater, NJ) aresmall peptides, which block the interaction betweenmutant presenilin and cytoplasmic linker protein 170(CLIP-170) that is linked to increased A� levels (BothThomson Reuters Pharma, update of June 6, 2012).

NX-210 (Neuronax, Saint Beauzire, France) is thelead compound of a series of peptides for the potentialtreatment of spinal cord injury and other neurologicaldisorders, such as stroke, AD, PD, and traumatic braininjury (Thomson Reuters Pharma, update of June 29,2012). The structure was not communicated.

Pepticlere (DP-68 and DP-74; ProteoTech, Kirk-land, WA) is the name of small molecule nasal sprays,6- to 9-mer peptides that inhibit A� fibril forma-tion (Thomson Reuters Pharma, update of August 22,2012). The structures were not disclosed.

PP-0301 (Hybio Pharmaceutical, Guangdong,China) is a polypeptide for the potential treatment AD(Thomson Reuters Pharma, update of September 20,2011).

RAP-310 (Rapid Pharmaceuticals, Zug, Switzer-land) is a small stabilized receptor active peptidetargeting the CCR5 receptor for the potential treatmentof AD (Thomson Reuters Pharma, update of October1, 2012). The structure was not communicated.

RG-01, RG-09, and RG-018 (ReGen Therapeutics,London) are neuroprotectant peptides from colostrinin

(vide infra) for the potential treatment of neurode-generative diseases including AD (Thomson ReutersPharma, update of June 27, 2012). The structures werenot communicated.

SX-AZD1 (Serometrix, Pittsford, NY) is a peptidemimetic interacting with APOE4 (Thomson ReutersPharma, update of July 29, 2011). The structure wasnot communicated.

XD4 is a heptapeptide isolated from a Ph.D.-C7library through phage display that rescued memorydeficits in AD transgenic mice by significantly inhibit-ing A�42-induced cytotoxicity, increasing microglialphagocytosis of A�, and decreasing A�-induced gen-eration of ROS and nitric oxide [890].

Colostrinin (ReGen Therapeutics, London) is apolypeptide complex isolated from ovine colostrumcontaining a high proportion of proline (25%) andhydrophobic amino acids (40%). It is composed ofpeptides of molecular mass up to 3,000 Da. It reducedaggregation of A� [891, 892] and alleviated A�-induced toxicity [893]. It facilitated learning andmemory in rats [894] and chicks [895]. Effects on geneexpression were described [896]. Clinical results werepresented (in chronological order) [897–901]. Reviewson colostrinin were published [902, 903].

The development of colostrinin for the treatmentof AD patients was discontinued. The compound waslaunched as a nutraceutical in Australia in July 2007(Thomson Reuters Pharma, update of May 17, 2011).

The development of ANA-1 and ANA-5 (AlzhymePty; phage peptides, which bind to A� to inhibit its gen-eration of hydrogen peroxide [904]), adrenomedullinpeptides (National Institutes of Health), AS-602704(Merck Serono under license from Axonyx), C-AVP-(4-9) (Yakult Central Institute for MicrobiologicalResearch), ebiratide (Hoe-427; Hoechst, now sanofi;an ACTH (6-9) derivative [905–907]), gilatide(a nonapeptide of Axonyx under license fromThomas Jefferson University), metallothionein (Neu-rosciences Victoria and the University of Tasmania[908, 909]) and of noopept (GVS-111, SGS-111;DVD-111; Saegis Pharmaceuticals under license fromthe Russian Academy of Sciences; a nootropicdipeptide analogue of piracetam [910–920]) wasterminated. The development of NC-1900 (Nip-pon Chemiphar, the active fragment analog ofarginine vasopressin [921–925]), PR-21C (Phar-maxon; a polysialylated form of the neural celladhesion molecule) and of RGX-100 and RGX-200 (RemeGenix Inc., Cortica Neuroscience; A�production-inhibiting BRI2-derived peptides for theintranasal administration to AD patients [926–933])


was discontinued. The development of SEM-606 (Uni-versity of Manchester) and of TKP-1001 (EUSAPharma, formerly Tasliker under license from TheOpen University) was terminated.

DRUGS PREVENTING AMYLOID-�AGGREGATION

Plasma A� levels can be linked directly to spe-cific cognitive changes that constitute the conversionfrom MCI to AD [934–939]. The relationship betweenatrophy and A� deposition in AD was investigatedthoroughly [940–942]. A review of the literature cor-relating Alzheimer disease neuropathologic changeswith cognitive status was provided [947]. The molecu-lar and neurophysiological mechanisms of amyloid-�and cognition in Alzheimer’s disease were outlined[1720]. A rapid decline of memory in healthy olderadults with high amyloid-� load was described [1721],which was more important than ApoE genotype[1722]. Cognitive decline in adults with high amyloid-� load was evaluated [1723]. A� assemblies mediatedrapid disruption of synaptic plasticity and memory[943]. The topic “A� toxicity in Alzheimer’s disease”was reviewed [944, 945]. A critical review on the amy-loid cascade hypothesis was published [946]. AlthoughA� plaques may play a key role in AD pathogenesis,the severity of cognitive impairment correlates bestwith the burden of neurofibrillary tangles [947]. Thekey interactions of apolipoprotein E and A� pathologywere reviewed [948].

The inhibition and reversion of A� misfolding andaggregation is an approach, which has been followedup by many research groups during years. Excellentreviews dealing with this subject were published (inchronological order) 1996: [949], 1998: [950, 951],1999: [952–956], 2001: [957], 2002: [958–960], 2005:[961, 962], 2006: [963], 2007: [964, 965], 2009: [495,966–968], 2010: [969–971], 2011: [972, 973], 2012:[974–976].

Tafamidis (PF-06291826, Fx-1006, Vyndaquel,Pfizer following its acquisition of FoldRx Pharma-ceuticals under license from the Scripps ResearchInstitute) (Fig. 12) is small-molecule transthyretin sta-bilizer for the oral treatment of transthyretin familialamyloid polyneuropathy [977–980]. The drug wasapproved by EMA in November 2011 was launchedin Europe in March 2012 [1724]. In June 2012, theFDA issued a complete response letter and requestedthe completion of a second efficacy study. For the iden-tification of A� binding sites on transthyretin see [981];

for transthyretin amyloidosis see [982, 983] (ThomsonReuters Pharma, update of September 25, 2012).

Eprodisate (1,3-propanedisulfonate disodium salt;NC-503, Fibrillex, Kiacta; Celtic Therapeutics, St.Thomas VI under license from Bellus Health) (Fig. 12)is an orally active sulfated glycosaminoglycan mimeticdesigned to inhibit the formation and deposition ofamyloid fibrils. A Phase III study was initiated inDecember 2010 for the treatment of renal disease inpatients with AA amyloidosis [984–987] (ThomsonReuters Pharma, update of September 5, 2012).

For ARC-029 (Archer Pharmaceuticals, RoskampInstitute, Sarasota, FL; Phase III clinical trials),see Chapter 7, Drugs interacting with Ion Channels( /= Receptors).

For Davunetide (intranasal of via i.v. or s.c admin-istration; Allon Therapeutics, Vancouver, Phase IIIclinical trials), see Chapter 15, Peptides.

For APH-0703 (Aphios Corp., Woburn MA), ananoparticle formulation of APPH-9601 in Phase IIclinical trials since May 2010 (Thomson ReutersPharma, update of July 5, 2012), see Part 2, Chapter2.35, Drugs interacting with Protein Kinase C.

Doxycycline hyclate (Fondazione IRCCS Policlin-ico San Matteo, Pavia, Italy) is in a Phase II study(NCT01171859) in patients with transthyretin amy-loidosis (n = 40) since July 2010. At oral doses of200 mg for three months, doxycycline produced asignificantly lower decline in the ADAScog scores in101 mild-to-moderate AD patients [988] (ThomsonReuters Pharma, update of April 27, 2012).

ELND-005 (AZD-103; scyllo-inositol; scyllo-cyclohexanehexol, Elan, Dublin, Ireland, and EllipsisNeurotherapeutics, formerly Transition Therapeutics,Toronto, Canada) (Fig. 12) is an orally availableinhibitor of A� peptide aggregation. Results of a PhaseII dose-ranging, randomized, placebo-controlled studyin 351 patients with mild-to-moderate AD treated for78 weeks with either 250, 1,000, or 2,000 mg/day werereported. Patients with mild AD receiving 250 mg ofELND-005 had higher scores on the Neuropsycho-logical Test Battery compared with placebo, whichwere significant. In contrast ADCS-ADL scores werenot significant. The two higher doses were discon-tinued [989]. In August 2012, a Phase II studywas initiated in bipolar disorder patients in the US.The study is expected to be completed in August2014 (Thomson Reuters Pharma, update of September14, 2012).

The endogenous brain inositols stabilized smallaggregates of A�, which are non-toxic to NGF-differentiated PC-12 cells and primary human neuronal


Fig. 12. Drugs interacting with amyloid-�.


cultures [990]. In particular scyllo-inositol, whengiven orally to transgenic mice, reversed AD phe-notype, improved impaired cognition, and alteredcerebral A� pathology [991, 992]. Scyllo-inositoldose-dependently rescued long-term potentiation inmouse hippocampus from the inhibitory effects of sol-uble oligomers of cell-derived human A� [993, 994].Elevated scyllo-inositol concentrations were found inpatients with AD [995].

Syntheses of scyllo-inositol derivatives have beenreported [996]. The synthesis of the PET ligand [18F]-1-deoxy-1-fluoro-scyllo-inositol was described [997].A comparison of three amyloid assembly inhibitors,scyllo inositol, epigallocatechin gallate and the molec-ular tweezer CLR01 (vide infra) was published[998].

SOM-0226 (SOM Biotech SL, Barcelona) is a drugfor the potential treatment of transthyretin amyloido-sis in Phase II clinical development (Thomson ReutersPharma, update of May 30, 2012). The structure wasnot communicated.

For AAD-2004 (GNT Pharma, Suwon, SouthKorea) in Phase I clinical trials (Thomson ReutersPharma, update of May 4, 2012). See Part 2, Chap-ter 2.34. Drugs interacting with Prostaglandin D & ESynthases, Part 2, Fig. 22.

Beta amyloid modulator (Medipost, Seoul) is inPhase I clinical trials in South Korea since Septem-ber 2011 for the potential treatment of AD (ThomsonReuters Pharma, update of May 7, 2012). The structurewas not communicated.

BLU-8499 (formerly NRM-8499; Bellus Health,formerly Neurochem, Quebec) is a prodrug oftramiprosate (vide infra). It was evaluated in a single-center, randomized, double-blind, placebo-controlledPhase I study in 84 young and elderly healthy subjectsto assess safety, tolerability and pharmacokinetics,which started in March 2010. The data were reportedin January 2011. It showed improved gastrointesti-nal tolerability and lower inter-individual variabilityof drug exposure compared to comparable doses oftramiposate (Thomson Reuters Pharma, update ofSeptember 5, 2012).

DWP-09031 (presumed to be DWJ-301; DaewongPharmaceutical Co. in collaboration with Medifron,both South Korea) inhibited the production and aggre-gation of A�. By January 2012, the Korean FDAhad approved an IND for a Phase I trial. Therandomized, double-blind, placebo-controlled study(NCT01522586) is planned in healthy male volun-teers (n = 64) to assess the safety, pharmacokinetics andpharmacodynamics of DWP-09031 (Thomson Reuters

Pharma, update of July 27, 2012). The structure wasnot disclosed.

For Exebryl-1 (ProteoTech, Kirkland, WA andChina licensee Tasly Pharmaceuticals; in Phase I clin-ical trials), see Chapter 13, Natural Products.

For NP-61 (NP-0361; Noscira, previously Neu-ropharma, Madrid; Phase I clinical trials; ThomsonReuters Pharma, update of May 10, 2012), see Part2, Chapter 2.1.1.2., Dual acetylcholinesterase and A�inhibitors.

Systebryl (ProteoTech, Kirkland, WA) is the leadof a series of small molecules including PTI-19 andPTI-51 for the potential treatment of systemic AA amy-loidosis. In December 2011, Systebryl was in Phase Istudies (Thomson Reuters Pharma, update of Decem-ber 21, 2011). Structures were not communicated.

There are many A� aggregation inhibitors in pre-clinical evaluation (in alphabetical order):

Alzheimer’s disease therapeutics (BioChromixPharma AB, Solna, Sweden) are compounds, whichachieved a significant reduction in plaque load andneurotoxic A� aggregates. (Thomson Reuters Pharma,update of August 24, 2012). The structures were notcommunicated.

A� oligomer cellular prion protein bindinginhibitors (AstraZeneca under a sublicense from Axe-rion Therapeutics under license from Yale University)are interacting with the cellular prion protein, thehigh affinity receptor for A� oligomers [999–1003](Thomson Reuters Pharma, update of August 17,2012). No structures were disclosed.

A� protein inhibitors (Neuropore Therapies, SanDiego CA) are peptidomimetic compounds that inter-fere with A� aggregates (Thomson Reuters Pharma,update of July 16, 2012). Structures were not commu-nicated.

A�/tau protein aggregation inhibitors (CNRS,FIST SA, Paris, France) are investigated for the poten-tial treatment of AD (Thomson Reuters Pharma, updateof August 24, 2012). Structures were not communi-cated.

Amyloid-derived diffusible ligands are investi-gated by Merz Frankfurt, Germany under license fromAcumen Pharmaceuticals (Thomson Reuters Pharma,update of June 12, 2012). The structures of the com-pounds were not communicated.

