Cognitive Enhancers (Nootropics). Part 1: Drugs ...€¦ · The present review covers the evolution of research in this ﬁeld through March 2014. Keywords: Alzheimer’s disease,

Journal of Alzheimer’s Disease 41 (2014) 961–1019DOI 10.3233/JAD-140228IOS Press

961

Review

Cognitive Enhancers (Nootropics). Part 1:Drugs interacting with Receptors. Update2014

Wolfgang Froestl∗, Andreas Muhs and Andrea PfeiferAC Immune SA, EPFL, Lausanne, Switzerland

Accepted 7 March 2014

Abstract. Scientists working in the fields of Alzheimer’s disease and, in particular, cognitive enhancers are very productive. Thereview “Cognitive enhancers (nootropics): drugs interacting with receptors” was accepted for publication in July 2012. Sincethen, new targets for the potential treatment of Alzheimer’s disease were identified. This update describes drugs interacting with42 receptors versus 32 receptors in the first paper. Some compounds progressed in their development, while many others werediscontinued. The present review covers the evolution of research in this field through March 2014.

Keywords: Alzheimer’s disease, cognitive enhancers, memantine, memory, nootropics, receptors

INTRODUCTION

As of April 19, 2014, there are 28,192 entries inPubMed under the term cognitive enhancers, 28,218entries under the term nootropic, and 312 entriesunder the term cognition enhancers. Scifinder lists5,687 references under the research topic nootropic,651 references under the term cognitive enhancer,and 11,214 references for cognition enhancers. TheThomson Reuters Pharma database lists 1,249 drugsas nootropic agents or cognition enhancers and giveszero results under the term cognitive enhancer. Theterm nootropics was coined by the father of piracetam,Corneliu Giurgea, in 1972/1973 [1, 2]; NOOS = mindand TROPEIN = toward.

∗Correspondence to: Dr. Wolfgang Froestl, AC Immune SA,EPFL, Innovation Park, Building B, CH-1015 Lausanne, Switzer-land. Tel.: +0041 21 693 91 43; Fax: +0041 21 693 91 20; E-mail:[email protected].

Cognitive enhancers (nootropics) are drugs to treatcognition deficits, which are most commonly foundin patients suffering from Alzheimer’s disease (AD),schizophrenia, stroke, attention deficit hyperactivitydisorder (ADHD), or aging. Cognition refers to acapacity for information processing, applying knowl-edge, and changing preferences. According to AstridNehlig [3], it involves memory, attention, execu-tive functions, perception, language, and psychomotorfunctions. Mark J. Millan and 24 eminent researchers[4] presented an excellent overview on cognitivedysfunction in psychiatric disorders in the Febru-ary 2012 issue of Nature Reviews Drug Discoveryand define cognition as “a suite of interrelated con-scious (and unconscious) mental activities, includingpre-attentional sensory gating, attention, learning andmemory, problem solving, planning, reasoning andjudgment, understanding, knowing and representing,creativity, intuition and insight, spontaneous thought,introspection, as well as mental time travel, self

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962 W. Froestl et al. / Cognitive Enhancers (Nootropics)

awareness and meta cognition (thinking and knowl-edge about cognition)”.

Since a first review in 1989 on “Families of Cogni-tion Enhancers” by Froestl and Maitre [5], 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 Receptors2. Drugs interacting with Enzymes3. Drugs interacting with Cytokines4. Drugs interacting with Gene Expression5. Drugs interacting with Heat Shock Proteins6. Drugs interacting with Hormones7. Drugs interacting with Ion Channels

( /= Receptors)8. Drugs interacting with Nerve Growth Factors9. Drugs interacting with Re-uptake Transporters

(Psychostimulants)10. Drugs interacting with Transcription Factors11. Antioxidants12. Metal Chelators13. Natural Products14. Nootropics (“Drugs without mechanism”)15. Peptides16. Drugs preventing amyloid-� aggregation

16.1 Ligands interacting with amyloid-�16.2 Inhibitors of serum amyloid P component

binding16.3 Vaccines against amyloid-�16.4 Antibodies against amyloid-�

17. Drugs interacting with tau, prion, and�-synuclein17.1 Small molecules preventing tau, prion, and

�-synuclein aggregation17.2 Ligands interacting with tau and

�-synuclein17.3 Vaccines against tau and �-synuclein17.4 Antibodies against tau, �-synuclein and

ApoE18. Stem Cells19. Miscellaneous

In Part 1 drugs interacting with receptors weredescribed [6], in Part 2 drugs interacting with enzymeswere detailed [7], and in Part 3 drugs interacting withtargets 3 to 10 and compounds and preparations of cat-egories 11 to 19 [8] were described. However, thisfield is very dynamic. New targets were identified.Some compounds progressed in their development,many others were discontinued. Therefore an updateis appropriate.

1. DRUGS INTERACTING WITHRECEPTORS

Researchers have been investigating drugs interact-ing with a wide variety of receptors in order to identifyvaluable cognitive enhancers [9–13]. These receptors(and drugs) are:

1.1. Acetylcholine Receptors1.1.1. Muscarinic Acetylcholine Receptors

1.1.1.1. Orthosteric mACh M1 Recep-tor Agonists

1.1.1.2. Allosteric mACh M1 ReceptorAgonists

1.1.2. Nicotinic Acetylcholine Receptors1.1.2.1 �4�2 and �3�4 Nicotinic

Acetylcholine Receptor Ago-nists

1.1.2.2 �7 Neuronal Nicotinic Acetyl-choline Receptor Agonists

1.2. Adenosine Receptors1.3. Adrenergic Receptors1.4. Amylin Receptors1.5. Androgen Receptors1.6. Angiotensin Receptors1.7. Calcium-sensing Receptors1.8. Cannabinoid Receptors1.9. Chemokine Receptors

1.10. Corticotropin Releasing Factor Receptors1.11. Cysteinyl Leukotriene Receptor 1 (CysLT1R)1.12. Dopamine Receptors1.13. Endothelin Receptors1.14. Estrogen Receptors1.15. GABA Receptors

1.15.1 GABAA Receptors1.15.2 GABAB Receptors1.15.3 GABAC Receptors

1.16. Galanin Receptors1.17. Glutamate Receptors

1.17.1 AMPA Receptors1.17.1.1 Piracetam-type compounds1.17.1.2 AMPAkines1.17.1.3 Biarylpropylsulfonamides

1.17.2 NMDA Receptors1.17.3 NMDA Receptors’ Glycine-Site1.17.4 Metabotropic Glutamate Receptors

1.18. G-protein coupled Orphan Receptors1.19. Histamine Receptors1.20. Imidazoline Receptors1.21. Insulin Receptors1.22. Liver X Receptors1.23. Melatonin Receptors

W. Froestl et al. / Cognitive Enhancers (Nootropics) 963

1.24. Neurotensin Receptors1.25. Nociceptin (ORL1) Receptors1.26. Opioid Receptors1.27. Peripheral Benzodiazepine Receptors1.28. Peroxisome Proliferator-Activated Receptors1.29. Prostaglandin Receptors1.30. Purinergic Receptors1.31. Receptor for Advanced Glycation End Products1.32. Retinoid X Receptors1.33. Ryanodine Receptors1.34. Scavenging Receptor Class A1.35. Serotonin Receptors

1.35.1 5-HT1A Receptors1.35.2 5-HT2 Receptors1.35.3 5-HT3 Receptors1.35.4 5-HT4 Receptors1.35.5 5-HT6 Receptors

1.36. Sigma Receptors1.37. Somatostatin Receptors1.38. Sortilin Receptors1.39. Sphingosine-1-Phosphate Receptors1.40. Tachykinin Receptors1.41. Tumor Necrosis Factor Receptors 1/21.42. Vitamin D Receptors

1.1. Acetylcholine receptors

After the publication of the cholinergic hypothesisof AD by Bartus et al. in 1982 [14] showing by bio-chemical, electrophysiological, and pharmacologicalevidence that cholinergic dysfunction is responsi-ble for age-related memory disturbances, tremendousefforts have been undertaken by academics and byresearchers from the pharmaceutical industry to findselective acetylcholine receptor agonists (and acetyl-cholinesterase inhibitors) to counteract cholinergicdysfunction.

1.1.1. Muscarinic acetylcholine receptorsNobel prize winner Brian K. Kobilka and 17 expert

colleagues described the X-ray crystal structures ofthe muscarinic acetylcholine M2 receptor bound to thehigh affinity agonist iperoxo [15].

1.1.1.1. Orthosteric muscarinic acetylcholine M1receptor agonists. Hundreds of (wo)men years wentinto syntheses and characterization of M1 selectivemuscarinic cholinergic agonists, five of which werefollowed up into extended Phase III clinical trialsbefore their development was terminated due to unac-ceptable side effects [16, 17].

Cevimeline (AF-102B, SNK-508, Exovac,hydrochloride hemihydrate, Israel Institute forBiological Research, Ness-Ziona; Fig. 1), aspiro-quinuclidine derivative, is probably thebest investigated selective M1 muscarinic acetyl-choline receptor (mAChR) agonist. It was in PhaseIII clinical trials for the treatment of AD patients inthe US, Japan, and Israel. It is the only orthostericacetylcholine receptor agonist, which made it to theUS and Japanese markets in 2001 for the treatmentof dry mouth of patients suffering from Sjogren’sdisease (xerostomia; marketed by Snow Brand MilkProducts, Tokyo and Daiichi Pharmaceuticals, Tokyo)[18–20]. The receptor profile of cevimeline accordingto [21] is: M1: EC50 = 23 nM, Emax = 82%, M2:EC50 = 1.04 �M, Emax = 98%, M1 selectivity overM2: 78 fold, M3: EC50 = 48 nM, Emax = 75%, M1selectivity over M3: 2 fold, M4: EC50 = 1.31 �M,Emax = 50%, M1 selectivity over M4: 58 fold, M5:EC50 = 63 nM, Emax = 43%, M1 selectivity over M5:3 fold. Cevimeline (AF-102B) decreased the levelsof total amyloid-� (A�) in cerebrospinal fluid (CSF)of patients with AD [22] (Thomson Reuters Pharma,update of March 14, 2014).

Fig. 1. Structures of orthosteric muscarinic acetylcholine receptor ligands.


AZPET (FluoroPharma, Montclair, NJ in collabora-tion with the Massachusetts General Hospital, Boston,MA, 18F-RS-86, Sandoz, now Novartis; Fig. 1) is eval-uated for the potential diagnosis of AD (ThomsonReuters Pharma, update of May 27, 2014).

The development of several orthosteric M1 selec-tive mAChR agonists was terminated (in alphabeticalorder): of MCD-386 (CDD-0102A; Mithridion underlicense from the University of Toledo; [23–26]), MI-09018, MI-08-016/35, and MI-10-022 (Mithridion)and of Sabcomeline (BrainCells under license fromProximagen and GSK; [27–29]).

1.1.1.2. Allosteric muscarinic acetylcholine M1receptor agonists. An important breakthrough wasachieved in 2002 at ACADIA Pharmaceuticals (SanDiego, CA), where scientists screened a library of145,000 structurally diverse small organic moleculesfor agonist activity on M1, M3, and M5 muscarinicreceptors using a cell-based functional assay. Theyidentified allosteric agonists acting at a site removedfrom the orthosteric site to directly activate thereceptor in the absence of acetylcholine [30–33].

MK-7622 (Merck, Whitehouse Station, NJ) is aM1 positive allosteric modulator (PAM) for the poten-tial oral treatment of mild to moderate AD. InNovember 2013, a Phase IIb clinical trial was ini-tiated in the US [34] (Thomson Reuters Pharma,update of May 16, 2014). Its structure was notcommunicated.

AC-262271 (Allergan, Irvine, CA, under licensefrom ACADIA Pharmaceuticals) is being developedfor the treatment of glaucoma in Phase I clinical trialssince August 2007 (Thomson Reuters Pharma, updateof November 7, 2013). Its structure was not communi-cated.

HTL-9936 (Heptares Therapeutics, Welwyn Gar-den City, Hertfordshire, UK) is an allosteric M1subtype selective muscarinic acetylcholine agonist forthe potential treatment of schizophrenia and AD. InDecember 2013a Phase I trial was initiated in healthyvolunteers (expected n > 100) in the UK to evaluate thesafety, tolerability, and pharmacokinetics of HTL-9936for AD (Thomson Reuters Pharma, update of April 30,2014). The structure was not communicated.

There are currently several allosteric M1 mAChRagonists in preclinical development (in alphabeticalorder):

ANAVEX 3-71 (AF-710B; Anavex Life Sciences,New York, NY under license from the Israel Institutefor Biological Research, Ness Ziona; Fig. 2) is a M1muscarinic allosteric modulator and a sigma 1 receptor

agonist with neuroprotective and cognition enhancingproperties (Thomson Reuters Pharma, update of May29, 2014).

ASN-51 (Asceneuron, Lausanne, Switzerland) is aM1-selective muscarinic AChR PAM for the potentialtreatment of AD. Data from mouse primary neuron cul-tures demonstrated that ASN-51 had shown efficacyat nanomolar concentrations and modulated only theM1 subtype. In vivo data showed that the drug eliciteda dose-dependent increase in inositol monophosphatelevels after one single oral dose (Thomson ReutersPharma, update of March 25, 2014). The structure wasnot disclosed.

AstraZeneca presented gem-difluoro bicyclics asnovel M1 muscarinic receptor agonists (Fig. 2), whichshowed enhanced metabolic stability in comparison tothe non-fluorinated analogues. A more potent deriva-tive PPBI (Fig. 2) was presented recently with a pEC50of 8.34 in human M1 AChRs. AstraZeneca, underlicense from Vanderbilt University, is investigatingcompounds that act on the M4 mAChR for the poten-tial treatment of neurological conditions includingpsychosis, AD and schizophrenia (Thomson ReutersPharma, update of April 22, 2014).

Dainippon Sumitomo Pharma (Osaka, Fig. 2) isevaluating M4 mAChR agonists for the potentialtreatment of psychotic disorders due to AD andschizophrenia (Thomson Reuters Pharma, update ofApril 16, 2013).

Dainippon Sumitomo Pharma (Osaka, Fig. 2) isevaluating M1 and M4 mAChR partial agonists forthe potential treatment of schizophrenia (ThomsonReuters Pharma, update of November 28, 2013).

Merck (Westpoint, PA) scientists presented a moreadvanced compound (Fig. 2) with good bioavailabil-ities in rats and dogs of 68 and 62%, respectively(Thomson Reuters Pharma, update of October 10,2012). For the medicinal chemistry, see [35–42]. Areview on patents claiming allosteric M1 receptor mod-ulators was presented [43].

The development of AM-831 (Acadia Pharmaceuti-cals in collaboration with Meiji Seika), BQCA (Merck;[44–48]), of TBPB, VU0255035 (ML012) [49, 50]and VU0415248 (all Vanderbilt University) was ter-minated.

1.1.2. Nicotinic acetylcholine receptorsNicotinic acetylcholine receptors (nAChRs) are

ion channel receptors belonging to the same classas 5-HT3, GABAA, and strychnine-sensitive glycinereceptors [51]. The nAChRs are encoded by 17 genes.Of these nine � subunits (�2-�10) and three � subunits


Fig. 2. Structures of allosteric muscarinic acetylcholine receptor ligands.

(�2–�4) are expressed in the brain ([52–54]). >90%of the nAChR in the CNS contain �4 and �2 subunitsforming �-bungarotoxin insensitive receptors. Anothersubtype consists of a homopentamer of �7 subunits,�-bungarotoxin sensitive receptors [55]. In the �4�2receptor (consisting of 2 �4 and 3 �2 subunits) thereare two, in the �7 homopentamer there are five AChbinding sites.

1.1.2.1. α4β2 and α3β4 nicotinic acetylcholine recep-tor agonists. Ispronicline (TC-1734; AZD-3480;Targacept, Winston-Salem, NC; Fig. 3) is developedfor potential oral treatment of AD and ADHD [56–63].Results of a Phase IIb AD trial were reported [64].Targacept has completed recruitment of patients foranother Phase IIb study of TC-1734 as a treatment formild to moderate AD. Targacept expects to report top-line results from the study in mid-2014. The drug wasalso under development for schizophrenia-associatedcognitive deficits, but failed to meet the primaryendpoints [65]. AstraZeneca returned all rights ofispronicline to Targacept (Thomson Reuters Pharma,update of May 8, 2014).

Pozanicline (ABT-089; AbbVie, North Chicago, IL;Fig. 3) was tested in AD, ADHD, schizophrenia, andsmoking cessation. The indication schizophrenia wasabandoned. Two Phase II trials in children afflictedby ADHD gave negative results. Efficacy and safetyof ABT-089 in adults with ADHD was reported [66](Thomson Reuters Pharma, update of December 4,2013).

ABT-560 (AbbVie, North Chicago, IL under licensefrom NeuroSearch, Ballerup, DK) is an �4�2 subtypeselective nAChR agonist in Phase I clinical trials sinceJuly 2007 (Thomson Reuters Pharma, update of Jan-uary 4, 2013). The structure was not communicated.

18F-Flutabine (norchloro-fluoro-homo-epibatidine, NCFHEB; University of Leipzig),which targets the neuronal �4�2 nicotinic AChRs, isevaluated as a positron emission tomography (PET)imaging agent for the potential diagnosis and imagingof AD in Phase I clinical trials since October 2011(Thomson Reuters Pharma, update of August 5, 2013).

There are several �4�2 subtype selective nAChRagonist in preclinical evaluation (in alphabeticalorder):

Aniona (Copenhagen, a spin-out from NsDiscovery,previously a division of Neurosearch, Ballerup, DK) isinvestigating �4�2 subtype allosteric modulators forthe potential treatment of cognitive disorders (Thom-son Reuters Pharma, update of November 22, 2013).Structures were not communicated.

S-35836-1 (Servier; Fig. 3) and S-38232-1 are anew cyclopropanamine derivatives for the potentialtreatment of age-related cognitive disorders [67, 68].A potential follow-up compound is S-47952, whosestructure was not communicated (Thomson ReutersPharma, update of June 26, 2013).

SUVN-911 (Suven Life Sciences, Hyderabad) isan oral �4�2 nAChR antagonist, for the potentialtreatment of mood disorders and major depressive dis-orders. Other �4�2 nAChR antagonists are evaluated


Fig. 3. �4�2 and �3�4 nicotinic acetylcholine receptor agonists.

for the potential treatment of schizophrenia, pain andcognitive disorders (Thomson Reuters Pharma, updateof April 11, 2014). Structures were not communicated.

ZY-1 (Shanghai Jiao Tong University, Fig. 3) is an�4�2 nAChR agonist, which enhanced cognitive func-tions in a transgenic model of AD [69]. It also promotedproliferation and migration of adult hippocampal neu-ral stem/progenitor cells [70].

Carbon-11 labeled pyridyl ethers for in vivo imagingof �4�2 nAChRs in brain were described [71].

The development of several compounds was ter-minated (in alphabetical order): of lobeline (CeptarisTherapeutics, formerly Yaupon Therapeutics), NS-9283 (A-969933; NeuroSearch in collaboration withAbbott; [72–74]), sazetidine-A (AMOP-H-OH; Axeu-ron Therapeutics), sofinicline (ABT-894; AbbVieunder license from NeuroSearch), SR-16584 and SR-17080 (non-competitive �3�4 nAChR antagonists;SRI International) and of SUVN-F91201 (Suven LifeSciences).

1.1.2.2. Alpha7 nicotinic acetylcholine receptor ago-nists. For excellent reviews, see [75, 76]. A recentreview described the �7-nAChR agonists in humanclinical AD trials [77] and in Down’s syndrome [563].

Encenicline (EVP-6124, MT-4666, FORUM Phar-maceuticals, previously EnVivo, Watertown, MA,under license from Bayer and Mitsubishi TanabePharma, Osaka; Fig. 4) is an �7 nAChR partial ago-

nist. In October 2012 a randomized, double-blind,placebo-controlled, Phase III trial began in the US inpatients (expected n = 640) with schizophrenia (Thom-son Reuters Pharma, update of April 23, 2014).

A potential follow-up compound is EVP-4473(Thomson Reuters Pharma, update of April 3, 2014).The structure of EVP-4473 was not communicated.

ABT-126 (AbbVie, North Chicago, IL; Fig. 4) isan �7 neuronal nicotinic receptor modulator for thepotential treatment of AD and for cognitive deficits inschizophrenia. In January 2013 a randomized, double-blind, placebo- and active-controlled Phase II studyto evaluate the efficacy and safety of ABT-126 inpatients with mild to moderate AD (n = 410) wasstarted (Thomson Reuters Pharma, update of April 24,2014).

GTS-21 (DMXB; CoMentis, South San Francisco,CA, licensed from the University of Florida; Fig. 4)is an �7 nAChR partial agonist in Phase II clinicaltrials for the treatment of AD, cognition deficits inschizophrenia, and ADHD [78–84]. The improvementof cognitive performance of rhesus monkeys by GTS-21 was described recently [85] (Thomson ReutersPharma, update of April 17, 2014).

ABT-272 (AbbVie Laboratories, North Chicago, IL)is an �7 nAChR modulator for the potential treatmentof pain in Phase I clinical trials since January 2013(Thomson Reuters Pharma, update of January 3, 2013).The structure was not communicated.


Fig. 4. �7 nicotinic acetylcholine receptor agonists.

BMS-933043 (Bristol-Myers Squibb) is a selec-tive �7 nAChR agonist in Phase I clinical trials inhealthy subjects (n = 135) in the US since July 2012(NCT01605994; Thomson Reuters Pharma, updateof December 31, 2013). The structure was notcommunicated.

SKL-A4R (SKL-15508; SK Biopharmaceuticals,Fair Lawn, NJ, formerly SK Life Science) is a novel

�7 nAChR partial agonist displaying pro-cognitive andneuroprotective effects. By September 2013 a PhaseIa trial had been initiated (Thomson Reuters Pharma,update of May 23, 2014). The structure was not com-municated.

There are many selective �7 neuronal nicotinicreceptor (partial) agonists in preclinical evaluation (inalphabetical order):


A-867744 (AbbVie, North Chicago, IL; Fig. 4)and ABT-779 are PAMs of the �7 nAChR (Thom-son Reuters Pharma, update of January 4, 2013).The extensive preclinical characterization of A-582941(Fig. 4) allowed the elucidation of its broad-spectrumcognition-enhancing properties [86].

ADispell (Rochester, NY under license from CornellUniversity) investigates small molecules with target anovel site on the nAChR (�7?) for the potential treat-ment of AD. Three lead compounds were identified,which increased cognition performance in multiple invivo studies. In March 2011, the Alzheimer’s DrugDiscovery Foundation awarded a grant to ADispell(Thomson Reuters Pharma, update of October 10,2013). The structures were not communicated.

AN-761 (NSD-761; Aniona, Copenhagen, a spin-out from NsDiscovery, previously a division ofNeuroSearch, Ballerup, DK) is an �7 nAChR ago-nist for the treatment of cognitive disorders includingschizophrenia (Thomson Reuters Pharma, update ofApril 29, 2014). The structure was not communicated.

BNC-259, BNC-375, BNC-1881, BNC-259, BL-10343, and BL-010362 (Bionomics, Adelaide) arePAMs of �7 nAChR for the potential memory improve-ment treatment in AD and schizophrenia (ThomsonReuters Pharma, update of February 24, 2014). Struc-tures were not communicated.

Lu AF-58801 (Lundbeck A/S, Valby, DK; Fig. 4)is a novel, selective, and brain penetrant PAM of�7 nAChRs. It attenuated subchronic phencyclidine-induced cognitive deficits in a novel object recognitiontask in rats following oral administration [87].

PheTQS (Promaxigen, London, UK, a subsidiary ofUpsher-Smith Laboratories, Maple Grove, MN, underlicense from GSK; Fig. 4) showed an EC50 value of20 nM as PAM of �7 nAChRs in transfected GH41Ccells (Thomson Reuters Pharma, update of April 16,2014).

PTI-125 (Pain Therapeutics, Austin, TX) is a smallmolecule targeting a specific novel site on filaminA preventing the filamin A- �7-nAChR associationand A�1-42 toxic signaling [88] (Thomson ReutersPharma, update of February 27, 2014). The structurewas not communicated.

SEN34625/WYE-103914 (Siena Biotech andPfizer; Fig. 4) is an optimized agonist at �7 nAChRswith an EC50 of 70 nM with excellent in vitro andin vivo profiles [89] [90] (Thomson Reuters Pharma,update of April 9, 2014).

SEN15924/WAY-361789 (Siena Biotech and Pfizer;Fig. 4) is a potent, selective, and orally active fullagonist at �7 nAChRs with excellent efficacy in

rodent behavioral cognition models, such as novelobject recognition and auditory sensory gating [91, 92](Thomson Reuters Pharma, update of April 9, 2014).

SEN78702/WYE-308775 (Siena Biotech andPfizer, Fig. 4) is a potent and selective full agonist atthe �7 nAChR that demonstrated improved plasmastability and brain levels and efficacy in behavioralcognition models [93] (Thomson Reuters Pharma,update of April 9, 2014).

UCI-40083 (University of California at Irvine;Fig. 4) is an isoxazole-acetamide derived �7 nAChRPAM for the potential treatment of cognitive disor-ders including schizophrenia and ADHD [94]. At the243rd ACS Meeting in San Diego in March 2012, anovel pyridine structure was disclosed (Fig. 4; Thom-son Reuters Pharma, update of October 15, 2013). Anovel hybrid series of potent and selective agonists atthe �7 nAChR was described [564].

Therapeutic vaccines comprised of synthetic pep-tide fragments of the �7 nAChR used to generateantibodies that block A� binding to neurons areexplored at Pharma Bio, Moscow, Russia (ThomsonReuters Pharma, update of January 31, 2014).

The development of several compounds of BMS-902483 (Bristol-Myers Squibb), JNJ-1930942 (John-son & Johnson; [95]), 11C-NS-12857 and 11C-NS-14492 (NeuroSearch and University of Copenhagen)and of TC-5619 (bradanicline; Targacept; [96, 97])was terminated.

1.2. Adenosine receptors

Adenosine receptors have been implicated in themodulation of cognitive functions. Chronic treatmentwith the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DCPCX) worsened long-termmemory in A�PPSWE/PS1dE9 transgenic mice [98].The topic “Using caffeine and other adenosine recep-tor antagonists and agonists as therapeutic toolsagainst neurodegenerative diseases” was reviewed[99].