ARN-4261 (New York University and Aria Neu-rosciences, Hamden CT) (Fig. 12) and ARN-2966(Fig. 12) are inhibitors of A� aggregation. ARN-2966reduced A� deposition and memory deficit in trans-genic mice. Following treatment a significant 25%reduction in A� plaque load was noted compared with


mice that received a vehicle control. The data demon-strated that ARN-2966 was biostable and well toleratedin transgenic mice with blood-brain barrier penetra-tion after both oral and intravenous dosing (ThomsonReuters Pharma, update of August 28, 2012).

AVCRI-104P4 (University of Barcelona) (Fig. 12)inhibited A� aggregation including acetylcholines-terase- and self-induced-A� aggregation, �-secretase,acetylcholinesterase, and butyrylcholinesterase (Tho-mson Reuters Pharma, update of September 28, 2012).

AVN-457, AVN-458 and AVN-492 (Avineuro Phar-maceuticals, San Francisco) are nootropic agents forthe potential treatment of cognitive disorders (Thom-son Reuters Pharma, update of October 22, 2012). Thestructures were not disclosed.

AZP-2006 (AlzProtect, Loos, France in collabora-tion with INSERM and the University of Lille II) is anA�PP modulator of undisclosed structure (ThomsonReuters Pharma, update of July 4, 2012).

Beta-amyloid aggregation inhibitors (MedisynTechnologies, Minnetonka, MN / Mount Sinai Schoolof Medicine) demonstrated significant A�-loweringand anti-aggregation activity in vitro. Two compoundsalso reduced the amount of A� in mouse brain in vivo(Thomson Reuters Pharma, update of June 21, 2012).Structures were not communicated.

Beta-amyloid/alpha-synuclein/tau aggregationinhibitors (Snowdon Inc., Vancouver) are expectedto enter Phase I trials in 2012 (Thomson ReutersPharma, update of August 19, 2011). The structuresof the compounds were not communicated.

Beta amyloid beta sheet formation inhibitors (ACImmune, Lausanne, Switzerland) are small molecules,which inhibited the aggregation of A� to oligomericand fibrillar species for the potential treatment of ADand glaucoma [1004]. Two 3-aminopyrazole moietiescarrying additional aryl substituents were connectedvia a linker. The concept of 3-aminopyrazoles with adonor-acceptor-donor hydrogen bond pattern compli-mentary to that of the �-sheet of A�42 was first investi-gated by Schrader and colleagues [1005–1013] (Thom-son Reuters Pharma, update of September 24, 2012).

Beta-amyloid inhibitor (Icogenex, Seattle, WA) isa small molecule therapeutic that normalizes the pro-duction of A� (Thomson Reuters Pharma, update ofJune 26, 2012). The structure was not disclosed.

Beta-amyloid inhibitor (Star Scientific, Glen AllenVI through its subsidiary Rock Creek Pharmaceuticalsin collaboration with the Roskamp Institute) reducedA� when applied to cells (Thomson Reuters Pharma,update of January 3, 2012). The structure was notdisclosed.

Beta-amyloid modulators (Crossbeta Biosciences,Utrecht, The Netherlands) are small molecules, whichtarget A� oligomers and misfolded proteins (ThomsonReuters Pharma, update of August 24, 2012). Struc-tures were not communicated.

Beta-amyloid precursor protein modulators(Alzcor Pharmaceuticals, Arlington, MA) are inves-tigated for the potential treatment of AD (ThomsonReuters Pharma, update of July 27, 2011). Structureswere not disclosed.

BMS-869780 (Bristol-Myers Squibb) (Fig. 12)reduced A�42 levels in transgenic mice at oral dosesand displayed an IC50 value at A�42 in the lownM range. It was not hepatotoxic (Thomson ReutersPharma, update of August 6, 2012).

BTA-EG4 (Johns Hopkins University and George-town University) is a benzothiazole aniline derivativeand amyloid-� synthesis inhibitor for the potentialtreatment of Alzheimer’s disease (Thomson ReutersPharma, update of October 30, 2012). The structurewas not communicated.

C36 (Medisyn Technologies, Minnetonka, MNin collaboration with the Mount Sinai School ofMedicine) is an A�40 and A�42 lowering smallmolecule for the potential treatment of AD (ThomsonReuters Pharma, update of December 6, 2011). Thestructure was not disclosed.

Caprospinol (SP-233; Samaritan Pharmaceuticals,Las Vegas, NV under license from Georgetown Uni-versity) (Fig. 12), a spirostenol drug, blocked theoligomerization of A�42 exerting a direct effecton mitochondria [1014–1017] (Thomson ReutersPharma, update of March 18, 2011).

Carvedilol is a launched unselective �1, �1 and �2blocker, which inhibited A� fibril formation [1018].

CLR01 (University of Duisburg-Essen, RensselaerPolytechnic Institute, NY and UCLA) (Fig. 12) is amolecular tweezer, which binds to lysine residues withmicromolar affinity and interferes with a combinationof hydrophobic and electrostatic interactions that areimportant in the self-assembly of most amyloidogenicproteins including A�, tau, and �-synuclein [1007,1018–1024].

CLR-097(Clera Inc., Toronto) inhibited the processof A� plaque formation (Thomson Reuters Pharma,update of December 5, 2011). The structure was notdisclosed.

Cotinine, a natural metabolite of nicotine, may be apotential new therapeutic agent against AD [1025]. Itreduced amyloid-� aggregation and improved memoryin Alzheimer’s disease mice [1725].

Daunomycin inhibited A� fibril formation [1018].


DBT-1339 (Medifron, Seoul and licensee Dae-woong, South Korea) (Fig. 12) is the lead compoundfrom A� protein deposition inhibitors (ThomsonReuters Pharma, update of June 1, 2012).

Enoxaparin (Enox, a low molecular weight hep-arin) lowered brain A� load in a mouse model of AD[1026]. It also improved cognition in APPSWE/PS1dE9mice [1027, 1028].

GAG/carbohydrate compounds (ProteoTech,Kirkland, WA) are glycosaminoglycan modulatorsfor the potential treatment of AD (Thomson ReutersPharma, update of June 7, 2012). Structures were notdisclosed.

Galantamine inhibited A� aggregation and cyto-toxicity [1029].

haw-AD-14 (Hawthorn, Madison, Mississippiunder license from CoPlex) is an A� synthesis and tauphosphorylation inhibitor (Thomson Reuters Pharma,update of September 26, 2011). The structure was notcommunicated.

HO-4160 (University of California at Davis)(Fig. 12) is a spin-labeled fluorene compound thatspecifically disrupted A� oligomers [1030].

Imipramine in part through inhibition of TNF-�prevented cognitive decline and A� accumulation in amouse model of AD [1031].

IPS-04001, IPS-04001 and IPS-04003 (InnoPhar-maScreen, South Korea) is a specific inhibitorof A� peptide and VEGF-165 interaction. ByJune 2012, in vivo efficacy studies had shown asignificantly enhanced effect on the memory ofNSE-PS2/N141Ltransgenic mice (Thomson ReutersPharma, update of July 16, 2012). The structure werenot communicated.

KMS-88 series (Hanmi Pharmaceutical, SouthKorea, the Korea Institute of Science and Technologyand Seoul National University) (Fig. 12) is a series ofaminostyryl-benzofuran derivatives inhibiting A� fib-ril formation [1032, 1033] (Thomson Reuters Pharma,update of September 12, 2012).

Minocycline is a second generation tetracyclinethat can effectively cross the blood-brain barrier.It improved cognitive impairment in AD models[1034]. It provided protection against A�25-35 inducedalterations of the somatostatin signaling pathway[1035, 1036]. It reduced microglial activation [1037,1038]) and A� derived neuroinflammation [1039]. Itrecovered MTT-formazan exocytosis impaired by A�[1040]. It reduced the development of abnormal tauspecies in models of AD [1041–1043]. Minocyclineprotected PC12 cells against NMDA-induced injuryvia inhibiting 5-lipoxygenase activation [1044, 1045].

Minocycline improved negative symptoms in patientswith early schizophrenia [1046]. See also Part 2, Chap-ter 2.25. Drugs interacting with 5-Lipoxygenase.

NPT-4003 (Neuropore Therapies, San Diego CA) isthe lead of heterocyclic compounds that interfere withamyloid-� aggregates. Detailed data were presentedat the ICAD Vancouver in July 2012 [1726]. (Thom-son Reuters Pharma, update of July 16, 2012). Thestructure was not communicated.

Rifampicin inhibited A� aggregation and neu-rotoxicity [1047–1049]. In a clinical trial in 101mild-to-moderate AD patients, statistically significantimprovements in the ADAScog scores after treatmentwith 300 mg rifampicin for three months were found[988]. Rifampicin and caffeine caused an upregula-tion of LRP1 [1050]. The brain efflux index of A�in rifampicin and caffeine treated mice was signifi-cantly higher (82% and 80%, respectively) than thebrain efflux index of control mice (62%). It appearsthat a yet to be identified transporter/receptor plays asignificant role in A� clearance, which is upregulatedby rifampicin and caffeine.

Rolitetracycline is effective as inhibitor of A� fibrilformation [1018].

SD-1002 (Synaptic Dynamics, Farmington CT) is alysosomal modulator that reduced protein depositionof amyloid-�1-42 oligomers for the potential treatmentof Alzheimer’s disease (Thomson Reuters Pharma,updates of October 22, 2012). The structure was notcommunicated.

SEN-1500 (Senexis, Cambridge, UK) (Fig. 12) andfollow-up compound SEN-1576 (structure not dis-closed) are small molecule A� aggregation inhibitors[1727] (Thomson Reuters Pharma, updates of March23 and August 2, 2012, respectively).

Small molecule A� modulators (Asceneuron, aspun-out of Merck Serono, Geneva, Switzerland) aredrugs for the potential treatment of AD (ThomsonReuters Pharma, update of October 3, 2012). Structureswere not disclosed.

SP-08 (Samaritan Pharmaceuticals, Las Vegas, NVunder license from Georgetown University) (Fig. 12)is an A� antagonist with neuroprotectant properties(Thomson Reuters Pharma, update of March 18, 2011).

TAK-070 (University of Tokyo under license fromTakeda) is a �-secretase and A� aggregation inhibitor(Thomson Reuters Pharma, update of July 10, 2012).The structure was not communicated.

Tetracycline(s) showed anti-amyloidogenic activ-ity in vitro [1051] and protected Caenorhabditiselegans from A�-induced toxicity by targetingoligomers [1052].


For VP-20629 (Indole-3-propionic acid; OX1; IN-OX1; OXIGON, ViroPharma, Exton PA, under licensefrom Intellect Neurosciences under license from NewYork University and Mindset BioPharmaceuticals;Thomson Reuters Pharma, update of August 10, 2012),see Chapter 11. Antioxidants.

AGT-160 (ArmaGen Technologies, Santa Mon-ica, CA) is a recombinant IgG fusion proteinformed by the fusion of a single chain Fv anti-body against A� plaque formation to the company’shuman insulin receptor-targeting monoclonal anti-body Trojan horse for transport across the blood-brainbarrier for the potential detection and treatment ofAD (Thomson Reuters Pharma, update of January23, 2012). See also Part 1. Chapter 1.16. Insulinreceptors.

EDN-OL1 (Edunn Biotechnology, St. Louis, Mis-souri under license from St. Louis University) is anantisense oligonucleotide targeting A� production,which improved memory and learning in three differ-ent AD mouse models. By February 2012, EDN-OL1had demonstrated activity in patients with Down syn-drome (Thomson Reuters Pharma, update of August24, 2012).

NPT-001 (NeuroPhage Pharmaceuticals, Cam-bridge, MA) is a filamentous M13 bacteriophage thatdisrupted plaque aggregation through binding of A�.Direct binding of M13 bacteriophage to fibrils ofaggregated A� was observed with high affinity of4 nM. In an AD mouse model, A� plaques werereduced by 70% after a single intracranial adminis-tration (Thomson Reuters Pharma, update of July 16,2012).

Spheron-based therapeutics (Nymox Pharmaceu-tical Corp., Quebec) are compounds capable ofblocking the transformation of human spherons intoplaques [1053, 1054] (Thomson Reuters Pharma,update of February 22, 2012).

A�-aggregation inhibitor research programs wereongoing at Elan [1055], at GrenPharma [1056], at GSK[1057, 1058], at Johnson & Johnson [1059], at Pfizer[1060], at Pharmacia-Farmitalia Carlo Erba [1061] andat Scios [1062].

Excellent papers on A� aggregation inhibitors fromuniversities were presented (in chronological order)1995: [1063], 1996: [1064], 1997: [1065, 1066], 2001:[1067], 2002: [563, 1068], 2004: [1069, 1070], 2005:[1071–1073], 2006: [1074–1082], 2007: [1083–1094],2008: [745, 1043, 1095, 1096, 1097–1105] 2009:[1106–1113], 2010: [391, 551, 980, 1114–1117], 2011:[549, 643, 1118–1122] and 2012: [1033, 1123–1129,1728].

Excellent papers on theoretical calculations onA�-aggregation inhibitors were published (in chrono-logical order) 2006: [1130, 1131], 2008: [1066,1132–1134], 2009: [1135–1137], 2011: [1138, 1139][1140, 1141], 2012: [1142–1144].