The best known A2A adenosine receptor antago-nist is caffeine (27,247 entries in PubMed as of April30, 2014). The KD values of caffeine at human A1receptors are 12 �M, at A2A receptors 2.4 �M, at A2Breceptors 13 �M, and at A3 receptors 80 �M [100]. Theassociation between caffeine and cognitive decline inboth sexes was re-evaluated [101]. Beneficial effects ofcaffeine in a transgenic model of AD-like tau pathol-ogy were shown [102]. A functional imaging studyrevealed the cortical areas affected by caffeine inges-tion [565].


Fig. 5. An adenosine A2A R antagonist, an androgen R modulator, an androgen R agonist, an angiotensin IV analogue and a cannabinoid R 2inverse agonist.

Tozadenant (SYN-115; Biotie Therapies Holding,formerly Synosia Therapeutics, Basel, Switzerlandunder license from Roche; Fig. 5) is a potent and selec-tive A2A receptor antagonist for the potential treatmentof PD in Phase IIb clinical trials since April 2011[103]. In December 2012, topline-data were reporteddemonstrating that the trial met its primary endpointof statistically significant decrease in ‘off’ time andincrease in ‘on’ time compared with placebo. ImprovedUnified Parkinson’s Disease Rating Scale (UPDRS)part III and UPDRS parts I-III combined scoresand improvements on clinician- and patient-assessedglobal impression scores were obtained (ThomsonReuters Pharma, update of April 25, 2014).

Heptares Therapeutics (Welwyn Garden City,Hertfordshire, UK) is investigating a series of A2Areceptor antagonists for the potential treatment ofPD, cognition deficits, and other CNS disorders.Two papers describing 1,2,4-triazine derivatives werepublished [104, 105] (Thomson Reuters Pharma,update of December 17, 2013).

1.3. Adrenergic receptors

The �2-adrenoceptor agonist guanfacine improvedperformance in an attention test in aged Rhesus

monkeys [106, 107]. �-Adrenergic receptors and Gprotein-coupled receptor kinase-2 may be new targetsfor drugs to treat AD [108]. A� peptides activated�1-adrenergic cardiovascular receptors [109].

ORM-12741 (Janssen Pharmaceuticals, Titusville,NJ under license from Orion Corporation, Espoo,Finland) is an �2C adrenoceptor antagonist for thepotential treatment of neurological diseases such asAD and Raynaud’s disease. By April 2011 a random-ized, double-blind, placebo-controlled Phase II trial inAD patients (n = 99) was started in Finland. A PhaseII trial in Raynaud’s disease was initiated in the UK(n = 18) in August 2011. At three months, the mem-ory scores for those who received the placebo pill hadworsened by 33%, whereas the scores improved by4% for those patients who took ORM-12741. Jansseninitiated a Phase II study in AD patients in the US inDecember 2013 (Thomson Reuters Pharma, update ofFebruary 11, 2014). The structure was not communi-cated.

ODM-102 (Janssen Pharmaceuticals, Titusville, NJunder license from Orion Corporation, Espoo, Finland)is an �2C adrenoceptor antagonist for the potentialtreatment of AD in Phase I clinical studies since April2013 in healthy males (expected n = 27) in Finland


(Thomson Reuters Pharma, update of December 23,2013). The structure was not communicated.

Fluparoxan (GR-50360A; GSK), an orally active�2 adrenoceptor antagonist, prevented age-relateddeficits in spatial working memory in A�PP/PS1 trans-genic mice without altering A� plaque load [110].

Nebivolol, a brain penetrating, selective �1 adren-ergic receptor antagonist, significantly reduced A�neuropathology in the brains of Tg2576 mice aftertreatment of three weeks at a dose of 1 mg/kg/day [111].

Prazosine, an �1-adrenoceptor antagonist, pre-vented memory deterioration in the A�PP23 trans-genic mouse model of AD [112].

Propranolol, a non-selective beta blocker, restoredcognitive deficits and improved A� and tau pathologiesin a senescence-accelerated mouse model [113–115].

1.4. Amylin receptors

Pharmacological blockade of the amylin receptor orits downregulation using siRNA in human fetal neu-rons conferred neuroprotection against oligomeric A�-induced caspase-dependent and caspase-independentapoptotic cell death. In transgenic mice (TgCRND8)that overexpress A�PP, the amylin receptor is upreg-ulated in specific brain regions that also demonstratedan elevated amyloid burden [116, 117]. A�1-42 did notelicit cAMP responses at any of the three amylin recep-tors [118]. Intraperitoneal injection of the pancreaticpeptide amylin potently reduced behavioral impair-ment and brain amyloid pathology in murine models ofAD [119]. The amylin analogue pramlintide on chronicinfusion improved performance in the novel objectrecognition task of senescence-accelerated prone mice[120].

AC-187 (Amylin Pharmaceuticals, San Diego, CA,in partnership with Johnson & Johnson) is a pep-tidic amylin antagonist for the treatment of diabetes[121, 122]. Human amylin and A� responses on wholecell currents in cholinergic basal forebrain neuronswere blocked by AC-187 [123] as was A�-inducedneurotoxicity [124]. The development was terminated(Thomson Reuters Pharma, update of May 15, 2013).

AC-253 (Amylin Pharmaceuticals, San Diego, CA,and GSK) is an injectable peptide amylin blockerfor the potential treatment of maturity-onset (type 2)diabetes, impaired glucose tolerance, and SyndromeX. It blocked increases in intracellular Ca2+, acti-vation of protein kinase A, MAPK, Akt, cFos, andcell death, which occurred upon activation of amylinreceptor-3 with human amylin, A�1-42, or their co-application [125]. Preapplication of AC-253 blocked

A� and human amylin-induced reduction of long-termpotentiation without affecting baseline transmission[126]. The structure was not communicated. The devel-opment was terminated (Thomson Reuters Pharma,update of May 16, 2013).

1.5. Androgen receptors

RAD-140 (Radius Health, Cambridge, MA, Fig. 5)is a nonsteroidal selective androgen receptor modula-tor (SARM). In vitro RAD-140 protected neurons fromneuronal apoptosis by mimicking testosterone activa-tion of a MAPK pathway. In male Sprague-Dawleyrats, RAD-140 induced androgen responses in mus-cle and brain, but not in reproductive tissues. For thedesign, synthesis and preclinical characterization ofRAD-140, see [127, 128].

The development of the androgen receptor agonistACP-105 (Acadia) and of dehydroepiandrosterone(DHEA; Fidelin; Fig. 5) was terminated [129].Part of DHEA’s pharmacology may also be due toits interaction with sigma-1 receptors [130]. Theenantiomer ent-DHEAS protected against A�25-35peptide-induced toxicity in vitro and in vivo in mice[131].

1.6. Angiotensin receptors

2,056 papers were published on the brain renin-angiotensin system (PubMed citations as of April30, 2014). The impact of angiotensin receptor block-ers on AD neuropathology was discussed [132–136].For the differential effects of angiotensin II receptorblockers on A� generation, see [566]. Angiotensinreceptor blockers as treatments for inflammatory braindisorders were presented [137]. Central angiotensinII induced tau phosphorylation in normal rat brains[138]. Drug repositioning for the treatment of AD wasdescribed recently [139].

Dihexa (MM-201; M3 Biotechnology, Pullman,WA, Fig. 5) is an angiotensin IV analogue for the poten-tial treatment of AD. It improved cognitive function ofrats with AD-like mental impairment [140] (ThomsonReuters Pharma, update of November 20, 2013).

1.7. Calcium-sensing receptors

A� protein activated Ca2+ permeable channelsthrough calcium-sensing receptors [141]. The findingswere compiled in a recent review [142]. Pharmacother-apy of diverse disorders can be approached via thecalcium-sensing receptor [143].


NPS-2143 (NPS Pharmaceuticals, Bedminster, NJin collaboration with GSK), a calcium-sensing receptorantagonist, specifically blocked the increased secre-tion of endogenous A�42 [144]. The developmentwas terminated (Thomson Reuters Pharma, update ofNovember 7, 2013).

1.8. Cannabinoid receptors

Cannabinoid receptor 1 deficiency in a mouse modelof AD led to enhanced cognitive impairment [145]. Areview on the CB2 receptor and amyloid pathology inAD patients was presented [146].

Dronabinol (ultrapure THC, Namisol; Echo Phar-maceuticals, Nijmegen, NL), a natural product andcannabinoid receptor agonist, is tested as a sub-lingual 1.5 mg tablet in Phase II clinical trials toevaluate efficacy, safety, and tolerability in chronicpancreatitis, multiple sclerosis, and AD patients sinceFebruary 2012. It enhanced extinction learning in anx-ious humans [147] (Thomson Reuters Pharma, updateof April 9, 2014).

Cannabidiol on chronic treatment improvedsocial and object recognition in double transgenicA�PPSWE/PS1�E9 mice [148].

Sativex (GW Pharmaceuticals, Salisbury, Wiltshire,UK), a launched mixture of �9-tetrahydrocannabinoland cannabidiol improved dopamine neurotransmis-sion [149].

Natural cannabinoids improved dopamine neuro-transmission and tau and amyloid pathology in a mousemodel of tauopathy [150].

SMM-189 (The University of Tennessee HealthScience Center, Knoxville, TN, Fig. 5) is a novelcannabinoid receptor 2 inverse agonist, for the poten-tial treatment of traumatic brain injury (ThomsonReuters Pharma, update of November 25, 2013).

1.9. Chemokine receptors

Chemokines and chemokine receptors in mood dis-orders, schizophrenia, and cognitive impairment werereviewed [151]. Chemokine receptors may play a rolein cognition and learning behavior [152]. Suppressionof central chemokine fraktalkine receptor signalingalleviated A�-induced memory deficiency [153]. Frak-taline activated NRF2/NFE2L2 and heme oxygenaseto restrain tauopathy-induced microgliosis [154]. Frak-talkine signaling and tau hyperphosphorylation areassociated with autophagic alterations [155].

Bindarit (Angelini Ricerche, Pomezia, Italy; Fig. 6)is an inhibitor of CCL2 synthesis and protected neu-

rons against A�-induced toxicity [156]. The drug isin Phase II clinical trials since June 2009 for thepotential oral treatment of inflammatory disorders andkidney disease, including diabetic nephropathy, and theprevention of restenosis (Thomson Reuters Pharma,update of March 17, 2014).

1.10. Corticotropin releasing factor receptors

Corticotrophin releasing factor accelerated neu-ropathology and cognitive decline in a mouse modelof AD [157]. For a report on cortical concentrationsof corticotropin-releasing hormone and its receptor inAlzheimer-type dementia and major depression, see[158].

The Clayton Foundation for Research (Houston,TX) is investigating corticotropin releasing factorreceptor-1 (CRFR-1) antagonists for the potentialtreatment of neurodegenerative diseases including AD.In November 2013 development was ongoing (Thom-son Reuters Pharma, update of November 8, 2013).

1.11. Cysteinyl leukotriene receptor 1 (CysLT1R)

Intrahippocampal injection of A�1-42 resulted ina significant decline of spatial learning and mem-ory of mice in the Morris water maze and Y-mazetests together with a serious depression of in vivohippocampal long-term potentiation in the CA1region of the mice. This treatment caused signif-icant increases in Cysteinyl leukotriene receptor 1(CysLT1R) expression and subsequent NF-κB signal-ing, caspase-3 activation and Bcl-2 downregulation inthe hippocampus or prefrontal cortex. Oral adminis-tration of the CysLT1R antagonist pranlukast [159]at 0.4 or 0.8 mg/kg for 4 weeks significantly reversedA�1-42-induced impairments of cognitive function andhippocampal long-term potentiation in mice. Further-more, pranlukast reversed A�1-42-induced CysLT1Rupregulation and markedly suppressed the A�1-42-triggered NF-κB pathway, caspase-3 activation andBcl-2 downregulation in the hippocampus and pre-frontal cortex in mice [160, 161]. Montekulastameliorated A�1-42-induced memory impairment andneuroinflammatory and apoptotic responses in mice[162].

1.12. Dopamine receptors

Brexpiprazole (Otsuka, Tokyo and Lundbeck,Valby, DK; Fig. 6) is an orally active dopamine D2/D3receptor partial agonist, a 5-HT1a receptor partial ago-


Fig. 6. A chemokine R ligand, six dopamine R modulators and an endothelin-A R antagonist.

nist, and a 5-HT2a antagonist for the potential treatmentof schizophrenia (in Phase III clinical trials since Octo-ber 2011), agitation associated with AD (in PhaseIII clinical trials since July 2013), and as adjunctivetreatment for major depressive disorders (in Phase IIIclinical trials since July 2011). Its pharmacology wasdescribed [163] (Thomson Reuters Pharma, update ofApril 18, 2014).

Dexpramipexole (KNS-760704; BIIB-050; KnoppNeurosciences, Pittsburgh, PA, under license from theUniversity of Virginia, Charlottesville, VA; Fig. 6) isthe (R)-enantiomer of pramipexole with weak affini-ties to D2 and D3 receptors (IC50’s of 1800 nM and610 nM, respectively). The compound is in Phase IIIclinical trials for an oral treatment of amyotrophic lat-eral sclerosis patients since March 2011 (n = 804) in theUS, Canada, Europe, and Australia [164–169]. PhaseIII data were reported in January 2013 [170] (ThomsonReuters Pharma, update of April 24, 2014).

Pridopidine (ARC16; Teva Pharmaceutical Indus-tries Ltd, Petach Tikva, Israel, following an assetacquisition from NeuroSearch, Ballerup, DK, Fig. 6)

is a fast-off dopamine D2 receptor antagonist thatstrengthens glutamate function for the potential oraltreatment of Huntington’s disease. In September 2012Teva initiated new Phase III clinical studies for thetreatment of Huntington’s disease in the US and inEurope [171–173] (Thomson Reuters Pharma, updateof October 22, 2013).

There are currently several dopamine receptor drugsin preclinical evaluation:

AG-0029 (Angita Pharmaceuticals, Groningen, theNetherlands, Fig. 6) is a dual D2 receptor agonistand H3 receptor antagonist (EC50 and IC50 values of1.1 and 519 nM, respectively) for the potential oraltreatment of PD. In 6-OHDA rats AG-0029 (0.1 and1 mg/kg s.c.) decreased striatal dopamine and striatalacetylcholine activity at D2 autoreceptors (ThomsonReuters Pharma, update of November 25, 2013).

AG-0098 (Angita Pharmaceuticals, Groningen, theNetherlands, Fig. 6) is a dual D2 receptor agonist andhistamine H3 receptor antagonist (EC50 and IC50 val-ues of 22.4 and 63 nM, respectively) for the potentialtreatment of PD and schizophrenia. AG-0098 antag-


Fig. 7. Drugs interacting with estrogen receptors.

onized phencyclidine-induced locomotor activity andphencyclidine-disrupted novel object recognition inrats (Thomson Reuters Pharma, update of November18, 2013).

Dinoxyline (Purdue University, West Lafayette, IN,Fig. 6), which acts as a potent full agonist at all fivedopamine receptor subtypes [174], is evaluated forthe potential treatment of cognitive diseases includingdementia and psychiatric disorders such as schizophre-nia (Thomson Reuters Pharma, update of July 23,2013).

DW-1006 (Dong Wha, Seoul in collaboration withthe Korea Research Institute of Chemical Technol-ogy KRICT) is a dopamine receptor antagonist forthe potential treatment of schizophrenia (ThomsonReuters Pharma, update of August 6, 2013). The struc-ture was not communicated.

The development of PF-03800130 (a D2 and a 5-HT1A partial agonist, Pfizer; [175]) was terminated.

1.13. Endothelin receptors

ENDG-6010 (EndogenX, Los Gatos, CA) isan endothelin receptor antagonist for the potentialtreatment of AD and dementia including vasculardementia in preclinical evaluation (Thomson ReutersPharma, update of August 12, 2013). The structure wasnot communicated. IRL-1620 (University of Illinois,Urbana, IL) prevented Ab-induced oxidative stress andcognitive impairment in normal and diabetic rats [567].

Zibotentan (University of Bristol as part of theMedical Research Council/AstraZeneca compoundcollaboration, Fig. 6), a selective reversible endothelin-A receptor antagonist, is investigated for the potentialtreatment of AD (Thomson Reuters Pharma, update ofMarch 7, 2014).

1.14. Estrogen receptors

A number of clinical studies suggested that estro-gen therapy may delay the onset or contribute to theprevention and/or attenuation of AD [176, 177].

The Kronos Early Estrogen Prevention Study(KEEPS) was a five year study initiated in 2005 tore-examine estrogen beneficial effects when initiatedat the beginning of the menopause [178, 179].

MF-101 (Menopause Formula-101, Menerba;Bionovo, Emeryville, CA) is a plant-derived mixturethat interacts with the estrogen receptor (ER)-� asagonist and contains liquiritigenin (Fig. 7) in Phase IIclinical trials since February 2006 (Thomson ReutersPharma, update of April 4, 2014).

Phyto-�-SERM (University of Southern Califor-nia, Los Angeles, CA) is an ER-�-selective phytoestro-genic formulation comprised of three phyto-estrogensfor the potential treatment of AD. By July 2011 PhaseII studies were ongoing in the US. Early interventionprolonged survival, improved spatial recognition mem-ory, and slowed progression of amyloid pathology ina female mouse model of AD [180, 181] (ThomsonReuters Pharma, update of September 27, 2013).

There are currently several estrogen receptor drugsin preclinical evaluations:

Estradiol enhanced object recognition memory inSwiss female mice by activating hippocampal estrogenreceptor � [182].

Liquiritigenin (7,4′-dihydroxy-flavanone; Fig. 7)is a highly selective ER-� agonist discovered ina traditional Chinese medicine in the roots ofGlycyrrhizae uralensis Fisch [183]. Liquiritigeninattenuated A�25-35 induced impairment of learning inrats [184].

Co-administration of the selective androgen recep-tor agonist ACP-105 with the selective ER-� agonist


Fig. 8. Inverse agonists at �5��2 GABAA receptors.

AC-186 (Acadia, Fig. 7) increased the A� degradingenzymes neprilysin and insulin-degrading enzyme anddecreased A� levels in the brain as well as improvedcognition in triple transgenic mice [185] (ThomsonReuters Pharma, update of August 20, 2013).

1.15. GABA receptors

1.15.1. GABAA receptorsThe cognitive deficits in Down’s syndrome are

attributed to an excessive hippocampal inhibition,which can be alleviated by GABAA and GABAB recep-tor antagonists [186–188].

CTP-354 (C-21191; CoNCERT Pharmaceuticals,Lexington, MA) is a deuterated �5 GABAA recep-tor inverse agonist derived from Merck’s L-838,417(Fig. 8), which showed good metabolic stability [189].In March 2013 a randomized, double-blind, placebo-controlled, single ascending dose, Phase I study toassess the safety, tolerability, and pharmacokinetics ofCTP-354 was initiated in healthy volunteers in the US(Thomson Reuters Pharma, update of July 15, 2013).

RG-1662 (Roche, Fig. 8) is a �5 GABAAinverse agonist. A randomized, double-blind, parallel-assignment, multicenter, placebo-controlled, PhaseII trial (NCT02024789; BP27832; 2013-001263-23;CLEMATIS) will be initiated in adults and adolescentsubjects (expected n = 180) with Down’s syndrome inNew Zealand and Singapore to evaluate the safety, effi-cacy and tolerability of RG-1662 (Thomson ReutersPharma, update of April 16, 2014).

There are many �5 GABAA receptor inverse ago-nists or negative allosteric modulators (NAMs) inpreclinical evaluation (in alphabetical order):

Dart NeuroScience LLC (San Diego, CA) is inves-tigating GABAA receptor modulators for the potential

treatment of cognitive impairment in AD patients(Thomson Reuters Pharma, update of January 30,2013). The structures were not disclosed.

GABAA receptor �5 inverse agonists are exploredat AgeneBio, Carmel, IN (Thomson Reuters Pharma,update of May 6, 2014). Structures were not disclosed.

GABAA �5 inverse agonists (Universite Pierreet Marie Curie, Paris) are investigated for the poten-tial treatment of Down’s syndrome. In October 2013,data were presented at the 26th European Collegeof Neuropsychopharmacology Congress in Barcelona,Spain (Thomson Reuters Pharma, update of October8, 2013). Structures were not disclosed.

GABAA receptor �5 PAMs improved cognitivefunction in aged rats with memory impairment [190].

GABAA receptor �5 subtype selective antag-onists are investigated jointly by scientists of theUniversity of Wisconsin at Milwaukee and ofMetabolic Solutions Development Co. for the poten-tial treatment of anxiety, amnesia, and alcoholism.The lead compound XLi-093 is a dimer of imidazo-benzodiazepines (Fig. 9) [191, 192]. Other compoundsunder evaluation include RY-023, RY-024, PWZ-029, and 3-propoxy-beta-carboline (3-PBC) (ThomsonReuters Pharma, update of April 9, 2014).

HZ-166 (Addiction Therapeutix, Wauwatosa, WI,under license from the University of Wisconsin-Milwaukee; Fig. 9) at doses from 0.03 to 0.3 mg/kg,i.v. reversed ketamine-induced cognitive impairmentin a dose-dependent manner in male Rhesus monkeys(Thomson Reuters Pharma, update of December 6,2013).

NP-260 (NeuroTherapeutics Pharma, Chicago, IL,and NeuroSolutions, Coventry, UK) is a GABAAreceptor antagonist for the potential treatment ofneurological disorders (Thomson Reuters Pharma,


Fig. 9. GABAA receptor antagonists and �5��2 GABAA receptor inverse agonists.

update of May 31, 2013). The structure was notcommunicated.

RO-4938581 (Roche; Fig. 9) and the dichloro-analogue RO-4882224 (Fig. 9) are inverse agonistsat �5��2 GABAA receptors [193–197]. In February2013, preclinical data were published demonstratingthe drug to reverse neurological deficits the Ts65Dnmouse model of Down’s syndrome. Abnormalities ofnerve cell number and function in the brain wereimproved [198] (Thomson Reuters Pharma, update ofMarch 1, 2013).

UC-1011 (Umecrine Cognition, Vasterbottens,Sweden and licensee CleveXel Pharma, MaisonsAlfort, Ile-de-France; Fig. 9) is a GABAA receptorantagonist for the treatment of memory and learn-ing disturbances associated with AD [199] (ThomsonReuters Pharma, update of December 20, 2012).

The development of a pyrido[2,3-d]pyrimidine-4(1H)-one by Kyowa Hakko Kirin [200] was termi-nated.

1.15.2. GABAB receptorsGABAB receptor antagonists proved to be valu-

able cognitive enhancers as was shown in many

animal experiments and in two clinical trials (videinfra).

CGP-36742 (SGS-742; National Institute of Health,Bethesda, MD acquired the rights from Lundbeck, whobought Saegis Pharmaceuticals in 2006, who licensedthe drug from Ciba-Geigy, now Novartis in 2001;Fig. 10) showed pronounced cognition enhancingproperties in mice, young and old rats, and in Rhe-sus monkeys [201–205]). It was taken into two Phase

Fig. 10. A GABAB receptor and a galanine-3 receptor antagonist.


II clinical trials first in patients with mild cognitiveimpairment (MCI) in 2002 and in mild to moder-ate AD patients in 2005 [206, 207]. It significantlyimproved attention and working memory in MCI andpatients with mild AD, but not in patients with mod-erate AD, as was found eight years later in PhaseIII studies of solanezumab (Lilly). In December 2013the National Institute of Neurological Disorders andStroke initiated a randomized, double-blind, crossover-assignment, Phase I/II trial (NCT02019667; 140033,14-N-0033) in patients (expected n = 22) with succinicsemialdehyde dehydrogenase deficiency in the US. Forthe biological background, see [208–211] (ThomsonReuters Pharma, update of December 31, 2013).

ADX-71441 (Addex Therapeutics, Geneva,Switzerland), a potent GABAB receptor PAM demon-strated a robust, dose-dependent, and long-lastingsuppression of alcohol intake in mice in a preclinicalmodel of alcohol binge drinking [212] and showedefficacy in a rodent model of overactive bladder [213].Addex and the National Institute of Drug Abuseentered a collaboration to advance both ADX-71441and ADX-88178 (a mGluR4 PAM; see Chapter 1.16.4.Metabotropic Glutamate Receptors) for treatment ofdrug abuse and addiction (Thomson Reuters Pharma,update of April 7, 2014). The structure was notcommunicated.

�-Hydroxybutyrate, a weak agonist at recombinantGABAB receptors [214] acting through an anti-apoptotic mechanism, protected native and amyloid-�protein precursor (A�PP) transfected neuroblastomacells against oxidative stress-induced death [215].

Medisyn Technologies (Minnetonka, MN, in collab-oration with MD Biosciences, Zurich, Switzerland) isinvestigating GABAB receptor agonists for the poten-tial treatment of neuropathic pain (Thomson ReutersPharma, update of January 21, 2014). Structures werenot communicated.

1.15.3. GABAC receptorsThe development of (R)-ACBPA and (S)-ACBPA

(University of Sydney) was terminated.

1.16. Galanin receptors

The roles of neuropeptides including galanin werediscussed [216].

HT-2157 (SNAP-37889; Dart NeuroScience, SanDiego, CA following the acquisition of Helicon Ther-apeutics, San Diego, CA, licensed from Lundbeck;Fig. 10) is a galanin-3 receptor antagonist for thetreatment of major depressive and cognitive disorders

such as memory loss in Phase II development in theUS (Thomson Reuters Pharma, update of January 30,2013).

NeuroTargets (Guildford, UK) in collaboration withthe University of Bristol is investigating allostericmodulators of galanin receptor 2 for the potential treat-ment of multiple sclerosis and AD (Thomson ReutersPharma, update of February 11, 2014). Structures werenot communicated.

1.17. Glutamate receptors

1.17.1. AMPA receptors1.17.1.1. Piracetam-type compounds. Piracetam(UCB-6215; Nootropil, UCB, Brussels, Belgium;Fig. 11) was discovered more than forty years ago[217]. For decades it was considered as “a drug withouta mechanism”, i.e., a “nootropic agent” [1, 2]. Nowit is firmly established that piracetam acts as a weakpositive modulator of AMPA receptors. Piracetamenhanced mitochondrial membrane potential and ATPproduction and reduced sensitivity to apoptosis [218].Molecular docking and quantum calculations wereperformed on piracetam [219]. Analgesic effects ofpiracetam were discovered in the chronic constrictioninjury of sciatic nerve in rats suggesting investigationsfor the treatment of neuropathic pain [568] (ThomsonReuters Pharma, update of April 18, 2014).

Dimiracetam (NT-11624; BND-11624; Neurotune,Zurich, Brane Discovery, Baranzate, Italy, Fig. 11) isin Phase II clinical trials for the treatment of HIV-associated pain in South Africa since April 2009. InOctober 2010 results from 111 patients showed thedrug was safe and well tolerated and all subjects had asignificant improvement in pain symptoms (ThomsonReuters Pharma, update of December 30, 2013).