The Phase III development of tramiprosate(3-amino-1-propanesulfonic acid, homo-taurine, NC-531, Alzhemed, Cerebril; Bellus Health, formerNeurochem), an orally available glycosaminogly-can mimetic, was terminated in 2007 [1145–1151].The compound was launched as a nutraceutical formemory protection [1152]. Also the development ofALS-499 and ALS-633 (Advanced Life Sciences,in collaboration with Argonne National Labora-tory), amyloid beta aggregation inhibitor (Zyentia),amyloid oligomer specific antagonists (Treventis),amyloid protein deposition inhibitor (ProteoTech),AN-531 (Athena Neurosciences, now Elan Phar-maceuticals), AS-602704 (Ac-FPFFD-NH2, MerckSerono [1153]), beta amyloid aggregation inhibitors(Cortex, Elan, Hybridon, Oceanix, Queens Universityat Kingston and University of Wisconsin-Madison),beta-amyloid modulators (Inflame Therapeutics,Neuro-Hitech and Q-RNA), beta-amyloid precur-sor protein modulators (SIBIA Neurosciences incollaboration with BMS), beta amyloid synthesisinhibitors (BTG), CLR-01 (Clear Therapeutics, aspin-off from UCLA), CT-500 (Creabilis Therapeu-tics), ID-1135 and ID-1567 (Bellus Health), lysosomalmodulators (Synaptic dynamics), MPI-442690 andMPI-442691 (Myriad Genetics in collaboration withthe Mayo Clinic), NC-503 and NC-531 (Neu-rochem; Bellus Health), NHT-0112 (Neuro-Hitech),NOX-A42 (Noxxon Pharma), NVP-AAM147 andNVP-AAM155 (Novartis), phenserine-based amy-loid inhibitors (Message Pharmaceuticals), PPI-368,PPI-558 and PPI-1019 (Apan; all Praecis Phar-maceuticals [953, 957]), PTI-777 (ProteoTech),Reumacon (Meda under license from Conpharm),Ro-47-1816-001, Ro-65-7652-000, Ro-65-8564-001and Ro-8815-001 (Roche), RS-1178 (BGC-20-1178;Senexis under license from BTG under licensefrom Sankyo [1154]), RS-0406 (BGC-20-0406;Senexis under license from BTG under license fromSankyo [1155–1158]) and RS-0466 (Sankyo), RX-AD(Rimonyx Pharmaceuticals), SAN-61 and SAN-161(Sanomune, a subsidiary of DiaMedica), Semapimod(CNI-1493; Cytokine PharmaSciences, CPSI, for-merly Cytokine Networks), a cytokine inhibitor, whichinhibited A� production, plaque formation and cogni-tive deterioration in an animal model of AD [39, 40,1729]), SEN-304, SEN-606, SEN-1186, SEN-1203,


and SEN-1329 (Senexis), SIB-1848 (SIBIA Neu-rosciences, now Merck and Bristol-Myers Squibb),SKF-746532 (SmithKline Beecham, now GSK),synthetic anti-beta sheet peptides (Mayo Foun-dation), THUR-24 (Thuris Corp.), transthyretin(Research Foundation of the State University of NewYork), and of VIP-SSM (University of Illinois) wasterminated.

Ligands interacting with amyloid-β

Since the discovery of the 11C-PiB-PET ligand,tremendous progress has been made in the devel-opment of new PET ligands. Considerable evidencesuggests that A� deposition precedes decline in cogni-tion [1159, 1160]. The development of PET amyloid-�imaging agents was described [1730].

11C-PiB (University Pittsburgh) (Fig. 13) had aKD = 1.4 nM for AD frontal cortex and KD = 4.7 nMfor A� fibrils and did not bind to neurofibrillary tan-gles [1161]. The log P value is 1.2 [1162]. Patientswith AD typically showed a marked 11C-PiB reten-tion (with a significant 1.5 to 2-fold increase) incortical areas known to contain large amounts ofA� plaques [1163–1165]. 11C-PiB positivity in MCIindicated already advanced A� pathology [1166].Significant correlations between 11C-PiB retentionand CSF biomarkers were found in MCI patients[1167]. Clinical severity of AD measured by theClinical Dementia Rating scale sum of boxes corre-lated with 11C-PiB uptake in PET [1168]. 11C-PiBimaging of human immunodeficiency virus-associatedneurocognitive disorder was described [1169]. For adirect comparison of 11C-PiB, 18F-Florbetapir, 18F-Florbetaben, and 18F-Flutemetamol, see [1170] fora comparison between Pittsburgh Compound B andFlorbetapir see [1731]. Longitudinal imaging of ADpathology with 11C-PiB, 18F-FDDNP, and 18F-FDGwas described [1171–1173]. For the prediction of cog-nitive decline via PET of brain A� and tau, see [1174].The clinical perspective of imaging of cerebral A�plaques was discussed [1175, 1205]. The correspon-dence between in vivo 11C-PiB-PET and postmortemassessment of plaques was discussed [1176]. Imag-ing brain amyloid in nondemented adults with Downsyndrome using Pittsburgh Compound B was reported[1732].

Fred Van Leuven and coworkers carried out a sys-tematic evaluation of the isomeric compounds withthe OH groups attached in 4, 5, and 7 positions. The5-hydroxy analogue had the most favorable in vivopharmacokinetics in brain [1177, 1178].

18F-Florbetapir (18F-AV-45; Amyvid; AvidRadiopharmaceuticals, Philadelphia, PA, a subsidiaryof Eli Lilly, under license from the University of Penn-sylvania) (Fig. 13) is a launched 18F PET imaging agenttargeting A�. It had a Ki of 2.87 nM, did not bind totau, and can easily be labeled with 18F by an automatedsynthesis [1179–1187]. By March 2010, more than700 patients were enrolled in a Phase III trial presumedto be the 18F-AV-45-A07 study. Several clinical papersappeared describing imaging with 18F-Florbetapir[1188–1195]. Correlations between 18F-Florpetapirand FDG images were reported [1196]. 18F-Florpetapiris useful to quantify brain amyloid load [1197]. Fora direct comparison of 11C-PiB, 18F-Florbetapir, 18F-Florbetaben, and 18F-Flutemetamol, see [1170]; for aclinical comparison of 18F-Florbetapir and 18F-FDGPET in patients with AD and controls, see [1198]. Aprospective cohort study was described [1199].

A longitudinal assessment of 18-month of cognitivedecline in mild cognitive impairment and Alzheimer’sdisease patients using florbetapir was communicated[1733]. “From Alois to Amyvid” see [1734]. PETimaging was also carried out in a murine model ofamyloid-� plaque deposition [1735].

FDA approved 18F-Florpetapir as a PET imag-ing agent to estimate A� neuritic plaque density inpatients with cognitive impairment on April 6, 2012.Lilly launched the imaging agent in June 2012. Thecompound will be manufactured and distributed byCardinal Health [1200] (Thomson Reuters Pharma,update of September 17, 2012).

18F-Florbetaben (18F-BAY 94-9172; 18F-AV-1/ZK; Piramal Healthcare, Mumbai, India from anasset acquisition from Bayer under license from AvidPharmaceuticals and the University of Pennsylvania)(Fig. 13) is the phenyl analogue of florbetapir. It hasa Ki of 2.22 nM [1181]. In November 2009, a PhaseIII clinical trial in AD patients (n = 292) began toassess safety and efficacy of florbetaben to detector exclude cerebral A�. Data from clinical studieswere reported [1201–1208]. An in vitro characteriza-tion was disclosed [1736]. The one-step radiosynthesiswas described [1209], as was the radiation dosimetry[1210]. In the NCT01138111 trial, 18F-FlorbetabenPET imaging was studied in MCI patients. For adirect comparison of 11C-PiB, 18F-Florbetapir, 18F-Florbetaben, and 18F-Flutemetamol, see [1170]; fora comparison of 11C-PiB and 18F-Florbetaben, see[1211]; for the impact of 18F-Florbetaben PET imag-ing on confidence in early diagnosis of AD, see [1212](Thomson Reuters Pharma, update of September 6,2012).


Fig. 13. Radioligands for PET scans of amyloid-�.

18F-Flutemetamol (GE-067; GE Healthcare, Chal-font, UK and Universities of Pittsburgh and Uppsala)(Fig. 13) has a Ki of 0.74 nM [1181]. Results of aPhase I study were reported [1213], as were resultsof a Phase II study [1214, 1215]. In December 2009,a Phase III trial sponsored by GE Healthcare was ini-tiated in the US. By April 2010, Phase III trials werealso underway in Europe. In April 2012, preliminarydata from the two Phase III studies in terminally illpatients and young healthy subjects were reported.Data showed that the primary endpoint was met.Patients (who underwent brain autopsy) showed con-cordance between 18F-Flutemetamol PET images andAD-associated A� brain pathology and healthy sub-jects showed concordance with the known lack of brainA�. The association between in vivo 18F-FlutemetamolPET imaging and in vivo cerebral cortical histopathol-ogy was described [1216], as was a combination ofbiomarkers PET 18F-Flutemetamol and MRI [1217].For a direct comparison of 11C-PiB, 18F-Florbetapir,18F-Florbetaben, and 18F-Flutemetamol, see [1170].Binary classification of 18F-Flutemetamol PET usingmachine learning was disclosed [1218]. The pharma-cokinetics of 18F-Flutemetamol in wild-type rodents

were reported [1219] (Thomson Reuters Pharma,update of October 3, 2012).

18F-AZD-4694 (Navidea Biopharmaceuticals,Dublin, Ohio, formerly Neoprobe Corporation underlicense from AstraZeneca) is an i.v. PET ligand for thepotential imaging of A� depositions in AD in PhaseII development [1220]. In December 2011, a Phase IIIprogram was planned to start in early 2013 (ThomsonReuters Pharma, update of September 21, 2012). Thestructure was not communicated. For syntheses ofadditional 18F-ligands of AstraZeneca see [1737].

BAY-1006578 (Bayer) is in Phase I clinical trials inFinland and Sweden since June 2010 (n = 36). By Octo-ber 2011, the trial was completed (Thomson ReutersPharma, update of April 30, 2012). The structure wasnot communicated. A potential follow up compound isBAY-1008472 [1221].

123I-MNI-168 (Institute for NeurodegenerativeDisorders, IND, New Haven, CT) is a SPECT lig-and to detect A� deposition in patients with AD. APhase I clinical trial was initiated in the US in January2009 (n = 34). In February 2011, the trial was termi-nated (Thomson Reuters Pharma, update of February10, 2012). The structure was not communicated.


18F-MNI-558 (Molecular NeuroImaging in col-laboration with the Institute for Neuro-degenerativeDisorders, IND, New Haven, CT) is a PET agent thatbinds A�. The compound was in a Phase 0 trial in ADpatients and in volunteers (n = 10) from October 2010to July 2011 (Thomson Reuters Pharma, update ofApril 30, 2012). The structure was not communicated.

11C-BF-227 (Fig. 14) was used for amyloid PETimaging [1222–1225], for PET imaging of �-synucleindeposition [1226, 1227], and for in vivo detection ofprion amyloid plaques [1228].

123I-DRM-106 (Fujifilm Pharma) (Fig. 14) isa radioiodinated imidazopyridine derivative for thepotential use as SPECT imaging agent for A� for thediagnosis of AD (Thomson Reuters Pharma, update ofSeptember 21, 2011).

18F-Hexethal (Pfizer, under license from the Uni-versity of Aberdeen), a barbiturate derivative, is an A�imaging agent (Thomson Reuters Pharma, update ofSeptember 24, 2012).

11C-SB-13 (Fig. 14) was evaluated first in post-mortem brain tissues [1229] and in AD patients [1230].

18F-Florbetapir dimer (Avid Radiopharmaceuti-cals, Philadelphia, PA, Eli Lilly) is a PET imagingagent for the potential diagnosis of cerebral amyloidangiopathy [1231] (Thomson Reuters Pharma, updateof May 8, 2012).

Dicyanovinylnaphtalenes were described for neu-roimaging of A� [1232]. Also 18F-labeled benzoxa-zoles [1233] and 18F-labeled 2-pyridinylbenzoxazolesand 2-pyridinylbenzothiazoles were presented for PETimaging of A� plaques [1234].

The development of 11C-AZD-2184 and 11C-AZD-2995 (both AstraZeneca [1235–1237, 1738])and 18F-FDDNP (Siemens Medical Solutions Molec-ular Imaging and UCLA) (Fig. 14) was terminated.18F-FDDNP was the first PET tracer used in vivo fordetection of cerebral A� plaques in 2002 [1238]. 18F-FDDNP binds to A� and neurofibrillary tangles in AD,to prion plaques in Creutzfeldt-Jakob disease, to A�deposits in cerebral amyloid angiopathy, and to Lewybodies in PD and DLB [1161]. It was used for mea-suring amyloid-� and tau levels in adults with Down’ssyndrome [1739]. The ligand is still used for predic-tion of cognitive decline [1174, 1740]. Longitudinalimaging of AD pathology using 11C-PiB, 18F-FDDNP,and 18F-FDG PET was described [1239]. 18F-FDDNPPET allowed a prediction of cognitive decline basedon hemispheric cortical surface maps [1240].

123I-IMPY (Avid Radiopharmaceuticals, Philadel-phia, PA, under license from University of Pennsylva-nia, Fig. 14) is a SPECT ligand for imaging studies

[1241, 1242]. Its Ki is 15 nM [1243]. The safety andbiodistribution was evaluated [1244]. The signal-to-noise ratio for plaque labeling is not as robust as thatof 11C-PiB. 11C-PiB showed a S/N ratio of about 2.5,while 123I-IMPY displayed a ratio of 1.8–2.0, between30 and 50 min after an i.v. injection [1181]. Its devel-opment was terminated.

The development of amyloid binding PETligands (Aventis), fluoropegylated indolyl-phenyl-acetylenes (Avid Radio-pharmaceuticals), 11C-6-Me-BTA (University of Pittsburgh), and of 18F-SMIBR-W372 (Siemens Medical Solutions Molecular Imag-ing) was terminated.

Inhibitor of serum amyloid P component binding

The normal plasma protein serum amyloid P com-ponent (SAP) binds to fibrils in all types of A� depositsand contributes to the pathogenesis of amyloidosis[1245–1247].

Ro-63-8695 (CPHPC; Pentraxin Therapeutics, Lon-don under license from Roche) (Fig. 14) is acompetitive inhibitor of serum amyloid P componentbinding to amyloid fibrils (IC50 = 0.9 �M). First resultsfrom in vivo mouse and human studies have been com-municated [1245, 1248–1250]. In addition, PentraxinTherapeutics and GSK are investigating a combinationof CPHPC with a humanized antibody for the potentialtreatment of amyloidosis (Thomson Reuters Pharma,update of March 22, 2012).

Vaccines against amyloid-β

AN-1792 (AIP-001; Elan and American HomeProducts, later Wyeth, now Pfizer) was the first vac-cine against AD in clinical trials. The antigen wassynthetic A�42, which was administered with QS-21from the Stimulon family of saponins purified from thebark of Quillaja saponaria as adjuvant [1251, 1252].The multicenter double-blind Phase IIa study in theUS and Europe involving 375 patients with mild-to-moderate AD started in the third quarter of 2001.Treatment of patients with AN-1792 plus adjuvantand the adjuvant alone as placebo was in a ratio of4 : 1. 18 patients developed meningoencephalitis prob-ably due to an inappropriate T cell activation and/orthe proinflammatory Th1 type of adjuvant. The studywas discontinued in March 2002 [1253]. Neverthe-less, many important data could be collected. From129 patients immunized with the drug, 25 were clas-sified as antibody responders after 4.5 years. Thesepatients showed significantly slower decline on the


Fig. 14. PET and SPECT ligands.

disability assessment for dementia and a significantdifference on a dependence scale compared to placebo-treated patients. Antibody responders also showed lessof a decline in a memory test. The scientific harvestof this single clinical trial is listed in chronologicalorder [1254–1286] (Thomson Reuters Pharma, updateof August 24, 2012).

Affitope AD-02 (Affiris, Vienna AT and licenseeGlaxoSmithKline Biologicals) is a six amino acid pep-tide vaccine targeting the N-terminus of A� only, whenit is free. The adjuvant is aluminum hydroxide. Theantibody response is focused exclusively on A� anddid not show crossreactivity to A�PP [1287, 1288]. AEuropean Phase II clinical trial in 420 patients in Aus-tria, Germany, France, the Czech Republic, Slovakia,and Croatia started in April 2010 (Thomson ReutersPharma, update of August 1, 2012).

CAD-106 (Cytos Biotechnology, Zurich and Novar-tis) is an A�1-6 peptide linked to a Q� virus-likeparticle for the s.c. treatment of patients with AD.One Phase IIa trial was initiated in July 2008 (n = 27),and a second Phase IIa trial was started in October2008 (n = 30). The safety, tolerability, and antibodyresponse of active A� immunotherapy with CAD-106 in patients with AD was published [1289]. Forcomments, see [1290, 1291]. It was found that 80%

of the patients involved in the trial developed theirown protective antibodies against A� without suffer-ing any side-effects over the three years of the study.The researchers believe that the CAD106 vaccine is atolerable treatment for patients with mild-to-moderateAD. In March 2010, a randomized, placebo-controlled,multicenter, Phase II trial began in patients (n = 120)in the US, Canada, and Europe with mild AD [1276,1292, 1293]. Preclinical results in transgenic mice werepresented [1294] (Thomson Reuters Pharma, update ofJuly 26, 2012).

Vanutide cridificar (ACC-001, PF-05236806;Janssen Alzheimer Immunotherapy, Dublin, Ire-land acquiring Elan’s Alzheimer’s ImmunotherapyProgram and Pfizer) is a peptide fragment of A� conju-gated to the mutated diphtheria toxin protein CRM197.The adjuvant is QS-21. In May 2007, a randomized,multicenter, double-blind, placebo-controlled, parallelassignment, safety/tolerability/immunogenicity PhaseII trial in patients with mild-to-moderate AD (n = 56)began [1295]. In July 2009, Pfizer began a multi-center, randomized, unblinded, QS-21-adjuvanted,long-term, Phase II trial of vanutide cridificar (3, 10,and 30 microg, im) in patients (n = 160) in the US.At that time the estimated study completion date wasSeptember 2014. In August 2009, an additional study


was initiated in Japanese subjects (n = 32) [1276](Thomson Reuters Pharma, update of August 13,2012).

ACI-24 (AC Immune, Lausanne, Switzerland) is anA�1-15 peptide to which on both ends two lysineswere attached, which are tetrapalmitoylated on the�-nitrogens. The antigen is embedded in a lipo-some membrane. Adjuvant is a mixture of the lipidsDMPC, DMPG, cholesterol, and MPLA in a ratioof 9 : 1 : 7 : 0.06, respectively [1296, 1297]. The drugrestored memory defects of transgenic AD mice.The IgF subclasses of the antibodies generated fromthe vaccine were mostly IgG2b indicating a non-inflammatory Th2 isotype. CD and NMR revealedpredominantly �-sheet conformation. The drug iscurrently evaluated in a Phase I/II clinical trial inDenmark, Finland, and Sweden (Thomson ReutersPharma, update of June 19, 2012).

Affitope-AD-03 (Affiris, Vienna, Austria andlicensee GlaxoSmithKline Biologicals) entered aPhase I clinical trial in October 2010. In Novem-ber 2011, the study was completed (Thomson ReutersPharma, update of April 4, 2012).

UB-311 (United Biomedical, Hauppauge, NY) isan intramuscularly administered vaccine targeting N-terminal amino acids 1-14 of A� in Phase I clinicaltrials in Taiwan in patients with mild-to-moderate AD(n = 18) [1298] (Thomson Reuters Pharma, update ofJune 25, 2012).

V-950 (Merck, Whitehouse Station, NJ) is anN-terminal A� peptide conjugated to an aluminum-containing adjuvant with or without ISCOMATRIX(an adjuvant containing saponin, cholesterol, andphospholipids) [1299]. Mild-to-moderate AD patients(n = 124) received six injections/year of increasingdoses of either placebo or V-950 in the presence orabsence of varying concentrations of ISCOMATRIXin Phase I clinical trials in the US and Sweden overa four year period [1276] (Thomson Reuters Pharma,update of February 24, 2012).

There are numerous vaccine preparations in preclin-ical evaluation (in alphabetical order):

ABvac40 and ABvac42 (Araclon Biotech,Zaragoza, Spain) are active therapeutic antibodyvaccines awaiting approval for clinical trials [1741](Thomson Reuters Pharma, update of June 25, 2012).

ADepVac (Ichor Medical Systems, San Diego, CAin collaboration with the University of California atIrvine and the Institute for Molecular Medicine) is aDNA vaccine using the TriGrid electroporation tech-nology [1300] (Thomson Reuters Pharma, update ofJuly 13, 2012).

ALZ-101 (Alzinova, Goteborg, Sweden, a spin-offof MIVAC Development) is a specific oligomer-directed therapeutic vaccine (Thomson ReutersPharma, update of July 18, 2012).

ALZ-301 (Alzinova, Goteborg, Sweden, a spin-offof MIVAC Development) is an A�40 oligomer tar-geted replacement therapy (Thomson Reuters Pharma,update of July 18, 2012).

Alzheimer’s disease vaccine (VLP Biotech, SanDiego CA) is a vaccine that activates antibodies againstA� protein (Thomson Reuters Pharma, update of May3, 2012).

Amyloid-� 3-10 DNA vaccination (China Medi-cal University, Shenyang) suggested a potential newtreatment for AD [1301–1305].

Active immunization with Ankyrin G, a neuronalcytoskeletal protein, with Freund’s adjuvant completeof arcA� mice reduced A� pathology [1306].

BAN-2203 (BioArctic Neuroscience, Stockholm,Sweden) is an immunotherapeutic vaccine targetingA� protofibrils (Thomson Reuters Pharma, update ofJanuary 7, 2011).

BBS-1 BACE inhibitor mAb vaccine (Nasvax,Ness Ziona, IL under license from Ramot at Tel AvivUniversity) is based on a lead mAb candidate blocking�-site-1, which inhibited the ability of BACE to cleaveA�PP (Thomson Reuters Pharma, update of July 30,2012).

C12 (Pharma Bio, Moscow, Russia) is a programof therapeutic vaccines comprised of synthetic peptidefragments of the �7 nicotinic acetylcholine receptorused to generate antibodies that block A� binding toneurons (Thomson Reuters Pharma, update of March29, 2012).

EB-101 (Atlas Pharmaceuticals, Sunnyvale, CA)is a synthetic human A�42/sphingosine-1-phosphate/liposome vaccine (Thomson Reuters Pharma, updateof July 27, 2012).

A T cell-based vaccination with Glatimer acetateof AD double-transgenic (A�PP/PS1) mice resultedin decreased plaque formation and induction ofneurogenesis. Dendritic-like (CD11c) cells producedinsulin-like growth factor 1 [1307].

MER-5101 (Mercia Pharma, Scarsdale, NY) is avaccine comprised of an A� peptide conjugate coupledto an immunogenic carrier protein and the com-pany’s Th2-biased adjuvant MAS-1 (Thomson ReutersPharma, update of January 27, 2012).

Mimovax (MV-01; Affiris, Vienna AT) is anAFFITOPE-based vaccine targeting truncated andmodified forms of A� (Thomson Reuters Pharma,update of April 2, 2012).


NU-700 (Nuron Biotech, Exton, PA under licensefrom Vitruvian BioMedical under license from theUniversity of Texas Southwestern Medical Center) isan adjuvant free, gene-base (DNA) A�42 vaccine forthe potential treatment or prevention of AD (ThomsonReuters Pharma, update of May 22, 2012).

Recombinant adenovirus vector vaccine (Vaxin,Birmingham, AL in collaboration with AnC Bio,South Korea) elicited an immune response against A�using Crucell’s PER.C6 technology for the potentialintranasal treatment of AD (Thomson Reuters Pharma,update of May 2, 2012).

RV-03 (Intellect Neurosciences, New York, NY) isa peptide vaccine developed using the RECALL-VAXtechnology targeting both A� and a truncated delta tauprotein (Thomson Reuters Pharma, update of August21, 2012).

SeV-amyloid beta RNA vaccine (DNAVEC,Tsukuba, Japan) is an intranasal vaccine comprisinga Sendai virus vector encoding the A� gene [1308](Thomson Reuters Pharma, update of September 21,2011).

Excellent papers on A� vaccines from universitieswere presented (in chronological order) 2000: [1309,1310]; 2001: [1311]; 2004: A�1-42 gene vaccination[1312]; 2005: a synthetic universal Th cell pan HLADR epitope, pan HLA DR-binding peptide (PADRE),in which the PADRE-A�1-15 sequence lacks the T cellepitope of A� [1313]; 2006: an A� derivative in alumadjuvant [1314], an intranasal dendrimeric A�1-15 vac-cine [1315–1319]; 2007: an oral vaccination usinga recombinant adeno-associated viral vector carry-ing A� cDNA (AAV/A�) [1320], a transcutaneousadministration of aggregated A�1-42 plus the adjuvantcholera toxin [1321], a mannan-A�28 conjugate [1322,1323]; 2008: a DNA epitope vaccine that expresses epi-topes of A�42 [1324]; 2009: K6 A�1-30-NH2 in alumadjuvant [1325], an A�1-33-MAP peptide to markedlyreduce intracellular A� deposits [1326], K6A�1-30 forimmunizations of old primates [1327], A�1-42 vac-cinations also reducing mouse tau pathology [1328];2010: an oral vaccination with GFP-A� [1329], immu-nization of aged beagle dogs with aggregated A�1-42formulated in an alum adjuvant [1330], active immu-nization with A�1-42 emulsified in CFA containingMycobacterium tuberulosis extract [1331], loweringof A� plaque burden by the SDPM1 peptide, a 20amino acid peptide bound by cysteines that bindstetramer forms of A�1-40 and A�1-42 amyloids [1332];2011: two novel anti-A� vaccines consisting of viruslike particles [1333], the identification of the short-est A�-peptide generating specific antibodies [1334];

2012: preventive immunization of aged primates[1335].

Excellent reviews on A� vaccines have been pro-vided (in chronological order) 2001: [1336], [1337],2002: [1257, 1338–1341], 2003: [1342]), 2004:[1343]), 2005: [1344–1346], 2006: [1347–1349],[1350], 2007: [1351–1355], 2008: [1356–1359],2009: [1282, 1360–1363], 2010: [1364–1370], 2011:[1371], [1372–1374], and 2012: [23].

A clinical review of active and passive immunother-apeutic approaches in AD targeting A� was presented[1375, 1376].