NT-24336 (NiK-13317; Brane Discovery, Baran-zate, Italy, after its spin-off from Nikem Research;Fig. 11) is in preclinical evaluation for the treatment ofdiabetic neuropathy and neuropathic pain (ThomsonReuters Pharma, update of December 30, 2013).

The development of nefiracetam (DM-9384;Motiva; Translon; Neuren Pharmaceuticals under lic-ense from Daiichi Sankyo; [220–224]) was terminated.

1.17.1.2. AMPAkines. The groups of Gary Lynch ofthe University of California Irvine and of Gary A.Rogers of the University of California Santa Barbarapresented the first benzamide drug 1-BCP (BA-14)[225, 226]. The drug crossed the blood-brain barrier(BBB) and reversibly increased the amplitude and pro-longed the duration of field excitatory postsynaptic


Fig. 11. Piracetam and its analogues.

potentials. Evidence for improved memory was shownin the Morris water maze and in a radial maze.

CX-1739 (Cortex Pharmaceuticals, Irvine, CA) isinvestigated for the potential treatment of sleep apneaand neurological diseases including ADHD and AD.Phase II results of a sleep apnea trial have beenreported in February 2011. Cortex is evaluating oraland injectable formulations. The drug enhanced thesocial interaction in the BTBR mouse model of autism[227] (Thomson Reuters Pharma, update of November24, 2013). The structure was not communicated.

CX-717 (Cortex Pharmaceuticals, Irvine, CA) is anAMPAkine for the potential treatment of ADHD, AD,and respiratory disorders. It is also evaluated to alle-viate the effects of sleep deprivation [228]. Oral andi.v. formulations were evaluated. The development oforal CX-717 was terminated, whereas CX-717 i.v. iscurrently in Phase I clinical trials for the potentialtreatment of respiratory disorders (Thomson ReutersPharma, update of May 16, 2013). The structure wasnot communicated.

Cortex is developing several other AMPAkines,whose structures were not disclosed, such as CX-1942and CX-2007 (Thomson Reuters Pharma, updates ofMay 16 and May 3, 2013, respectively).

JAMI1001A (Colorado State University, FortCollins, CO, University of Strathclyde, Glasgow,Morehouse School of Medicine, Atlanta, GA andMerck Research Laboratories, Boston, MA; Fig. 12)is a novel PAM of AMPA receptors derived from astructure-based drug design strategy [229].

The development of CX-717 oral (Cortex Pharma-ceuticals) was terminated.

1.17.1.3. Biarylpropylsulfonamides. PF-04958242(Pfizer; Fig. 12) is an AMPA receptor potentiator forthe potential treatment of cognitive defects associatedwith schizophrenia in Phase I trials in healthy volun-teers (n = 24) since August 2010. In addition, a clinicalstudy (NCT01518920) is underway to evaluate theeffects of PF-049582432 in subjects with age-relatedhearing loss (n = 42) in the US [230] (ThomsonReuters Pharma, update of April 18, 2013).

PF-04778574 (Pfizer, Fig. 12) is a potential follow-up compound of PF-04958242 for the treatment ofcognitive deficits in schizophrenia [231] (ThomsonReuters Pharma, update of November 11, 2013).

1.17.2. NMDA receptorsA review on the NMDA receptor as a target for

cognitive enhancement was published [232].A substantial progress in the treatment of patients

suffering from AD was achieved with the launch of theNMDA receptor channel blocker Memantine (Axura,Ebixa, Namenda, Memary; Merz, Frankfurt am Main;Fig. 13). Sales for Namenda by Forest in 2012 wereUSD 1.52 billion, sales for Ebixa by Lundbeck in 2012USD 484 million and sales for Daiichi Sankyo in 2012USD 300 million (Thomson Reuters Pharma, updateof April 30, 2014).

There are currently 2,393 papers on memantinelisted in PubMed (as of April 30, 2014). Two meta-


Fig. 12. AMPAkines.

Fig. 13. NMDA receptor antagonists and a memantine prodrug.

analyses of the efficacy of donepezil, rivastigmine,galantamine and memantine for the treatment of ADwere published [233, 234].

Merz and Forest developed memantine extendedrelease (memantine ER; Namenda XR), a once-daily 28 mg extended-release formulation, which wasapproved by the FDA in June 2010. The formulation

was launched in the US in June 2013 (Thomson ReutersPharma, update of April 16, 2014).

A combination treatment of donepezil and meman-tine showed synergistic effects in a test for spatiallearning and recall in a transgenic mouse model of AD[235]. These benefits were confirmed in AD patients[236, 237].


ADS-8704 (Arimenda; MDX-8704, Adamas Phar-maceuticals, Emeryville, CA, and licensee ForestLaboratories, New York) is a memantine + donepezilfixed dose combination in an extended release for-mulation. Phase III studies started in December 2013in the EU and the US. In October 2013 Forest wasplanning to file an NDA in 1H14 and launch in2015 (Thomson Reuters Pharma, update of April 30,2014).

Neramexane (MRZ-2/579; KRP-209; Merz, Frank-furt am Main; Fig. 13) is currently in Phase III clinicaltrials for the treatment of tinnitus, severe acne, and aspreemptive analgesic, as add-on therapy to opioids inthe management of postoperative pain and as add-ontherapy to opioids in cancer patients for the manage-ment of chronic pain attributable to skeletal metastases.Japanese licensee Kyorin is codeveloping the drug inJapan (Thomson Reuters Pharma, update of April 23,2014).

EVT-101 (Fig. 13) and EVT-103 (Janssen Pharma-ceuticals, Titusville, NJ under a license from Evotec,Hamburg under exclusive license from Roche) areorally active NMDA NR2B subtype specific antago-nists for the potential treatment of treatment-resistantdepression and AD (Thomson Reuters Pharma, updateof May 29, 2014). The structure of EVT-103 was notcommunicated.

Johns Hopkins University (Baltimore, MD) is inves-tigating modulators of NMDA glutamate receptorfor the potential treatment of AD (Thomson ReutersPharma, update of June 4, 2013). The structures werenot communicated.

MeN-061016-1 (Lijun International Pharmaceuti-cal, Hong Kong, Fig. 13) is a memantine prodrugas a nicotinic acid amide in preclinical evaluation inChina (Thomson Reuters Pharma, update of April 10,2014).

Mnemosyne Pharmaceuticals (Providence, RI) isinvestigating small molecule NR2B allosteric modula-tors to improve cognitive dysfunction in AD (ThomsonReuters Pharma, update of July 2, 2013). The structureswere not communicated.

NRX-20xx (Naurex, Evanston, IL) are NMDAreceptor partial agonists for the potential oral treatmentof autism, neurological diseases including AD, andneuropathic pain (Thomson Reuters Pharma, update ofMay 26, 2014). The structures were not communicated.

SGE-301 (Sage Therapeutics, Cambridge, MA) isa potent and selective PAM of NMDA receptor func-tion. In preclinical studies, treatment with SGE-301,a synthetic analogue of the major brain cholesterolmetabolite 24-(S)-hydroxy-cholesterol, showed rever-

sal of cognitive and social deficits in rats [238](Thomson Reuters Pharma, update of March 31, 2014).The structure was not communicated. The devel-opment of NRX-1059 (Naurex, Evanston, IL) wasterminated.

1.17.3. NMDA receptors’ glycine-siteFor a review on the glycine site of the NMDA recep-

tor see [239].GLYX-13 (Naurex, Evanston, IL) is a tetrapeptide

and NMDA receptor glycine site functional partialagonist for the potential i.v. treatment of psychi-atric disorders such as depression and neuropathicpain. It enhanced cognition and produced antidepres-sant effects without the psychomimetic side effects ofNMDA receptor antagonists [240, 241]. It is in Phase IIclinical trials for treatment-resistant depression sinceMay 2011 in the US. In December 2012 a Phase IIb trialbegan. It was claimed that GLYX-13 has a therapeu-tic potential for treatment of autism [242] (ThomsonReuters Pharma, update of February 11, 2014).

1.17.4. Metabotropic glutamate receptorsNeuroprotective and symptomatic effects of target-

ing group III mGlu receptors in neurodegenerativediseases were reviewed [243].

ADX-71149 (Janssen Pharmaceuticals, formerlyOrtho-McNeil, Titusville, NJ under license fromAddex Therapeutics, Geneva, Switzerland; Fig. 14)is a PAM of metabotropic glutamate receptor 2for the treatment of psychiatric disorders includingschizophrenia, anxiety, AD, and depression. In June2012 a multicenter, double-blind, placebo-controlled,Phase II trial of the drug as an adjunct to antidepressanttreatment was initiated in 94 adult patients with majordepressive disorder who are also suffering from anxi-ety symptoms in Ukraine, Russia, Romania, Hungary,and Bulgaria. Subjects will receive oral twice dailyADX-71149 (25 to 150 mg) as an adjunct to antide-pressant therapy and the primary endpoint would be thechange from baseline in the Hamilton Anxiety RatingScale (HAM-A6) score. Janssen Research & Develop-ment LLC has completed enrollment of 120 patientsin a multicenter, double-blind, Phase II study of ADX-71149 in adults with major depressive disorder whoare also suffering from anxiety symptoms. Medicinalchemistry papers were published [244, 245] (ThomsonReuters Pharma, update of April 7, 2014).

RG-1578 (R-1578; RO-4995819, Roche) is a small-molecule mGluR2/3 NAM in a Phase II study inpatients with major depressive disorders (n = 480)since December 2011 in the US. By February 2012,


Fig. 14. Metabotropic glutamate receptor ligands.

RG-1578 had shown antidepressant and cognitiveenhancing effects in a broad range of preclinical mod-els (Thomson Reuters Pharma, update of April 17,2014). The structure was not disclosed.

Basimglurant (RG-7090, RO-4917523; Roche,Fig. 14) is a mGluR5 antagonist for the potential treat-ment of treatment-resistant depression and fragile Xsyndrome. In February 2012 recruitment began fora randomized, double-blind, parallel-group, Phase IIstudy (n = 315) in the US, Europe, Chile, Mexico, andTaiwan. In September 2013 the trial was completed. InJanuary 2013, a randomized, double-blind, placebo-controlled, Phase II study started to assess the safetyand efficacy and pharmacokinetics of RG-7090 in pedi-atric patients (estimated n = 45) in the US with fragile Xsyndrome (Thomson Reuters Pharma, update of April17, 2014).

Other cognition enhancing mGluR ligands are inpreclinical evaluation (in alphabetical order):

ADX-88178 (Addex Therapeutics, Geneva,Switzerland in collaboration with the NationalInstitute of Drug Abuse, Bethesda, MD; Fig. 14) isan orally available PAM of metabotropic glutamate

receptor 4 (mGluR4 PAM) for the potential treatmentof nicotine and cocaine dependence (Thomson ReutersPharma, update of November 5, 2013).

DT-2442 (Domain Therapeutics, Illkirch-Graffenstaden, France; Fig. 14) is a mGluR2 NAMfor the potential treatment of AD and depression [246](Thomson Reuters Pharma, update of April 7, 2014).

LSN-2463359 (Eli Lilly, Fig. 14) is a mGluR5PAM, which modulated motor, instrumental and cog-nitive effects of NMDA receptor antagonists in rats[247–249] (Thomson Reuters Pharma, update of Jan-uary 3, 2014).

Pfizer is investigating mGluR2 PAMs (lead structureshown in Fig. 14) for the treatment of CNS disor-ders [250–252]. (Thomson Reuters Pharma, update ofMarch 24, 2011). For a highly potent mGluR5 NAMof Pfizer, see [253].

Sanofi is investigating mGluR2 PAMs for the poten-tial treatment of cognitive impairment associated withschizophrenia (Thomson Reuters Pharma, update ofFebruary 8, 2013). Structures were not communicated.

STX-110 (Roche under license from Seaside Thera-peutics, Cambridge, MA under license from Vanderbilt


University, Nashville, TN) is a mGluR5 inhibitor forthe potential treatment of fragile X syndrome andautism (Thomson Reuters Pharma, update of February13, 2014). The structure was not communicated.

VU-0430644 (ML-254; Janssen Pharmaceutica,Beerse, Belgium under license from Vanderbilt Uni-versity, Nashville, TN; Fig. 14) is a mGluR5 PAMfor the potential treatment of schizophrenia. Thecompound showed efficacy in animal models ofcognitive enhancement and was found to effec-tively treat the positive symptoms of schizophrenia.Other evaluated compounds are VU-0469942 (ML-337), VU-0405372, VU-0404251, JNJ-42659604,VU-0360172 (VU-172), and VU-0092273. The medic-inal chemistry was presented [254] (Thomson ReutersPharma, update of February 11, 2014).

The development of ADX-47273 (mGluR5PAM; Addex Therapeutics; [255]), ADX-50938(mGluR5 PAM; [256]), ADX-63365 (mGluR5PAM), ADX-71743 (mGluR7 NAM), ADX-92639(mGluR2 NAM), BCI-632 (MGS-0039) and BCI-838(MGS-0210; BrainCells under license from TaishoPharmaceutical Co; [257–260]), DT-2228 (DomainTherapeutics), 18F-MK-3328 (Merck; [261]) andSTX-107 (Roche under license from SeasideTherapeutics; [262–269]) was terminated.

1.18. G-protein coupled orphan receptors

The pharmacology and signaling of Mas-relatedG-protein coupled receptors was reviewed [569].

Mas-related G-protein coupled receptor (MAS1)antagonists (Omeros, Seattle, WA) are investigatedfor the potential treatment of cognitive impairment(Thomson Reuters Pharma, update of October 4,2013). The structures were not communicated.

The development of G-protein coupled receptor 3antagonists (gene designated GT177; Galapagos) wasterminated.

1.19. Histamine receptors

AZD-5213 (AstraZeneca; Fig. 15) will not be fol-lowed up in the indications AD or ADHD. New PhaseII studies were initiated for the treatment of Tourette’ssyndrome in September 2013 and for neuropathic painin November 2013 (Thomson Reuters Pharma updateof April 24, 2014).

S-38093 (Servier) and the related structuresS-38471-1 (Fig. 15) and S-41150 are lead com-pounds from a series of histamine H3 antagonistswith wakefulness-promoting and cognitive-enhancing

effects. Since July 2011 a Phase IIb study of S-38093is underway in 600 mild to moderate AD patients. Thetrial is expected to complete in April 2014 (ThomsonReuters Pharma, update of May 21, 2014).

PD-9475 (betahistine; P2D Biosciences, Cincinnati,OH; Fig. 15) is an oral formulation of the H3 receptorantagonist betahistine in a Phase Ib trial since Febru-ary 2011 for the treatment of ADHD in the US [270](Thomson Reuters Pharma, update of March 31, 2014).

There are several histamine H3 receptor antagonistsor inverse agonists in preclinical evaluation (in alpha-betical order):

Angita Pharmaceuticals (Groningen, the Nether-lands) investigates a dual N-acetyltransferase reuptakeinhibitor and histamine H3 receptor antagonist for thepotential oral treatment of cognitive disorders. (Thom-son Reuters Pharma, update of March 14, 2014). Thestructure was not communicated.

EVT-501 (EDC-2) and EVT-502 (EDC-3; Evotec,Hamburg) are small molecule H3 receptor antagonistsfor the potential treatment of cognitive and sleep disor-ders (Thomson Reuters Pharma, update of March 19,2013). The structures were not communicated.

LGD-3437 (Ligand Pharmaceuticals, San Diego,CA), a histamine H3 antagonist, is investigated for thepotential treatment of excessive daytime somnolence.By June 2013 LGD-3437 had demonstrated a favor-able PK/ADME and safety profile in preclinical studies(Thomson Reuters Pharma, update of April 24, 2014).The structure was not communicated.

Oxygen Healthcare Research (Ahmedabad, India)is investigating histamine H3 receptor antago-nists/inverse agonists for the potential treatment ofcognitive disorders such as AD (Thomson ReutersPharma, update of August 10, 2012). Structures werenot communicated.

SAR-110068 (Sanofi-Aventis US, Bridgewater, NJ;Fig. 15) is a H3 receptor antagonist for the potentialtreatment of sleep disorders including narcolepsy [271,272] (Thomson Reuters Pharma, update of April 10,2014).

SUVN-G1031, SUVN-G3031, and SUVN-G1010034 (Suven Life Sciences, Hyderabad, India)are potent selective H3 receptor antagonists for thetreatment of cognitive deficits. A 4,5-dihydrobenzo[1,4]oxazepine-3-one (Fig. 15) was presented at the 243rd

ACS Meeting in San Diego March 2012. The com-pound increased the release of cognitive-enhancingneurotransmitters. SUVN-G3031 displayed gains inobject recognition at doses of 1 and 3 mg/kg anddose-dependently reduced path length and latency in awater maze test at doses from 0.03 to 10 mg/kg p.o. It


Fig. 15. Histamine H3 receptor antagonists or inverse agonists.

had a Ki value of 8.7 nM and it showed an ED50 valueof 0.30 mg/kg with up to 85% receptor occupancy(Thomson Reuters Pharma, update of April 11, 2014).

UCB (Brussels, Belgium) investigates H3 receptorantagonists for the potential treatment of cognitivedisorders including AD (Thomson Reuters Pharma,update of October 2, 2012).

The development of ABT-288 (AbbVie; [273–275]),GSK-239512 (GSK, the development for the indica-tion AD was terminated but the drug is in Phase IIclinical trials for the potential oral treatment of mul-tiple sclerosis; Thomson Reuters Pharma, update ofApril 17, 2014), Irdabisant (CEP-26401; Cephalon,now Teva; [276–291]), JNJ-10181457 (Johnson &Johnson; [292, 293]), JNJ-17216498 (ALZA Corp.;[294]), MK-3134 (Merck; [295]) and SAR-110894(sanofi; [296]) was terminated.

1.20. Imidazoline receptors

Targeting the imidazoline I2 receptor emerged as anew mechanism of action to inhibit tissue plasminogenactivator-induced signaling in neurons for the treat-ment of AD [297].

1.21. Insulin receptors

For reviews on impaired insulin signaling andmechanisms of memory loss, see [298, 299]. Therelationship between diabetes and cognitive impair-

ment was described [300, 301]. Impaired glycemiaincreased disease progression in MCI [302]. Infusionof insulin increased plasma concentrations of A�42[303]. The common pathological processes in AD anddiabetes were reviewed [300, 304–313]. Genetic abla-tion of tau mitigated cognitive impairment induced bytype 1 diabetes [314]. Conversely, insulin dysfunctionand tau pathology was discussed [315]. Type 2 diabeticand AD mice present similar behavioral, cognitive,and vascular abnormalities [316]. The impact ofmetabolic syndrome on cognition and brain wasreviewed [317], as was the topic diabetes and the brain[570]. The common pathway of both diseases seems tobe serine phosphorylation of insulin receptor substrate1 (IRS-1). ADDLs activated the JNK/TNF-� pathwayand induced IRS-1 phosphorylation at multiple serineresidues. The neuronal pathology could be preventedby exposure to the glucagon-like peptide 1 receptoragonist exenatide (exendin-4, launched by AmylinPharmaceuticals and Lilly) [318]. Another possiblelink between AD and type 2 diabetes may be aberrantinsulin signaling and inflammation [319]. The insulinreceptor expression and activity in the brains ofnondiabetic sporadic AD cases was analyzed recently[320]. A review deals with the insulin-like growthfactor-1 and the risk of Alzheimer dementia and brainatrophy [571]. Insulin-like growth factor-1 receptorstimulating activity is associated with dementia [572].There is emerging evidence that insulin-like growthfactor 2 may act as a memory enhancer [573].


sNN-0465 (NeuroNova AB, Stockholm, a whollyowned subsidiary of Newron Pharmaceuticals,Milano) is a formulation of exenatide, a peptidicglucagon-like peptide-1 agonist and neurogenesisstimulator, for the potential treatment of PD in PhaseII clinical trials since June 2011 (Thomson ReutersPharma, update of December 18, 2012). See reference[321].

SYN-20090510RU (SuliXen; SynBio LLC,Moscow in collaboration with Xenetic Biosciences;London) is a long-acting insulin formulation, whichincorporates bacterial polysialic acid for the potentialinjectable treatment of type 1 and 2 diabetes andneurological disorders such as AD [322]. Phase Istudies in diabetic patients were started in August2011 and in patients with neurological disease inNovember 2012 (Thomson Reuters Pharma, updateof December 4, 2013).

There are several drugs interacting with insulinreceptors in preclinical evaluations:

CB-211 (CohBar, Pacific Palisades, CA) is amitochondrial-derived peptide that acts as cytopro-tective and improved mitochondrial function byinteraction with the insulin receptor. It is evaluatedfor the potential treatment of type 2 diabetes and AD(Thomson Reuters Pharma, update of December 7,2012). The structure was not communicated.

Humanin analogues (CohBar, Pacific Palisades,CA) such as CB-102, HNG6FA, and S14G-humaninare peptides encoded within the mitochondria forthe potential treatment of AD and type 2 diabetes[323–327]. Humanin may be a possible linkagebetween AD and type 2 diabetes [328] (ThomsonReuters Pharma, update of May 24, 2013). The struc-tures were not communicated.

Liraglutide (Victoza, NN-2211, NNC-90-1170;launched in 2009 by Novo Nordisk, BagsvaerdDK, under license from Scios, Sunnyvale, CA andMassachusetts General Hospital, Boston, MA) isa recombinant protein, a once-daily stable analogof glucagon-like peptide-1 for s.c. administration.It ameliorated aberrant insulin receptor localizationand signaling in parallel with decreasing both A�plaque and glial pathology in a mouse model ofAD [329]. Liraglutide protected against A� protein-induced impairment of spatial learning and memory inrats [330] and reversed memory impairment and synap-tic loss and reduced plaque load in aged A�PP/PS1mice [331]. Subcutaneous administration of liraglutideameliorated AD-associated tau hyperphosphorylationin rats with type 2 diabetes [332]. Sales reportedby Novo Nordisk for 2012 were USD 1.640 bil-

lion (Thomson Reuters Pharma, update of April 15,2014).

NA-135 (Nerve Access, Chicago Ridge, IL) is anasal formulation of insulin, which enters the CNSwithout having to cross the BBB for the potential treat-ment of AD (Thomson Reuters Pharma, update of April3, 2014).

NA-753 (Nerve Access, Chicago Ridge, IL) is anasal formulation of insulin and clioquinol that entersCNS without having to cross the BBB and actsby enhancing regenerative capacity of the CNS forthe potential treatment of neurodegenerative diseases,including AD (Thomson Reuters Pharma, update ofOctober 8, 2013).

AGT-160 (ArmaGen Technologies, Calabasas, CA)is a recombinant IgG fusion protein formed by thefusion of a single chain Fv (ScFv) antibody againstA� plaque formation to the company’s human insulinreceptor-targeting monoclonal antibody Trojan horsefor transport across the BBB for the potential detec-tion and treatment of AD [333, 334] (Thomson ReutersPharma, update of September 20, 2013).

1.22. Liver X receptors

The liver X receptors (LXR� and LXR�) are mem-bers of the nuclear hormone receptor family and areinvolved in the regulation of cholesterol and lipidmetabolism. LXRs may be an emerging target forAD [335]. Hypercholesterolemia induced short-termspatial memory impairments in mice [336]. Pre- andpost-traumatic brain injury treatment of mice withT0901317 (Fig. 16) [337] increased ABCA1 levels at24 hours post-injury and reduced the post-traumaticbrain injury-induced increase of A� [338]. The ATP-binding cassette transporter A1 mediated the beneficialeffects of the LXR agonist GW3965 (GSK, Fig. 16)on object recognition memory and A� burden inA�PP/PS1 mice [339]. Reduction of LXR expressionin primary rat neurons by antisense oligonucleotidesdecreased secreted A� levels [340].

XL-652 (XL-014; Bristol-Myers Squibb underlicense from Exeliris, South San Francisco, CA, for-merly X-Ceptor Therapeutics) is a LXR agonist inPhase I clinical trials since March 2008 for the treat-ment of atherosclerosis (Thomson Reuters Pharma,update of February 11, 2014). The structure was notcommunicated.

MAD-8100 (Madera Biosciences, San Diego,CA) is a small molecule therapeutic that increasedapolipoprotein E and ATP binding cassette transporter1 (ABCA1) levels in the brain. Targeted diseases are


Fig. 16. Two liver X receptor agonists, a melatonin R antagonist and seven ligands for PBRs.


AD, age-related macular degeneration, and traumaticbrain injury (Thomson Reuters Pharma, update of May22, 2014). The structure was not communicated.

1.23. Melatonin receptors

Melatonin facilitated short-term memory [341]. Themelatonin receptor agonist agomelatine blocked theadverse effect of stress on memory and enabled spatiallearning of rats [342]. Memory enhancing effects ofagomelatine were also observed in the novel recogni-tion memory paradigm in rats [343].

Piromelatine (Neu-P11; Neurim Pharmaceuticals,Tel Aviv; Fig. 16) is a melatonin MT1, MT2 and MT3agonist, a 5-HT1A, 5-HT1B and 5-HT1D agonist and5-HT2b antagonist. It also inhibits P2X3, TRPV12and Nav1.7 channels. It is in Phase II clinical trialsfor the treatment of insomnia since November 2011in Israel [344]. The company is also investigatingNeu-P11 for the treatment of MCI in early-stage AD.Neu-P11 facilitated memory performance andimproved cognitive impairment in a rat model of AD[345] (Thomson Reuters Pharma, update of November29, 2013).

1.24. Neurotensin receptors

NTSR3 is now called sortilin receptor [346]. SeeChapter 1.35. Sortilin Receptor.

NT-69-L (Mayo Foundation, Rochester, MN) is aneurotensin hexapeptide of disclosed structure act-ing as neurotensin receptor agonist for the potentialtreatment of pain, schizophrenia, AD, PD, nicotineand alcohol dependence, and schizophrenia-associatedcognitive impairment [347–355]. The developmentwas terminated in 2013 (Thomson Reuters Pharma,update of February 26, 2013).

1.25. Nociceptin (ORL1) receptors

LY-2940094 (Lilly) is a nociceptin/orphanin FQpeptide (ORL1) receptor modulator in Phase II clin-ical trials for the potential oral treatment of depressionsince November 2012 (Thomson Reuters Pharma,update of October 24, 2013). The structure was notcommunicated.

The development of PF-454583 and PF-4926965(Pfizer) was terminated.

1.26. Opioid Receptors

A review on the opioid system and AD was pub-lished [356].