The development of A� retroparticles (Universityof Heidelberg and Novartis [1377]), Abloid (Virion-ics), ACC-002 (Elan), AFFITOPE AD-01 (Affiris),Alzheimer’s vaccine (Lundbeck under license fromPharmexa), Alzheimer’s vaccine (Mindset BioPhar-maceuticals), Alzheimer’s disease vaccines (Univer-sity of South Florida and University of New Mexico),anti-amyloid-� vaccines (Wyeth, now Pfizer andJanssen Alzheimer Immunotherapy), DNA vaccine(University of Texas, Southwestern Medical Cen-ter), immunotherapy vaccine (Prana Biotechnology),KNX-Vaccine3A (Kinexis under license from the Uni-versity of California at Irvine), PEVIPRO (PevionBiotech [1378]), PX-106 (Lundbeck/Pharmexa), andRV-01 (Intellect Neurosciences) was terminated.

Antibodies against amyloid-β

Bapineuzumab (AAB-001; Janssen AlzheimerImmunotherapy, Dublin, Ireland following the acqui-sition of Elan’s Alzheimer’s Immunotherapy Programand Pfizer) is a humanized monoclonal antibody raisedagainst eight amino acids in the N-terminus of A� forthe potential i.v. and s.c. treatment of AD. A Phase IIIclinical study started in December 2007. The Phase IIIprogram included two trials in ApoE4-positive patients(n = 800 in the US and EU) and two in ApoE4-negativepatients (n = 1,250 in the US and EU) for 18 monthseach and three extension studies for both ApoE4 andnon-ApoE4 arms with three doses, 0.5, 1, and 2 mg/kg.The highest dose had to be abandoned due to vasogenicedema safety concerns. One extension study started inJuly 2009 (n = 1,350), two additional extension studiesin December 2009 in the EU and Australia (n = 800 and1,000, respectively). Clinical results from the PhaseI and Phase II studies were reported [1276, 1361,1379–1382] as was a 11C-PiB PET assessment [1383]and the effects on CSF biomarkers [1384]. Reviews onbapineuzumab were published (in chronological order)[23, 1385–1392]. For the scientific basis see the Nature


Medicine paper [1393]. The pharmacokinetic profile of125I-labeled 3D6, the mouse parent antibody of bap-ineuzumab, in transgenic mice was reported [1742].

In July 2012, Pfizer reported that the ’302 study inApoE4 carriers did not meet its primary endpoints.Pfizer, Johnson & Johnson, and Elan announced thatdevelopment of i.v. bapineuzumab was terminated(Thomson Reuters Pharma, update of September 18,2012).

Solanezumab (LY-20622430; Lilly) is a mid-domain humanized monoclonal antibody selective forsoluble A�. Three Phase III studies were initiatedin patients with mild-to-moderate AD (n = 1,000) inMay 2009, patients received 400 mg of solanezumabor placebo i.v. every 4 weeks for 80 weeks.First results were disclosed (in chronological order)[1276, 1394–1398]. Safety and biomarker effects ofsolanezumab in patients with AD was communicated[1399]. Solanezumab failed to meet the cognitive andfunctional primary endpoints of two Phase III AD tri-als. But it showed a significant reduction in cognitivedecline in patients with mild AD. The open-labelEXPEDITION-EXT extension trial, which is fullyenrolled, will continue as planned (Thomson ReutersPharma, update of September 7, 2012).

Gantenerumab (R-1450; Roche under license fromMorphoSys) is a human anti-A� monoclonal anti-body. A Phase II clinical trial in Canada (n = 360)was initiated in January 2011. Prodromal AD patients(NCT01224106) are to receive 105 or 225 mg admin-istered by s.c. injection every 4 weeks for 104 weeks toevaluate effects on cognition and functioning, safety,and pharmacokinetics. In June 2012, the trial wasexpanded to a Phase II/III trial. The trial size will beincreased from 360 to 770 participants. The mecha-nism of A� removal was described [1400, 1401]. Anexpert opinion was provided [1402] (Thomson ReutersPharma, update of September 5, 2012).

Crenezumab (MABT-5102A; RG-7412; Genen-tech under license from AC Immune, Lausanne,Switzerland) is an anti-A� humanized mono-clonal antibody as a conformation-specific, passiveimmunotherapy for the potential i.v or s.c. treatment ofAD. A Phase II clinical trial (n = 372; NCT01397578)was initiated in April 2011. The first Alzheimer’s Pre-vention Initiative will study the effects of crenezumabin 300 people from a large family in Columbia witha rare genetic mutation that typically triggers ADsymptoms around age of 45. It is a collaborationbetween the National Institutes of Health (NIH), Ban-ner’s Alzheimer’s Institute, and Genentech over fiveyears starting in 2013. Data and findings will be shared

publicly after the study completion. The scientific basisfor the selection of crenezumab was published recently[1403] (Thomson Reuters Pharma, update of Septem-ber 5, 2012).

GSK-933776A (GSK) is a monoclonal antibodyfor the i.v. treatment of AD and age-related maculardegeneration. A Phase II trial (n = 162) of age-relatedmacular degeneration started in the US in August2011 (Thomson Reuters Pharma, update of August 24,2012).

The topic intravenous immunoglobulins as a treat-ment for AD, the rationale and current evidence wasdescribed in reviews [1404, 1405, 1743].

Immune globulin intravenous human (IVIg;launched as Gammagard in the US and as Kiovigin Europe; Baxter International, Deerfield, IL) isa highly purified solvent/detergent-treated, sterile,freeze-dried preparation derived from human plasmafor the treatment of primary immunodeficiency dis-ease. This pool of human immunoglobulins obtainedfrom healthy donors contains naturally occurringanti-A� antibodies. In a Phase II trial in 24 patients,the eight-person placebo group worsened, whereasthe 16 treated patients improved moderately on bothcognitive and quality-of-life measures over the first6 months [1406–1408]. A Phase III clinical trial inAD patients enrolling 390 patients was initiated inSeptember 2008. Trial completion is expected by theend of 2012 (NCT00818662, NCT00299988) [1276].The first report of long-term (three-year) stabilizationof AD symptoms with IVIG (Gammagard, Baxter),including no decline on measures of cognition, mem-ory, daily functioning, and mood, was reported inJuly 2012 at the Alzheimer’s Association InternationalConference in Vancouver. Sales in 2011 amounted to1,541 million USD. For preclinical data, see [1409,1410] (Thomson Reuters Pharma, update of October3, 2012).

Octagam (Octapharma, Lachen, Switzerland) isa 10% liquid intravenous immunoglobulin launchedfor the treatment of primary immunodeficiency. ByDecember 2008, a double-blind, randomized, PhaseII clinical trial (NCT 00812565) in 58 patients withAD had been initiated in the US. Clinical data werepresented at the AAIC in Paris in July 2011 (ThomsonReuters Pharma, update of April 3, 2012).

Flebogamma DIF 10% (or 5%) (Grifols SA,Barcelona) is a 10% (or 5%) double inactivated andfiltered immunoglobulin therapy for the treatment ofprimary immunodeficiency. Data were presented on asingle-center, open-label, pilot study on the use of Fle-bogamma DIF 0.5 g/kg i.v., q2w for 6 months in AD


patients (n = 4) (Thomson Reuters Pharma, update ofMarch 23, 2012).

BAN-2401 (Eisai under license from BioarcticNeuroscience, Stockholm, Sweden) is a humanizedmonoclonal antibody that targets the large solubleamyloid product (protofibril A�). A Phase I trial in 80patients with mild-to-moderate AD began in Septem-ber 2010. Eisai plans to co-administer BAN-2401 withdonepezil and memantine (Thomson Reuters Pharma,update of July 19, 2012).

NI-101 (BIIB-037, BART; Biogen Idec, Weston,MA under license from Neuroimmune Therapeutics,Zurich Switzerland) is a recombinant chimeric humanIgG1 mAb targeted against A�. A Phase I clinical trial(n = 40) in patients with mild-to-moderate AD startedin the US in July 2011 (Thomson Reuters Pharma,update of September 24, 2012).

PF-05236812 (AAB-003; Janssen Alzheimer Imm-unotherapy and Pfizer) is a humanized monoclonalantibody targeted against A�. In October 2010, a ran-domized, double-blind, placebo-controlled, adaptive,Phase I trial was initiated in patients with mild-to-moderate AD (n = 80) in the US [1411] (ThomsonReuters Pharma, update of August 13, 2012).

RN6G (Rinat Neuroscience Corp., New York, nowPfizer) is an anti-A� antibody for the potential i.v.treatment of age-related macular degeneration in PhaseI trial (n = 45) since April 2009 in the US. In April2012, a randomized, double-blind, placebo-controlled,Phase II study was planned in patients with geographicatrophy secondary to age-related macular degeneration(expected n = 276) to assess the safety and efficacy ofRN6G [1412] (Thomson Reuters Pharma, update ofSeptember 11, 2012).

SAR-228810 (sanofi) is an anti-protofibrillar A�monoclonal antibody. A randomized, double-blind,placebo-controlled, Phase I trial in patients with mild-to-moderate AD (n = 48) was initiated in Sweden inJanuary 2012. The study is scheduled to complete inDecember 2013 (Thomson Reuters Pharma, update ofJuly 27, 2012).

There are currently many antibodies for the poten-tial treatment of AD and closely related diseases inpreclinical evaluation (in alphabetical order):

4E10 (Prana Biotechnology, Parkville, Australia) isa monoclonal antibody targeting a proprietary patho-logical A� target epitope (Thomson Reuters Pharma,update of November 2, 2011).

6F6 (GSK) is an anti-A� monoclonal antibody forthe potential treatment of age-related macular degen-eration (Thomson Reuters Pharma, update of June 9,2011).

9D5 (University of Gottingen, MBM Science-Bridge) targets pyro-Glu-A� peptide oligomers for thepotential diagnosis and treatment of AD [1413] (Thom-son Reuters Pharma, update of August 7, 2011).

A-887755 (Abbott Laboratories) is an A�,oligomer-selective, mouse monoclonal antibodygenerated using a homogenous, synthetic A�20-42oligomer peptide (Thomson Reuters Pharma, updateof February 27, 2012).

A-992401 (Abbott Laboratories) is a mAb target-ing the receptor for advanced glycation-end-products(Thomson Reuters Pharma, update of December 1,2010).

Ab40-4-42 (Ilsung Pharmaceutical, Seoul) is abiological therapeutic, which acted by inhibitingA� aggregation and cytotoxicity (Thomson ReutersPharma, update of May 14, 2012).

ACU-193 (Acumen Pharmaceuticals, LivermoreCA) is a monoclonal antibody against amyloid-deriveddiffusible ligands (Thomson Reuters Pharma, updateof August 16, 2012).

AD-0802 (Bioarctic Neuroscience, Stockholm,Sweden) is a humanized mAb with affinity for bindingto A� protofibrils. It is a potential follow-up compoundto BAN-2401 (vide supra) (Thomson Reuters Pharma,update of January 7, 2011).

AGT-160 (ArmaGen Technologies, Santa Monica,CA) is a recombinant IgG fusion protein formed by thefusion of a single chain Fv antibody against A� plaqueformation to the company’s human insulin receptor-targeting monoclonal antibody Trojan horse for thetransport across the blood-brain barrier. A 1 mg/kg i.v.dose of AGT-160 was administered twice a week for12 weeks to transgenic AD mice resulting in a 40%decrease in the brain concentration of A� (ThomsonReuters Pharma, update of January 23, 2012). See alsoPart 1. Chapter 1.16. Drugs interacting with the insulinreceptor.

ALZ-201 (Alzinova, Goteborg, Sweden, a spin-off of MIVAC Development) is an oligomer-specificA� monoclonal antibody (Thomson Reuters Pharma,update of July 20, 2012).

Amyloid precursor protein C-terminalfragment-targeted monoclonal antibodies (EcolePolytechnique Federale de Lausanne, EPFL) isa monoclonal antibody targeted to the 99 aminoacid C-terminal fragment of A�PP (A�PP-C99)(Thomson Reuters Pharma, update of March 31,2011).

Anti-amyloid beta antibodies (Kyowa HakkoKirin under license from Immunas Pharma, OncoTher-apy Science Inc.) are antibodies targeting A�


oligomers (Thomson Reuters Pharma, update ofAugust 6, 2012).

Brain-targeted BACE1 antibody (Genentech,Roche Holding) is a bi-specific antibody againstBACE1 and the transferrin receptor to allow tran-scytosis across the blood-brain barrier [1414, 1415](Thomson Reuters Pharma, update of May 14, 2012).This technique was pioneered by Prof. William M.Pardridge of UCLA [1416–1422].

CPHPC+antibody (Pentraxin, London and GSK) isa combination of CPHPC, which lowers blood levels ofserum amyloid P component (see Chapter 16.2) and ahumanized antibody for the treatment of amyloidosis[1249] (Thomson Reuters Pharma, update of March22, 2012).

DLX-212 (Delenex Therapeutics, Zurich, Switzer-land) is an anti-A� antibody fragment (ThomsonReuters Pharma, update of March 29, 2012).

Fully human monoclonal antibodies (Intrexon,Blacksburg VI after its acquisition of Immunologix)are targeting A� plaques for the potential treatmentof AD (Thomson Reuters Pharma, update of June 13,2012).

IN-N01 (Intellect Neurosciences under license fromImmuno-Biological Laboratories, IBL, New York,NY) is an antibody drug conjugate consisting of aA�-specific humanized mAb employing its ANTI-SENILIN technology, for the potential treatment ofAD, glaucoma, age-related macular degeneration andtraumatic brain injury. In September 2012, Intellectplanned to conduct studies in combination with taumAbs TOC-1and TauC3 (Thomson Reuters Pharma,update of September 20, 2012).

IN-N01-OX2 (Intellect Neurosciences, New York,NY) is a humanized IgG4 monoclonal antibody conju-gated to melatonin developed using its CONJUMAB-A technology for the potential treatment of age-relatedmacular degeneration and Alzheimer’s disease (Thom-son Reuters Pharma, update of October 2, 2012).