1.27. Peripheral benzodiazepine receptors

AD is associated with local glial responses inthe brain parenchyma, which involves activation ofmicroglia. The mitochondria of these cells expressincreased amounts of peripheral benzodiazepine recep-tors (PBRs or translocator protein) [357, 358]). Thisincrease of PBRs can be measured quantitatively viaPET imaging. A review on the translocator protein asa drug target in AD was published [359].

18F-BAY-85-8102 (18F-DPA-714, F-18-DPA-714;Bayer in collaboration with INSERM under licensefrom the University of Sydney, Fig. 16) is in Phase Iclinical evaluations for the imaging of patients withbrain disease since June 2008 in France and sinceOctober 2009 in Finland. INSERM is developing thecompound for the potential imaging of neuroinflam-mation. In June 2013 data from a neuroinflammationclinical study were presented. MRI imaging resultsshowed increased 18F-DPA-714 uptake in the infarcttissue reflecting BBB breakage in the infarcted area andthis was thought to relate to activation of microglia anda different radiotracer kinetic in the injured and normaltissues (Thomson Reuters Pharma, update of February12, 2014).

11C-DPA-713 (National Institutes of Health,Bethesda, MD) is a PBR PET ligand for the poten-tial imaging of epilepsy. In January 2013 a Phase Istudy was initiated in the US. The study will compare11C-PBR-28 (vide infra) and 11C-DPA-713. Uptakeof 11C-DPA-713 was comparable to that of 11C-R-PK-11195 (vide infra), but 11C-DPA-713 showedlower non-specific binding (Thomson Reuters Pharma,update of August 2, 2013). The structure was not com-municated.

18F-FEDAA-1106 (ZK-6032924, BAY-85-8101;Bayer Schering, Berlin under license from Taisho Phar-maceuticals, Tokyo; Fig. 16) is an i.v. injectable PETligand for potential diagnostic imaging of AD and mul-tiple sclerosis (Thomson Reuters Pharma, update ofAugust 2, 2013).

18F-Flutriciclamide (GE Healthcare, PollardsWood, UK, Fig. 16) is a PET tracer for the for thepotential imaging of neuronal inflammation. In April2013 a Phase I trial was initiated in the US (ThomsonReuters Pharma, update of February 5, 2014).

11C-PBR-28 (National Institutes of Health,Bethesda, MD, Fig. 16) is a PET ligand to measuretranslocator protein 18 kDa, a putative biomarker forinflammation in Phase I clinical trials since January2006. In January 2013, a second Phase I study wasinitiated in the US and at that time the study was


expected to complete in July 2014. The in vivoradioligand binding correlated with the severity ofAD measured by scans with 11C-PiB [360]. Thisligand may be useful for longitudinal studies to markconversion from MCI to AD (Thomson ReutersPharma, update of May 30, 2014).

11C-DAA-1106 (Taisho Pharmaceuticals, Tokyo,Fig. 16) has a very high affinity to PBRs in mito-chondrial fractions of rat (Ki = 0.043 nM) and monkey(Ki = 0.188 nM) brains. logP is 3.65. This compoundhas a four times higher uptake in vivo than PK11195 inmonkey brain [361–366] (Thomson Reuters Pharma,update of December 5, 2011).

11C-(R)-PK11195 (Fig. 16) was used for PET scansin a clinical study with 13 AD patients and 10 controls.Voxel-wise statistical parametric mapping analysisshowed small clusters of significantly increased (R)-11C-PK11195 binding potential in the occipital lobesin AD dementia patients compared with healthy controlsubjects [367].

11C-SSR-180575 (sanofi, Fig. 16) is a valuable toolto measure neuroinflammation in the brain [368, 369](Thomson Reuters Pharma, update of February 25,2014).

11C-Vinpocetine (Gedeon Richter, Budapest) dis-played a significantly higher brain uptake than11C-(R)-PK11195 to reach PBRs in human brain [370,371].

1.28. Peroxisome proliferator-activated receptors

The mechanisms underlying the rapid peroxi-some proliferator-activated receptor gamma (PPAR�)-mediated A� clearance and reversal of cognitivedeficits in a murine model of AD were described[372]. Peroxisome proliferators reduced spatial mem-ory impairment in double transgenic AD mice [373].The potential roles of peroxisomes in AD weredescribed [374]. The PPAR� co-activator-1� (PGC-1�) reduced A� generation [375]. Its overexpressionexacerbated A� and tau deposition in a transgenicmouse model of AD [376]. The upregulation of PGC-1� by an AD-associated pathway was described [377].The modulation of microglia activity by PPAR� ago-nists may provide a promising therapy for PD [378].For a review on PPARs in AD, see [379].

Rosiglitazone (Avandia, GSK; launched in 1999;Fig. 17) enhanced synaptic plasticity in experimen-tal animals [380–382]. Cognitive enhancement withrosiglitazone is linking the hippocampal PPAR� andERK MAPK signaling pathways [383–385] (ThomsonReuters Pharma, update of April 24, 2014).

Pioglitazone (Actos, Takeda, Osaka, launched in1999; Fig. 17) was tested in five randomized controlledPhase II trials on cognition in AD patients [386–388].In August 2013 Takeda and Zinfandel initiated aglobal, multicenter, double-blind, placebo-controlled,parallel-group, Phase III study (TOMMORROW) toinvestigate a genetic-based biomarker risk assignmentalgorithm to predict the risk of developing MCI due toAD within a 5-year period and to evaluate the efficacyof low-dose pioglitazone in delaying the onset of MCIdue to AD in cognitively normal individuals (expectedn = 5,800) at high risk as determined by the risk assign-ment algorithm. The primary endpoint was time todiagnosis of MCI due to AD for placebo-treated, high-risk subjects versus placebo-treated, low-risk subjects.

Pioglitazone improved reversal learning and exertsmixed cerebrovascular effects in a mouse model ofAD with combined A� and cerebrovascular pathology[389]. It reduced glial inflammation and A�1-42 lev-els in A�PPV717I transgenic mice [390]. Pioglitazoneimproved scopolamine-induced memory impairmentin mice [391], see also [392]. Sales of pioglitazonein 2012 were USD 1.548 billion (Thomson ReutersPharma, update of April 30, 2014).

MSDC-0160 (Mitoglitazone, Metabolic SolutionsDevelopment Co., Kalamazoo, MI; Fig. 17), the activemetabolite of pioglitazone, is an insulin-sensitizing,PPAR�-sparing thiazolidine-dione with antihyperten-sive and lipid-lowering properties. The novel insulinsensitizer modulated nutrient sensing pathways andmaintained �-cell phenotype in human islets [393].In September 2013 data from the 29-patient trialwere presented at the 14th International Conferenceon Alzheimer’s Drug Discovery, Jersey City, NJ. Datademonstrated that glucose metabolism was maintainedin non-diabetic AD-related dementia patients treatedwith MSDC-0160, in key regions of brain associatedwith cognitive decline due to AD as confirmed byFDG-PET imaging (Thomson Reuters Pharma, updateof January 21, 2014).

DSP-8658 (Dainippon Sumitomo, Osaka, one com-pound of this series is shown in Fig. 17) is a dualPPAR�/� agonist, which also reduces A� levels, forthe potential treatment of diabetes and AD. A PhaseI clinical trial in patients with AD started in February2011 in the US (Thomson Reuters Pharma, update ofDecember 30, 2013).

Other PPAR agonsits are currently in preclinicalevaluation (in alphabetical order):

Bezafibrate (Bezalip, Bezatol; BoehringerMannheim, now Roche, co-marketed with KisseiPharmaceuticals, Nagano, launched in 1977), a drug


Fig. 17. Seven PPAR� agonists, two prostaglandin E2R, a thromboxane A2R and two RAGE antagonist(s).


for the treatment of hyperlipidemia, is a pan-PPARagonist, which improved behavioral deficits and taupathology in P301S mice exerting a preventive effect[394] (Thomson Reuters Pharma, update of February19, 2014).

GFT-1803 (Genfit, Loos, France and University ofBonn, Germany), a novel potent PPAR agonist thatactivates all the three PPAR isoforms (α/δ/γ), pro-tected APP/PS1 mice from amyloid-� deposition andcognitive deficits [574]. The structure was not commu-nicated.

Glimepiride (sanofi, launched in 1996 by Hoechst)is a medium- to long-acting sulfonylurea antidia-betic drug with PPAR-� stimulating activity, whichdecreased extracellular A�40 and A�42 levels [395].The effect was reversed by the specific PPAR� antag-onist GW-9662 (Thomson Reuters Pharma, update ofJanuary 10, 2014).

Pirinixic acid (WY-14643; Wyeth, now Pfizer,Fig. 17) reduced spatial memory impairment, synap-tic failure, and neurodegeneration in brains of doubletransgenic AD mice [373]. Its development as anantidiabetic drug was terminated (Thomson ReutersPharma, update of January 22, 2013).

SR-1664 (Scripps Research Institute, Jupiter, FL,Fig. 17) is a PPAR� ligand blocking Cdk-5-mediatedphosphorylation [396] (Thomson Reuters Pharma,update of December 9, 2013).

T3D-959 (DB-959; T3D Therapeutics, Raleigh-Durham, NC, Fig. 17) is a dual PPARδ andPPAR� agonist with HDL cholesterol-promoting andtriglyceride-reducing properties for the potential oraltreatment of AD in preclinical development (ThomsonReuters Pharma, update of April 22, 2014).

TGFTX-1 (Genfit, Loos, Nord-Pas de Calais) is anagonist at the nuclear receptor ROR� (NR1F1) for thepotential treatment of inflammation, cardiometabolicand neurodegenerative diseases, such as AD [397](Thomson Reuters Pharma, update of April 1, 2014).The structure was not communicated.

TGFTX-3 (Genfit, Loos, Nord-Pas de Calais) tar-gets the Rev-Erb � nuclear receptor, for the potentialtreatment of inflammation, cardiometabolic and neu-rodegenerative diseases. In October 2012, positive invivo data demonstrated that the compound regulatedglucose metabolism in diabetes models (ThomsonReuters Pharma, update of April 1, 2014). The structurewas not communicated.

Troglitazone (Daiichi Sankyo, Tokyo; withdrawnfrom the market) decreased tau phosphorylationthrough the inhibition of CDK5 activity in SH-SY5Yneuroblastoma cells and primary neurons [398].

1.29. Prostaglandin receptors

Therapeutic implications of the prostaglandin path-way in AD were discussed [399]. EP2 signaling isimplicated in inflammation early in the AD course[400]. Positive and negative effects of prostaglandinsin AD were described [401]. AD-associated inflamma-tion was suppressed via microglial prostaglandin-E2EP4 receptor signaling [402].

Amgen (Thousand Oaks, CA) is investigating EP2antagonists for the potential treatment of AD. A leadcompound (Fig. 17) was identified with moderate i.v.pharmaco-kinetic properties in mice, a Cmax of 1.2 �Mand an oral bioavailability of 31%. The compounddemonstrated good CNS permeability and significantlyincreased A� phagocytosis with an IC50 value of 8 nMfor EP2 receptors The development was terminated(Thomson Reuters Pharma, update of May 12, 2014).

CNDR-51526 and CNDR-51529 (University ofPennsylvania, Philadelphia, PA; one compound isshown in Fig. 17) are thromboxane A2-prostanoidreceptor antagonists in preclinical evaluation for thepotential treatment of AD (Thomson Reuters Pharma,update of June 5, 2013).

TG-6101 (Emory University, Atlanta, GA; Fig. 17)is the lead compound of prostaglandin EP2 receptorantagonists for the potential treatment of inflamma-tion associated with neurological disease such as AD,PD, stroke, traumatic brain injury, migraine, and neu-ropathic pain [403] (Thomson Reuters Pharma, updateof December 10, 2012).

1.30. Purinergic receptors

Silencing of the P2X7 receptor enhanced A� phago-cytosis by microglia [404]. Loss of P2Y2 receptorsenhanced early pathology in a transgenic mouse modelof AD [405]. P2Y4 receptor-mediated pinocytosis con-tributed to A�-induced self-uptake by microglia [406].Activation of the purinergic receptor P2X7 stimu-lated sA�PP� release from mouse neuroblastoma cellsexpressing human A�PP [407].

The development of P2X7 purinoceptor antagonistsof Axxam was terminated.

1.31. Receptor for advanced glycation end products

RAGE is a member of the microglial scav-enger receptors [408–411]. Hypertension inducedbrain A� accumulation, cognitive impairment, andmemory deterioration through activation of RAGE[412].


TTP-488 (PF-04494700; Trans Tech Pharma, HighPoint, NC in collaboration with Pfizer) is a smallmolecule and orally active RAGE antagonist in a multi-center, randomized, double-blind, placebo-controlled,Phase IIb trial in the US in 400 subjects with mild-to-moderate AD since December 2007. In October 2012data were reported from the trial demonstrating 26%benefit relative to placebo in cognitive decline over 18months in patients receiving a 5 mg dose. Patients withmild AD showed a 46% benefit over placebo. Extensivepost-hoc analyses showed a consistent signal indica-tive of a therapeutic benefit at the 5 mg dose level.At 18-month, decline in ADAS-cog11 was reducedto 26% compared to placebo. Pharmacokinetic andpharmacodynamic data showed statistically significantdifferences in ADAS-cog11 from month 6 through 18in population through plasma concentrations in an opti-mal range. The drug was safe and well tolerated. TheFDA granted Trans Tech Pharma fast track designationfor TTP-488 for the treatment of AD. The results of aclinical trial with 5 mg/d and 20 mg/d for 18 monthswere communicated. The high dose increased cog-nitive decline at 6 months [413] (Thomson ReutersPharma, update of April 16, 2014). The structure wasnot communicated.