Lpathomab (LT-3015; Lpath Inc., San Diego,CA) is a systemic formulation of a humanized anti-lysophosphatidic acid monoclonal antibody for thepotential treatment of fibrosis, ocular inflammation,and CNS disorders including AD [1423] (ThomsonReuters Pharma, update of August 28, 2012).

MDT-2007 (Medronic, Minneapolis, MN) is ahumanized anti-A� monoclonal antibody, the human-ized version of the mouse mAb 6E10 (ThomsonReuters Pharma, update of January 6, 2012).

Nanobody therapeutics (Ablynx, Gent Belgiumand licensee Boehringer Ingelheim) are naturally-occurring single chain antibodies of Camelidae. In

April 2012, a CTA was submitted to European regula-tory authorities for a Phase I study (Thomson ReutersPharma, update of August 23, 2012).

NEOD-001 (Onclave Therapeutics, Dublin, Irelandand Neotope Biosciences, South San Francisco, CAand Elan) is a proprietary monoclonal antibody forthe potential treatment of AL amyloidosis. In February2012, the drug was awarded Orphan status by the FDAfor AA amyloidosis and AL amyloidosis (ThomsonReuters Pharma, update of June 27, 2012).

STC-103 (STC Biologics, Cambridge, MA) is anovel Fc fusion protein therapeutic for the potentialtreatment of AD (Thomson Reuters Pharma, update ofAugust 10, 2012).

Excellent papers on A� antibodies from universitiesand basic research from companies were presented (inchronological order) 1996: [1424], 1997: [1425]; 2000:[1393]; 2005: [1426, 1427], 2006: [1428, 1429], 2007:[1430–1441], 2008: [1442–1447], 2009: [1448–1454],2010: [1366, 1455–1460], 2011: [1461–1465], 2012:[1466, 1467, 1744].

Excellent reviews were provided (in chronologi-cal order) 2006: [1350], 2007: [1468–1470], 2008:[1356, 1358, 1471, 1472], 2009: [1360, 1361,1473–1475], 2010: [1369]; 2011: [23, 1371, 1388,1389, 1476–1478], 2012: [1479]. The challengeof adverse effects of immunotherapy for AD wasaddressed [1480].

A clinical review of active and passive immunother-apeutic approaches in AD targeting A� was presented[1375, 1376].

The development of 11A1 (a monoclonal anti-body against the toxic conformer of A�42; TokyoMetropolitan Institute of Gerontology, Kyoto Uni-versity and Immuno-Biological Laboratories), A-11(A� deposition-inhibiting antibody; Kinexis underlicense from the University of California), AAB-002 (Janssen Alzheimer Immunotherapy and Pfizer),ABP-102 (Abiogen Pharma; a catalytic monoclonalantibody, an abzyme), ACU-5A5, ACU-0101979and huC091 (Acumen Pharmaceuticals), anti-Abetamonoclonal antibodies (Mapp Biopharmaceutical incollaboration with Johns Hopkins University), theanti-amyloid beta antibody therapy targeting spe-cific forms of the A� parenchymal plaque (sanofi underlicense from Rockefeller University), anticalin (Pieris,an antibody against residues 16-26 of A�), AZD-3102 (AstraZeneca), bapineuzumab (AAB-001;Janssen Alzheimer Immuno-therapy and Pfizer), betaamyloid deposition-inhibiting antibodies (amyloi-dosis, Kinexis), beta amyloid-targeting antibodies(Mindset BioPharmaceuticals), encapsulated scFv-


beta 1-expressing cells targeting the EFRH tetrapep-tide region of A� (scFv-beta 1; Novartis in collabo-ration with the Institute for Research in Biomedicineand the Ecole Polytechnique Federale de Lau-sanne), ESBA-212 (ESBA Tech, Nestle, a humanizedsingle-chain antibody directed against A�), KNX-Monoclonal204 and KNX-Monoclonal205 (Kinexisunder license from the University of California atIrvine), m266 (an antibody specific for the centraldomain of A�; Lilly [1481, 1482]), and ponezumab(PF-4360365; RN-1219; RI-1219; Rinat Neuroscienceand Pfizer) [1276, 1483–1485] a humanized mono-clonal antibody specific for the C-terminus of A�40,was terminated.

DRUGS INTERACTING WITH TAU

A hallmark of the AD brain is the presenceof inclusions within neurons that are comprised offibrils formed from hyperphosphorylated microtubule-stabilizing protein tau (paired helical filaments andneurofibrillary tangles [1486–1489]. The formationof misfolded multimeric tau species is believed tocontribute to the progressive neuron loss and cogni-tive impairments of AD [1490]. Tau suppression ina neurodegenerative mouse model improved memoryfunction [1491]. The precise composition of the neu-rotoxic species Tau-P* is not defined yet [1486]. Thelevels of early multimeric tau-aggregates that precededthe neurofibrillary tangles were found to correlate withmemory deficits [1492]. The sites of phosphoryla-tion and the involved kinases were compiled [1493,1494]. The tau phosphorylation pathway genes weredescribed [1495]. Although A� plaques may play akey role in AD pathogenesis the severity of cognitiveimpairment correlated best with the burden of neu-rofibrillary tangles described in an exhaustive reviewof the literature [1496, 956]. A� and tau influence eachother in the mediation of toxicity. A� formation inA�PP transgenic mice caused hyperphosphorylationof tau, whereas there was no overt A� plaque pathol-ogy in tau transgenic mice. Immunization against A�in triple transgenic mice resulted in reduced levelsof hyperphosphorylated tau. Tau reduction preventedA� induced defects in the axonal transport of mito-chondria. Combination of these data led to the twostep tau axis hypothesis of AD [1497–1499]. First,postsynaptic toxicity of A� is tau-dependent, becausetau interacts with FYN [1500], which is localized tothe dendritic compartment, where it phosphorylatesthe NMDA receptor subunit 2B, mediates their inter-

action with the postsynaptic density protein 95, aninteraction required for A� toxicity and second, A�triggers progressively increased phosphorylation of taucompromising the binding of tau to microtubules lead-ing to increasing dendritic tau levels [1501]. For avery instructive figure depicting these interactions, see[1502]. The synaptic accumulation of hyperphospho-rylated tau oligomers is associated with dysfunction ofthe ubiquitin-proteasome system [1503].

A cascade of biomarkers was proposed: A� precedestau-mediated neuronal injury; A�- and tau-mediatedabnormalities precede neuroimaging biomarkers suchas changes in hippocampal or ventricular volumetrymeasured by MRI; and all of these precede cog-nitive change marked by progressive deteriorationin episodic memory and other cognitive domainssuch as executive functions abilities [1504–1506].In a longitudinal study in 172 participants (AD:n = 41; MCI: n = 85; and normal controls: n = 46),the temporal relations among the four classes ofbiomarkers were examined. Results indicated that CSFA� effects on cognition change were substantiallyattenuated by CSF tau and measures of brain structureand function and CSF tau effects on cognitive changewere attenuated by neuroimaging variables. Contraryto hypotheses, CSF A� and CSF tau were observed tohave independent effects on neuroimaging and CSF tauhad a direct effect on baseline cognition independentof brain structure and function [1507].

Small molecules preventing tau aggregation

TRx-0014 (methylthioninium chloride, methyleneblue, Rember; TauRx Therapeutics, Singapore, a spin-out from the University of Aberdeen) (Fig. 15) is atau protein aggregation inhibitor. In August 2004, aplacebo-controlled, dose-ranging Phase II trial wasinitiated in subjects (n = 275) with AD associateddementia in the UK. The doses were 30, 60, or 100 mgtid. In July 2007, a Phase II open-label continuationstudy of two doses of 30 or 60 mg tid gelatin cap-sules started for 52 weeks. The drug reduced cognitivedecline by 81% over 1 year and no significant lossof cognitive function was seen over 19 months [1508,1509]. In November 2010, the EC granted the drugOrphan status for frontotemporal dementia, progres-sive non-fluent aphasia and progressive supranuclearpalsy. In February 2012, an open-label trial in patientswith frontotemporal dementia was ongoing. For thepreclinical characterization, see [1510–1516]. Onlywhen levels of soluble tau protein were concomitantly


reduced by a very high concentration of methylene bluecognitive improvement was observed in a mouse modelof human tauopathy [1517]. Methylene blue also inhib-ited the aggregation of A� [1518, 1519] (ThomsonReuters Pharma, update of September 10, 2012).

LMT-X (TauRx Therapeutics, Singapore) is apotential follow-up compound and prodrug of Rember.In September 2012, a Phase III study for frontotem-poral dementia began in 180 subjects for 12 months.In October 2012 two global phase III studies wereinitiated for AD. The first study will involve 833patients with mild to moderate Alzheimer’s diseaseover 12 months, while the second study will include500 patients with mild Alzheimer’s disease over 18months. The clinical trials will be conducted in paralleland on a global basis including sites in Australia, Bel-gium, Canada, Finland, Germany, Italy, Russia, Spain,Netherlands, Singapore, Malaysia, Taiwan, US and UK(Thomson Reuters Pharma, update of November 21,2012). The structure was not communicated.

PBT-2 (Prana Biotechnology, Parkville, Australia)(see Fig. 9) is an oral zinc ionophore metal-proteinattenuating compound that reduced levels of solu-ble A� and tau hyperphosphorylation in a Phase IIastudy in AD patients. (Thomson Reuters Pharma,update of October 2, 2012) See also Chapter 12. MetalChelators.

Tideglusib (NP-12, NP-031112; Nypta; Noscira,previously known as Neuropharma, Madrid) (Fig. 15)is a GSK-3� inhibitor in Phase II clinical trials for AD.Results from the 309-patient study were expected byOctober 2012. First positive results of a clinical pilotstudy were reported [1520] (Thomson Reuters Pharma,update of July 23, 2012). See also Part 2, Chapter 2.16.Drugs interacting with GSK-3�.

BMS-241027 (Bristol-Myers Squibb) is a smallmolecule microtubule stabilizer aimed at preventingthe production of abnormal tau protein. A randomized,double-blind, placebo-controlled Phase I study was ini-tiated in patients with mild AD (expected n = 100) inthe US and in Europe in March 2012 (Thomson ReutersPharma, update of August 6, 2012). The structure wasnot communicated.

PP2A stimulator (Se-015; Ve-015; Velacor Ther-apeutics, Victoria, Australia) is a selenium derivativeacting as protein phosphatase 2A (PP2A) stimulatorresulting in dephosphorylation of Akt kinase and tau.By February 2011, a Phase I trial had been completedand the company received the approval to initiate aPhase IIa trial in AD patients in Australia (ThomsonReuters Pharma, update of February 10, 2011). Thestructure has not been communicated.

There are many compounds inhibiting tau aggre-gation in preclinical evaluation (in alphabeticalorder):

A�/tau protein aggregation inhibitors (CNRS,FIST SA, Paris, France) are investigated for the poten-tial treatment of AD (Thomson Reuters Pharma, updateof August 24, 2012). The structures of the compoundswere not communicated.

Astemizole and Lansoprazole have been found toselectively interact with tau polymers [1521].

Berberine attenuated tau hyperphosphorylation inHEK293 cells [1745].

Bezafibrate (Bezalip, Bezatol; BoehringerMannheim, now Roche, co-marketing with KisseiPharmaceuticals, launched 1977) (Fig. 15), a drugfor the treatment of hyperlipidemia, is a pan-PPARagonist, which improved behavioral deficits and taupathology in P301S mice exerting a preventive effect[1522].

BLV-0703 (BLV-200703; Bioalvo, Lisbon, Por-tugal) (Fig. 15) is a tau aggregation inhibitor inpreclinical development (Thomson Reuters Pharma,update of May 9, 2011).

Epothilone D improved microtubule density, axonalintegrity and cognition in a transgenic mouse model oftauopathy [1523].

Fulvic acid inhibited aggregation and promoted thedisassembly of tau fibrils associated with AD [639].

Insulin intranasal ameliorated tau hyperphospho-rylation in a rat model of type 2 diabetes [1524].

L-3-n-butylphthalide reduced tau phosphorylationand improved cognitive deficits in A�PP/PS1-Alzheimer’s transgenic mice [1746].

NBB BSc3504 (TU Darmstadt and Max-Planck-Unit for Structural Molecular Biology Hamburg)(Fig. 15) is a N ′-benzylidene-benzohydrazideshowing remarkable tau aggregation inhibition(IC50 > 0.97 �M) and paired helical filamentdepolymerization (DC50 > 1.14 �M), but pooraffinity towards A�1-42 fibrils (IC50 > 33 �M) [1525].

NC-11813 (Eli Lilly and Nymirum, Ann Arbor, MI)is an inhibitor of tau exon 10 splicing, which stabilizedthe tau splice regulatory element (Thomson ReutersPharma, update of August 10, 2012). The structure wasnot communicated.

NP-111001 derivatives (Noscira, Madrid) act as tauphosphorylation inhibitors (Thomson Reuters Pharma,update of January 12, 2012). The structures were notcommunicated.

NPT-002 (NeuroPhage Pharmaceuticals, Cam-bridge, MA) targets A� and tau aggregates for thepotential treatment of AD (Thomson Reuters Pharma,


Fig. 15. Molecules preventing tau aggregation.


update of July 16, 2012). The structure was not com-municated.

Protein phosphatase methylesterase 1 (PME1)inhibitors (Signum Biosciences and GSK) are smallmolecules blocking the enzyme which demethylatesPP2A. Normally PP2A is almost all methylated, but inAlzheimer’s disease PP2A methylation is reduced inhalf. The structural mechanism of demethylation andinactivation of protein phosphatase 2a was described[1747–1749] (Thomson Reuters Pharma, updateof November 15, 2012). The structures were notcommunicated.

Protein phosphatase 2A stimulators (Cognosci,Research Triangle Park, NC) inhibit the formation ofapoE/inhibitor 2 of PP2A (I2PP2A) complex. The to-pic protein phosphatases and AD was reviewed [1526,1527] (Thomson Reuters Pharma, update of February24, 2012). The structures were not communicated.

ReS3-T, ReS8-T, ReS10-T and ReS19-T(reMYND, a spin-off from the University of Leuven,Belgium and licensee Roche) are four series of taudetoxifying compounds targeting tau-mediated cyto-toxicity (Thomson Reuters Pharma, update of Septem-ber 14, 2012). The structures were not communicated.

The ReS9-S7 and ReS12-S programs (reMYND,a spin-off from the University of Leuven, Belgiumand licensee Roche) investigate the attenuation ofthe cytotoxic effects of �-synuclein aggregation indopaminergic neurons for the potential treatment ofPD (Thomson Reuters Pharma, update of September14, 2012). The structures were not communicated.

SIG-1012 (Cognion) and SIG-1106 (Signum Bio-sciences, Monmouth Junction NJ in collaboration withPrinceton Univ.) are phosphoprotein 2A modulatorsand presumed to also include the PP2A methylesterase1 inhibitor eicosanoyl-5-hydroxytryptamide (EHT), allextracted from coffee and acting as tau aggregationinhibitors. (Thomson Reuters Pharma, update of Octo-ber 05, 2012). The structures were not communicated.

Small molecule Tau protein modulators(Asceneuron, a spun-out of Merck Serono, Geneva,Switzerland) are drugs for the potential treatment ofAD (Thomson Reuters Pharma, update of October 3,2012). Structures were not disclosed.

Small molecule tau modulators (Yuma Thera-peutics, Brookline, MA) target neurofibrillary tanglesresulting from abnormal forms of the protein tau(Thomson Reuters Pharma, update of March 29, 2011).

Sodium selenate mitigated tau pathology and func-tional deficits in AD models [1528].

Tau aggregation inhibitors (Catholic University ofLeuven, Belgium) are currently in the preclinical Phase

(Thomson Reuters Pharma, update of July 30, 2012).Structures were not communicated.

Tau aggregation inhibitors (ProteoTech, Kirk-land, WA) have a potential for the treatment of AD(Thomson Reuters Pharma, update of July 30, 2012).Structures were not communicated.

Tau oligomer inhibitors (Oligomerix, New York,NY) are presumably curcumin derivatives (ThomsonReuters Pharma, update of April 24, 2012).

Tau phosphorylation inhibitors (ProQinase,Freiburg im Breisgau, Germany) (Fig. 15) reducedin vivo GSK-3� selective phosphorylation ofSer396/Ser404 and Ser262 in the brains of tripletransgenic mice after i.p. administration. It appearsthat the development was terminated (ThomsonReuters Pharma update of October 11, 2012).

Therapeutic program (B & C Biopharm andEquispharm, both South Korea) is targeting taukinase (Thomson Reuters Pharma update of May 18,2012).

Thiamet-G (Simon Fraser University) is a potentinhibitor of human O-GlcNAcase (Ki = 21 nM)(Fig. 15) and efficiently reduced phosphorylation oftau at Thr231, Ser396, and Ser422 in both rat cor-tex and hippocampus [1529–1533]. For commentaries,see [1534, 1535]. See also Part 2, Chapter 2.27. Drugsinteracting with O-GlcNAcase.

THQ-4S and THQ-55 (Fig. 15) interact specificallywith oligomeric forms of tau inhibiting their assemblyinto AD filaments [1536, 1537].

TRx-0237 (TauRx Therapeutics, Singapore) is thelead compound of second-generation tau aggregationinhibitors. Safety and efficacy studies in AD and fron-totemporal dementia patients are planned for 2012(Thomson Reuters Pharma, update of September 25,2012). The structure was not communicated.

Tubastatin A (Fig. 15) is a potent and selectiveHDAC6 inhibitor [1750]. Chronic tubastatin treatmentfor two months decreased total tau levels in rtg4510mice [1751].

Natural products as a source of tau-targeting drugswere described [1538].

Excellent papers on small molecule inhibitors oftau aggregation were published by researchers atuniversities (in chronological order) 2004: [1539],2005: [1540] (benzothiazoles such as N-744, Fig. 15),[1541, 1542] 2006: [1543]; 2007: [1544–1550], 2009:[1551–1555], 2010: [1556, 1557], 2011: [1558, 1559],2012: [1560, 1561].

Excellent reviews on tau-focused drug discoveryfor AD were presented (in chronological order)2000: [1562]; 2002: [1563], 2006: [1564], 2007:


[1565], 2008: [1566–1569], 2009: [1570, 1571], 2010:[1572–1574], 2011: [1575, 1576] [1577, 1578], 2012:[1579–1581]. Interestingly, synergistic interactionsbetween repeats in tau protein and A� were described[1582].

The development of the tau aggregation inhibitorsaminothienopyridazines (University of Pennsyl-vania), AZD-1080 (AstraZeneca), BPU-410 andBPU-430 (Champions Biotechnology under licensefrom Johns Hopkins University), LDN-33960 (astriatal-enriched protein tyrosine phosphatase (STEP)inhibitor, Yale University), NHT-0112 (Neuro-Hitech), protein phosphatase methylesterase 1(PME1) inhibitors (Scripps Research Institute andMassachusetts Institute of Technology), SDGI-T200801 and SDGII-T200801 (both Bioalvo),SRN-003-556 (SIRENADE Pharmaceuticals) and ofTRx-0037 (TauRx) were terminated.

Ligands interacting with tau

T-777, T-807, and T-808 (Siemens Medical Solu-tion Molecular Imaging) (Fig. 15) are tau-bindingmolecules as PET tracers for the diagnosis of AD.They are benz[4,5]imidazo[1,2-a]pyrimidines. 18F-T808 displayed a high level of binding affinity(Kd = 22 nM) and good selectivity for tau aggregatesover A� plaques [1583] (Thomson Reuters Pharma,update of September 19, 2011).

Novel in vivo tau imaging agents 18F-THK-523(University of Melbourne) [1584] and 11C-THK-951(Tohoku University) (both Fig. 15) were published[1585] after preliminary results of 2005 [1752] (Thom-son Reuters Pharma, update of September 219, 2012).

The University of Melbourne is investigating18F labeled arylquinoline derivatives, such as18F-THK-5105, 18F-THK-5116, 18F-THK-5117, and18F-THK-5125 for the potential use in imaging taudeposition in neurofibrillary tangles for AD (Thom-son Reuters Pharma, update of June 13, 2012). Thestructures were not communicated.

Researchers of Amersham (GE Healthcare) pub-lished a patent describing ligands with an exceptionalselectivity to tau: compound 18 (Fig. 15): Kd = 0.9 nMfor tau and Kd = 30 �M for A�1-40 [1586].

A 125I-3-oxindole derivative stained neurofib-rillary tangles in AD brain sections [1587].Also bis(arylvinyl)pyrazines, -pyrimidines, and-pyridazines were described as imaging agents for taufibrils and A� plaques [1588] as were 2-styrylindoliumbased fluorescent probes [1753].

Research toward tau imaging was reviewed [1553,1589, 1590] stating that ligand polarizability con-tributes to tau fibril binding affinity.

Vaccines against tau

Recombinant misfolded truncated tau pro-tein vaccine (Axon Neurosciences, Vienna, Austria)attenuated pathology in vivo in a transgenic rat modelof tauopathy (Thomson Reuters Pharma, update ofFebruary 17, 2011).

RV-03 (Intellect Neurosciences, New York, NY)is a peptide vaccine developed using the RECALL-VAX technology targeting both the A� and a truncateddelta tau protein (Thomson Reuters Pharma, update ofAugust 21, 2012).

Phosphorylated tau peptides were used to immunizetransgenic mice to produce robust anti-neurofibrillarytangle effects [1591].

The development of the chimeric peptide vaccineRV-02 (Intellect Neurosciences) was terminated.

Antibodies against tau and α-synuclein

Humanized tau monoclonal antibodies (ACImmune, Lausanne, Switzerland) had high specificaffinity binding to pTau. The compound was out-licensed to Genentech (Thomson Reuters Pharma,update of June 19, 2012).

Lilly presented data on passive immunization withanti-tau antibodies in two transgenic mouse models[1754].

NI-105 (Biogen Idec, Weston, MA through theacquisition of Panima, previously a subsidiary ofNeurimmune Therapeutics, Zurich Switzerland) is ahuman recombinant monoclonal antibody targeted totau protein created using Neurimmune’s reverse trans-lational medicine platform (Thomson Reuters Pharma,update of May 4, 2012).

PD-0805 (Bioarctic Neuroscience, Stockholm,Sweden) is a monoclonal antibody targeting �-synuclein for the potential treatment of PD and DLB(Thomson Reuters Pharma, update of September 2,2011).

Pfizer presented the first X-ray structure of an avianantibody to its cognate phosphopeptide pT231/pS235at 1.9 A resolution [1755].

T01-OX2 (Intellect Neurosciences, New York, NY)is an antibody drug conjugate that consists of a mAbtargeting oligomeric forms of tau protein conjugatedto melatonin (Thomson Reuters Pharma, update ofAugust 17, 2012).


TauC3 monoclonal antibody (Intellect Neu-rosciences, New York, NY under license fromNorthwestern University) is targeting the neoepitopetauC3 (Thomson Reuters Pharma, update of September20, 2012).

Tau protein modulator (iPierian, South SanFrancisco, CA) is a monoclonal antibody for thepotential treatment of AD, frontotemporal dementiaand progressive supranuclear palsy (Thomson ReutersPharma, update of May 22, 2012).

Tau-targeted antibody therapy (Neotope Bio-sciences, South San Francisco, CA and Elan) is amonoclonal antibody targeted to tau (Thomson ReutersPharma, update of August 13, 2012).

TOC-1 (Intellect Neurosciences, New York underlicense from Northwestern University) is a tau-oligomer-targeting monoclonal antibody [1592, 1593](Thomson Reuters Pharma, update of September 20,2012).

The detection of naturally occurring anti-tau anti-bodies was described [1594].

Already in 1985 monoclonal antibodies to AD neu-rofibrillary tangles were described [1595]. Excellentpapers on passive immunization targeting pathologicalphospho-tau protein were published (in chronologi-cal order) 2005: [1596], 2007: [1597], 2008: [1598,1599], 2009: [1600, 1601], 2010: [1602, 1603], 2011:[1604–1607], 2012: [1756].

The development of TTRY78F (University ofPorto), an anti-transthyretin monoclonal antibody, wasterminated.

STEM CELLS

Substantial progress has been achieved in researchof stem cells for the potential treatment of ADcommunicated in chronological order: 2000: [1608],2001: [1609–1611], 2006: [1612–1614], 2007: [1615,1616], 2008: [1617, 1618], 2009: [1619–1622], 2010:[1623–1630], 2011: [1631–1635], 2012: [1636–1642,1757].

Human neural stem cells overexpressing cholineacetyltransferase restored cognitive function of kainic-acid-induced learning and memory deficits in rats[1643, 1644]. Neural stem cells reduced hippocam-pal tau and reelin accumulation [1645]. Intracerebraltransplantation of bone marrow-derived mesenchymalstem cells reduced A� deposition and rescued mem-ory deficits in AD mice by modulation of immuneresponses [1626]. Neural stem cells improved cog-nition via BDNF in a transgenic model of AD

[1646–1648]. Human neural stem cells geneticallymodified to express human NGF gene restoredcognition in mice [1649]. Human neural stem cellsgenetically modified to overexpress BDNF promotefunctional recovery and neuroprotection in a mousestroke model [1650]. Neural stem cells improved learn-ing and memory in rats with AD [1651] and improvedneuronal survival in cultured postmortem brain tissuefrom aged and AD patients [1652].

Induced pluripotent stem cells may be used to modelpatient-specific AD in vitro [1653, 1654]. For a com-mentary, see [1655]; to model pathology in Downsyndrome [1656] and in HD [1657]. They may cre-ate new opportunities for disease modeling and drugdiscovery [1758].

GDNF/BDNF-producing glial and brain-derivedstem cells (NurOwn; BrainStorm Cell Therapeutics,New York, NY) is investigated as a potential treatmentof PD, sciatica, and multiple sclerosis [1658, 1659].A Phase I/II clinical trial in ALS patients started inJune 2011 in Israel. In January 2012 positive data werereported (Thomson Reuters Pharma, update of July 24,2012).

Human neural stem cell therapy (HuCNS-SC;StemCells, Newark, CA, formerly CytoTherapeuticsunder license from NeuroSperes) is a proprietary trans-plantable human neural stem cell therapy for thepotential treatment of spinal cord injury, age-relatedmacular degeneration, and AD. Human neural stemcells induced functional myelination in mice [1759]and in the human brain [1760]. A Phase II trial forspinal cord injury was initiated in Switzerland in March2011. The neuroprotective effects in retinal degenera-tion were described [1660] (Thomson Reuters Pharma,update of September 28, 2012).

Mesenchymal bone marrow-derived stem celltherapy (Stemedica Cell Technologies, San Diego,CA) is being developed for the intravenous treatmentof ischemic stroke in Phase I/II since February 2011in the US (n = 35). The study was expected to be com-pleted in February 2013 (Thomson Reuters Pharma,update of April 11, 2012).

NSI-189 (Neuralstem, Rockville, MD, in collabora-tion with Japanese licensee Summit Pharmaceuticals)(Fig. 16) is an orally bioavailable small-molecule neu-rogenesis stimulator in Phase I, which was completedin October 2011. The FDA approved the Phase Ib trialin December 2011 (three cohorts of eight patients each). In June 2012, the first patients were dosed (ThomsonReuters Pharma, update of September 28, 2012).

NSI-566RSC (Neuralstem, Rockville, MD) arehuman neural stem cells including spinal cord stem


Fig. 16. A neurogenesis stimulator and two SV2A ligands.

cells for the potential injectable treatment of ALS,stroke, HD, and AD. Long-distance growth and con-nectivity of neural stem cells after severe spinal cordinjury were investigated [1661]. A Phase I clinicaltrial for ALS started in January 2010 in the US. Theresults of a Phase I trial in 12 ALS patients receivinglumbar intraspinal injection of neural stem cells weredescribed [1662] (Thomson Reuters Pharma, update ofSeptember 28, 2012).

Neurostem-AD (Medipost, South Korea) is anumbilical cord blood-derived mesenchymal stem celltherapy, which regenerates nerve cells. A Phase Itrial has been initiated in February 2011 in patients(expected n = 9) with dementia of AD-type (ThomsonReuters Pharma, update of September 25, 2012).

There are several stem cell preparations in preclini-cal evaluation (in alphabetical order):

Adult mesenchymal precursor stem cell therapy(Mesoblast, Melbourne, Australia and Cephalon, awholly-owned subsidiary of Teva) is evaluated for thepotential treatment of AD and PD and stroke (ThomsonReuters Pharma, update of September 6, 2012).

Allogenic umbilical cord stem cell therapy(U-CORD; CellPraxis Bioengenharia, Bela Vista,Brazil) is investigated for the potential treatmentof Alzheimer’s disease. (Thomson Reuters Pharma,update of November 07, 2012).

Brain-derived stem cell therapy (Celprogen, SanPedro, CA, in collaboration with the Indiana UniversitySchool of Medicine) can be differentiated into neurons.In vivo preclinical studies demonstrated improvementin short and long term memory in AD experimentalmodels (Thomson Reuters Pharma, update of July 14,2011).

CPG23NEUR (Celprogen, San Pedro, CA) derivesfrom cord blood stem cells, which are trans-differentiating into neuronal cells (Thomson ReutersPharma, update of January 30, 2012).

Glial progenitor cell therapy (Q Therapeutics, SaltLake City, UT) has the potential to replace myelinon damaged neurons for the treatment of transversemyelinitis, spinal cord injury, multiple sclerosis, PD,and AD (Thomson Reuters Pharma, update of January20, 2012).

Human neural progenitor cells (Cedars-SinaiMedical Center, Los Angeles, CA), which secretegrowth factors including glial cell-derived neurotro-phic factor, may be useful for the treatment of ALS(Thomson Reuters Pharma, update of July 31, 2012).

Human umbilical cord blood cells (Saneron CCELTherapeutics, Tampa FL) are cerebroprotective agentswhich showed cognition enhancing and amyloid-�reducing activities for the potential treatment of strokeand Alzheimer’s disease (Thomson Reuters Pharma,update of October 26, 2012).

NBI-18 (NeoCytex Biopharma, Covington, KY),a heterocyclic pyrimidine derivative, is a stem cellstimulator for the potential treatment of neurodegener-ative diseases including ALS, AD, and PD (ThomsonReuters Pharma, update of January 19, 2012). Thestructure was not communicated.

Neural stem cell therapy (Stemedica Cell Tech-nologies, San Diego, CA) is an allogeneic therapyfor the potential treatment of AD (Thomson ReutersPharma, update of February 22, 2012). Anotherstem cell therapy is evaluated for spinal cord injury(Thomson Reuters Pharma, update of February 28,2012).

NeurotrophinCell (Living Cell Technologies,Auckland, NZ) is an alginate-microencapsulatedporcine choroid plexus cell product for the potentialtreatment of neurodegenerative diseases including HD,PD, and dementia [1663, 1664] (Thomson ReutersPharma, update of May 16, 2012).

NGN-9079 (neural stem cell therapy; NeuroGener-ation, Los Angeles, CA) is evaluated for the potential


treatment of AD. Transplantation of neuronal cellsinto the brain was shown to improve and delay thesymptoms of AD in animal models (Thomson ReutersPharma, update of March 2, 2012).

ReN-004 (ReNeuron, Guildford, UK) is a neuralstem cell therapy for PD and AD (Thomson ReutersPharma, update of September 5, 2012).

ReN-005 (ReNeuron, Guildford, UK) is a neuralstem cell therapy for HD (Thomson Reuters Pharma,update of December 24, 2010).

Stem cell therapeutics (Samaritan Pharmaceuti-cals, Las Vegas, NV) are non-embryonic neuronal stemcell differentiation therapeutics including the naturallyoccurring compounds SP-sc4 and SP-sc7 to inducestem cell differentiation for the potential treatment ofAD (Thomson Reuters Pharma, update of March 16,2011).

Allopregnanolone (University of Southern Califor-nia, Los Angeles, CA) is a potent and highly efficaciousproliferative agent in vitro and in vivo of both rodentand human neural stem cells [1665–1667].

Granulocyte colony-stimulating factor is knownto mobilize hematopoietic stem cells from the bonemarrow into the peripheral blood. Subcutaneousadministration of granulocyte colony-stimulating fac-tor into two different A�-induced AD mouse modelssubstantially rescued their cognitive/memory func-tions [1668].

Valproic acid can induce neurogenesis of neuralprogenitor/stem cells both in vitro and in vivo via mul-tiple signaling pathways [1669].

The development of GRNOPC-1 (Geron), oligo-dendrocyte precursor cells differentiated from a humanembryonic stem cell line that produce neurotrophic fac-tors and remyelinate axons for the potential injectabletreatment of PD, stroke, AD, multiple sclerosis, andspinal cord injury in Phase I since October 2010was terminated. Also the development of the humanembryonic stem cell therapy (GRNIC-1, Geron),the cell-based therapy MDA-200C (Medeia Thera-peutics), NEBO-176 (Neuro Bioscience and RLI),propentofylline (Endogenous Stem Cells Activators(ESAI) under license from sanofi) and of stem celltherapies for glaucoma, macular degeneration, PD,traumatic brain injury, and vascular dementia (Stemed-ica) was terminated.

MISCELLANEOUS

Autophagy inducer JRP-900 (Prous Institute forBiomedical Research, Barcelona) is investigated for

the potential treatment of neurodegenerative diseaseincluding AD, ALS, HD, and PD (Thomson ReutersPharma, update of July 23, 2012). The structurewas not communicated. For reviews on autophagy inAlzheimer’s disease and tauopathies see [1761–1764].

Cellular homeostasis modulator CNS-102 (Coy-ote Pharmaceuticals) acts on protein misfolding forthe potential treatment of AD, multiple sclerosis, andALS (Thomson Reuters Pharma, update of October 2,2012). The structure was not communicated.

Glycan inhibitors (Stelic Institute, Tokyo) areinvestigated for the potential treatment of Parkinson’sand Alzheimer’s disease. An exhaustive review wasprovided [1765]. (Thomson Reuters Pharma, update ofOctober 16, 2012). Structures were not communicated.

Macrophage migration inhibitory factor (MIF)inhibitor INV-88 (Innovimmune Biotherapeutics,New York) is investigated for the potential oral treat-ment of inflammatory diseases, central nervous systemdiseases including Alzheimer’s disease and multiplesclerosis and age-related macular degeneration (Thom-son Reuters Pharma, update of October 18, 2012). Thestructure was not communicated.

MicroRNA (miRNA) mimetics (University ofGottingen, MBM Science) are evaluated for the poten-tial diagnosis and treatment of memory impairment.By June 2012, proof of concept was achieved in anAD mouse model and in human AD patient samples.The relationship of miRNAs in the brain and A� gener-ation was discussed [1670] (Thomson Reuters Pharma,update of August 7, 2012).

Proteasome-gating modulators are investigatedby Proteostasis Therapeutics, Cambridge, MA underlicense from Harvard University for the potential treat-ment of neurodegenerative diseases including AD andPD (Thomson Reuters Pharma, update of August 15,2012).

Synaptic vesicle glycoprotein 2A (SV2A) ligandlevetiracetam (L-059, Keppra; UCB Pharma, Brus-sels, Belgium and Japanese licensee Otsuka) (Fig. 16)is an antiepileptic drug launched in the US and EUin 2000 and in Japan in 2010 [1671–1676]. It bindsto the same binding site as botulinum neurotoxin Aand tetanus neurotoxin [1677, 1678]. It is still unclearhow levetiracetam modulates SV2A’s function(s). Itinhibited presynaptic Ca2+ channels through an intra-cellular pathway [1679, 1680]. It may promoteglutamate uptake by increasing glutamate transporterexpression [1681]. There are hints that levetiracetammay interact with GABAA receptors [1682–1684].Levetiracetam had a positive impact on emotionallearning and memory in naıve mice [1685] and


reversed cognitive deficits in hA�PP transgenic mice[1686]. Levetiracetam improved cognitive function indrug-naıve epilepsy patients [1687] and in childrenaged 4 to 16 years [1688]. The sales of levetiracetamreported by UCB for 2011 were USD 1,345 million andby Otsuka, USD 60.5. An injectable formulation waslaunched in the US in August 2006, an extended releaseformulation in September 2008 (Thomson ReutersPharma, update of October 1, 2012).

Low-dose therapy Levetiracetam (AgeneBio,Carmel, IN under license from John Hopkins Uni-versity) is investigated for the potential treatmentof amnestic MCI (aMCI) in Phase II clinical tri-als since December 2009 in 144 aMCI patients inthe US. Reduction of hippocampal hyperactivity inaMCI patients by using a low dose of levetiracetamimproved cognition [1766]. It appears that the devel-opment was terminated (Thomson Reuters Pharma,update of September 7, 2011).

Brivaracetam (UCB-34714; Rikelta; UCB Pharma,Brussels, Belgium) (Fig. 16), the n-propyl analogueof levetiracetam, is an orally active ligand of synapticvesicle protein 2A (SV2A) currently in Phase III clini-cal trials for the treatment of epilepsy since November2008 (n = 600). The study is expected to complete inJune 2015 [1689, 1690]. Its binding characteristics asa high affinity SV2A ligand in rat, mouse and humanbrain were reported [1691] as was its effect on theinhibition of Na+ currents [1692]. Its neurocognitiveeffects were similar to the ones of levetiracetam [1693,1694] (Thomson Reuters Pharma, update of August 8,2012).

CONCLUSION

Two products were launched in 2012: tafamidis(Vyndaquel, Pfizer) for the treatment of transthyretinfamilial amyloid polyneuropathy in Europe in Marchand 18F-florbetapir (Amyvid; Avid Radiopharma-ceuticals, Lilly) as a PET imaging agent to estimateA� neuritic plaque density in patients with cognitiveimpairment in the US in June.

Phase III Alzheimer’s disease trials of a diseasemodifying drug, the monoclonal antibody against A�solanezumab (Lilly), are close to completion. Firstresults showed that solanezumab failed to meet the cog-nitive and functional primary endpoints. But it showeda significant reduction in cognitive decline in patientswith mild AD. For a commentary, see [1695]. Theopen-label EXPEDITION-EXT extension trial, whichis fully enrolled, is continuing as planned.

The development of the second Phase III mono-clonal antibody bapineuzumab (Janssen AlzheimerImmunotherapy and Pfizer) was terminated.

The Phase III clinical trials of other A� PETimaging agents, 18F-florbetaben (Piramal) and 18F-flutemetamol (GE Healthcare), may be successfullycompleted by next year. The completion of PhaseIII clinical trials of the VMAT2 PET ligand 18F-florbenazine (Avid Radiopharmaceuticals, Lilly) isplanned for September 2014.

Phase II clinical trials of other disease modi-fying drugs, of monoclonal antibodies against A�gantenerumab, crenezumab, GSK-93377A, intra-venous immune globulin, and octagam, of vaccinesagainst A� AD-02, CAD-106, and vanutide cridi-ficar and the PET ligand 18F-AZD-4694 (Navidea)will require several years. This applies also for thePhase II clinical trials of small molecules preventingA� aggregation or inhibiting formation of transthyretinamyloid fibrils, such as doxycycline hyclate, ELND-005, and SOM-0226 or preventing tau aggregation,such as PBT-2, tideglusib, and TRx-0014.

Concerning drugs for palliative treatment of AD,two Phase III compounds are currently frontrunners,DP-b99 (a calcium and zinc chelator) and SK-PC-B70M (a natural product) followed by 22 Phase IIcompounds, RV-208 (a gene expression stimulator),ARC-029 and ZSET-1446/ST-101 (calcium channelblockers), CERE-110, GM-607, PYM-50058, andT-817MA (trophic factor stimulators), circadin, KD-501, PPL, PTX-200, resveratrol, RPh-201 (naturalproducts), LSL-001, N-251, PF-03049423, TRM-189, VI-1121 (nootropics), davunetide, AM-111,etanercept, and FGL (peptides).

DISCLOSURE STATEMENT

Authors’ disclosures available online (http://www.j-alz.com/disclosures/view.php?id=1543).

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