TTP-4000 (Pfizer under license from Trans TechPharma, High Point, NC) is a fusion protein containingthe extracellular portion of RAGE. In March 2012, arandomized, double-blind, placebo-controlled, PhaseI study (NCT01548430) was initiated in patients withAD (expected n = 16) in the US to assess safety andpharmacokinetics (Thomson Reuters Pharma, updateof January 6, 2014).

Other RAGE antagonists are currently in preclinicalevaluation (in alphabetical order):

A-992401 (AbbVie, North Chicago, IL) is a mon-oclonal antibody targeting RAGE for the potentialtreatment of AD (Thomson Reuters Pharma, updateof January 4, 2013).

DBT-066 and DBT-320 (Roche under license fromDigital Biotech, Ansan, South Korea and the SeoulNational University) are RAGE antagonists that blockthe entry of A� into the brain (Thomson ReutersPharma, update of October 3, 2013). The structureswere not communicated.

FPS2-BM and FPS-ZM1 (Socratech, Rochester,NY, a spin-off of the University of Rochester, Fig. 17)are high affinity RAGE-specific inhibitors that blockedA� binding to the V domain of RAGE and inhibitedA�40 and A�42-induced cellular stress in RAGE-expressing cells in vitro and in mouse brain in vivo (Th-omson Reuters Pharma, update of August 13, 2013).

Medifron DBT (Seoul, Fig. 17) published a paper onligand-based design, synthesis, and biological evalua-tion of 2-aminopyrimidines, a novel series of RAGEinhibitors [414, 415] (Thomson Reuters Pharma,update of February 25, 2014).

Pfizer scientists published the pharmacokinetics andlung distribution of a humanized anti-RAGE anti-body in wild-type and in RAGE −/− mice [416].

An aqueous orally active vaccine targeted againstthe RAGE/A� complex was described by scientistsfrom Georgia Health Sciences University, Augusta,GA [417].

The development of small molecule RAGE antago-nists by Hermo Pharma Oy (Helsinki) and by MabPrex(San Diego, CA) was terminated.

1.32. Retinoid X receptors

Stimulation of the retinoid X receptor facilitatedA� clearance across the BBB [418]. For a review,see [419]. More precisely, only retinoic acid � ago-nists (e.g., AM-580, Roche) reduced the numberof A� plaques, whereas retinoic acid � (e.g., CD-2019) or retinoic acid � agonists (e.g., CD-437)had no effect on plaque load [420, 421]. The A�production is attenuated by direct inhibition of �-secretase-mediated cleavage of A�PP [422]. Retinoicacid-elicited RAR�/RXR� signaling attenuated theA� production by direct inhibition of �-secretase-mediated cleavage of A�PP [423]. The retinoicacid-inducible gene-I (RIG-1) receptor is significantlyelevated in the temporal cortex and plasma in patientswith MCI [424]. A recent review was disclosed [425].

IRX-4204 (AGN-194204; Io Therapeutics, SantaAna, CA under license from Allergan, Irvine, CA,Fig. 18) is a second generation orally active retinoid Xreceptor agonist for the potential treatment of prostatecancer and AD in Phase II clinical trials since October2011 (Thomson Reuters Pharma, update of April 10,2014).

Acitretin (Roche, launched IN 1997) up-regulatedthe �-secretase ADAM10 [426, 427].

All-trans retinoic acid rescued memory deficitsand neuropathological changes in a mouse modelof streptozocin-induced dementia of Alzheimer-type[428].

Bexarotene (Targretin, LGD-1069; Eisai; Fig. 18)is a retinoid X receptor agonist, which after oraladministration to a murine model of AD causedenhanced clearance of soluble A� within hours inan ApoE-dependent manner. ApoE expression is tran-scriptionally induced through the action of the nuclearreceptors PPAR� and LXR in coordination with


Fig. 18. Two retinoid X R, three 5-HT1A R agonists, three 5-HT2A R antagonists, three 5-HT4R agonists and one 5-HT4R antagonist PETligand.


retinoid X receptors. Aß plaque area was reducedby 50% within 72 hours [575]. Bexarotene blockedcalcium-permeable ion channels formed by neuro-toxic A� peptides [429]. What did we learn fromthe bexarotene discussion [430]? Bexarotene ana-logues with higher affinity to retinoid receptors weredescribed [431] (Thomson Reuters Pharma, update ofFebruary 17, 2014).

GT-1036 (MC-1036; Gerinda Therapeutics, Cary,NC, under license from MaxoCore, Solana Beach, CA)is the lead from selective retinoid X receptor ago-nists which acts by increasing ApoE protein levels forthe potential oral treatment of AD (Thomson ReutersPharma, update of November 18, 2013). The structurewas not communicated.

Retinoic acid receptor-� agonists (CoCo Ther-apeutics, Oxford, UK under license from King’sCollege, London) are investigated for the potentialtreatment of AD. They are aryl-amido-aryl compounds(Thomson Reuters Pharma, update of September 4,2013). The precise structures were not communicated.

The development of Tamibarotene (Am80; NipponShinyaku, Kyoto, under license from the University ofTokyo; [432–434]) was terminated.

1.33. Ryanodine receptors

S-107 (Armgo Pharma, Tarrytown, NY underlicense from Columbia University, New York) is a rycalthat enhanced binding of calstabin to leaky ryanodinereceptor/calcium release channels in the closed statefor the potential oral treatment of muscle diseases,neurodegenerative disease including AD and cogni-tive disorders. Mice were treated with S-107 beforeand during a chronic stress test. The drug significantlyimproved all measures tested which included learningand memory. S-107 also significantly improved neu-ronal signaling measured by reduced long-term poten-tiation [435] (Thomson Reuters Pharma, update ofMay 21, 2014). The structure was not communicated.

1.34. Scavenging receptors class A

Scavenger receptors are a group of receptors thatrecognize modified low-density lipoprotein (LDL) byoxidation or acetylation. This naming is based on afunction of cleaning (scavenging): Scavenger receptorswidely recognize and uptake macromolecules havinga negative charge as well as modified LDL. Class A ismainly expressed in the macrophage with a molecularweight of 80 kDa [436]. It was shown that heptapeptideXD4 activated the class A scavenger receptor (SR-A) on glia by increasing the binding of A� to SR-A,

thereby promoting glial phagocytosis of A� oligomerin microglia and astrocytes and triggering intracel-lular MAPK signaling cascades. XD4 enhanced theinternalization of A� monomers to microglia and astro-cytes through macropinocytosis or SR-A-mediatedphagocytosis. XD4 significantly inhibits A� oligomer-induced cytotoxicity to glial cells and decreases theproduction of proinflammatory cytokines, such asTNF-� and IL-1�, in vitro and in vivo. These find-ings may provide a novel strategy for AD treatment byactivating SR-A [437].

1.35. Serotonin receptors

1.35.1. 5-HT1A Receptor agonists andantagonists

Tandospirone (Sediel, SM-3997; Dainippon Sum-itomo Pharmaceuticals, Osaka, Fig. 18) is an orallyactive 5-HT1A agonist for the treatment of generalizedanxiety disorders and cognitive function deficits. Thedrug was launched in Japan in December 1996 and inChina in February 2004 [438–442] (Thomson ReutersPharma, update of March 19, 2014).

Vortioxetine (Brintellix, Lu-AA21004; Lundbeck,Valby, DK and Takeda, Osaka, Fig. 18) is a 5-HT1Areceptor agonist, a 5-HT1B receptor partial agonist, a5-HT1D, 5-HT3, and 5-HT7 receptor antagonist, anda 5-HT transporter inhibitor launched in the US inOctober 2013 for the treatment of adult major depres-sive disorders. Vortioxetine enhanced contextual andepisodic memory in rat behavioral models [443, 444].For the efficacy and safety of vortioxetine in patients,see [445–453]. The outcome of the FOCUS study waspresented at ACNP and Brintellix 10 mg and 20 mgdemonstrated a statistically significant improvementin cognitive performance as assessed by DANTESSubject Standardized Test and Rey Auditory VerbalLearning Test versus placebo. Vortioxetine receivedEU approval as well as approval in Iceland, Liecht-enstein, and Norway for the treatment of adults withmajor depressive episodes. First European launches areexpected in 2H14 (Thomson Reuters Pharma, updateof May 27, 2014).

F-15599 (Pierre Fabre, Burlats, France, Fig. 18) isa preferential postsynaptic 5-HT1A receptor agonistshowing a favorable profile in models of cognitionin comparison to reference 5-HT1A receptor agonistssuch as F-13714. F-15599 is currently in preclinicalevaluation for the potential treatment of depres-sion [454–458] (Thomson Reuters Pharma, update ofDecember 10, 2013). 18F-F15599 was used as a novelradioligand for PET neuroimaging [459].


1.35.2. 5-HT2 receptor antagonistsDisease-specific expression of 5-HT2C receptors in

patients with AD was reported [460].Aripiprazole (Abilify; Otsuka Pharmaceuticals,

Tokyo, launched in 2002) was tested in AD patients.It should only be used in selected patient populationsresistant to non-pharmacological treatment with per-sisting or severe psychotic symptoms and/or agitation[461]. Sales in 2012 reported by Otsuka were USD5,481 billion (Thomson Reuters Pharma, update ofMay 31, 2014).

Asenapine (Saphris, Organon, later Schering-Plough, now Merck & Lundbeck, launched in 2009)is a 5-HT2A and dopamine D1/D2 antagonist for thetreatment of schizophrenia in adults administered asa sub-lingual formulation. Sales in 2012 reported byMerck were USD 166 million and by Lundbeck atUSD 19 million (Thomson Reuters Pharma, update ofJanuary 15, 2014).

Blonanserin (Lonasen, AD-5423, DSP-5423;Dainippon Sumitomo Pharmaceuticals, Osaka,Fig. 18) is a 5-HT2A and dopamine D2/D3 antagonistlaunched in Japan in 2008 for the treatment ofschizophrenia. The pharmacological profile wasdescribed including reports on the improvement ofsome types of cognitive function in patients withfirst-episode and chronic schizophrenia [462]. Salesin 2012 were USD 134 million (Thomson ReutersPharma, update of May 30, 2014).

Lurasidone (Latuda, SM-13496; Dainippon Sum-itomo Pharmaceuticals, Osaka, Fig. 18) is a 5-HT2Aand 5-HT7 antagonist, 5-HT1A partial agonistand dopamine D2 antagonist atypical antipsychoticlaunched in the US by Dainippon’s US subsidiarySynovion Pharmaceuticals (Marlborough, MA) inFebruary 2011. The product is indicated in the US forthe treatment of schizophrenia in adults with depres-sive episodes associated with bipolar I disorder andcognitive function deficits [463–467]. Sales in 2012were USD 201 million (Thomson Reuters Pharma,update of May 29, 2014).

Pimavanserin (ACP-103; BVF-036; ACADIAPharmaceuticals, San Diego, CA; Fig. 18), a 5HT2Areceptor inverse agonist reversed psychosis-like behav-iors in a rodent models of AD and PD [468–470]. Thecompound is in Phase III clinical trials since January2003 in Europe and since June 2007 in the US. Adetailed report on Pimavanserin for patients with PDpsychosis: a randomized, placebo-controlled Phase IIItrial was published [471]. Acadia announced that ithad initiated a Phase II feasibility trial designed toexamine the efficacy and safety of pimavanserin as a

treatment for patients with AD psychosis (ThomsonReuters Pharma, update of May 7, 2014).

ITI-007 (Intra-Cellular Therapies, New York, NYunder license from Bristol-Myers Squibb) is a 5-HT2Areceptor antagonist, dopamine D2 receptor partial ago-nist, and serotonin reuptake transporter modulator, forthe potential treatment of schizophrenia, depression,bipolar disorder, and sleep disturbances in psychiatricand neurodegenerative diseases in Phase II clinical tri-als since May 2010 in the US. In December 2013,positive results were reported. In March 2014, a PhaseI/II trial (ITI-007-200) was initiated to evaluate thesafety, tolerability, pharmacokinetics, and pharma-codynamics of low dose ITI-007. The first part ofthe trial was a randomized, double-blind, placebo-controlled multiple ascending dose study in which10 healthy geriatric subjects in each cohort wouldreceive ITI-007 or placebo for 7 days. The secondpart of the trial would be conducted in dementiapatients (expected n = 12) [472] (Thomson ReutersPharma, update of May 7, 2014). The structure was notcommunicated.

Quetiapine (Seroquel; AstraZeneca) is an orallyactive dibenzothiazepine atypical antipsychotic with 5-HT2 and D2 antagonistic activity launched in the UKand the US in 1997. It attenuated recognition mem-ory impairment and hippocampal oxidative stress ina transgenic mouse model of AD [473] (ThomsonReuters Pharma, update of May 31, 2014).

1.35.3. 5-HT3 Receptor antagonistsCognitive implications for histamine H3 and 5-HT3

receptor modulation of cortical cholinergic functionwere elucidated [474] as was the role of 5-HT3 recep-tors in selective animal models of cognition [475].

1.35.4. 5-HT4 receptor (partial) agonistsPRX-3140 (Nanotherapeutics, Alachua, FL,

Fig. 18) is a 5-HT4 receptor agonist in Phase II clinicaltrials for treatment of AD and post-traumatic stressdisorders since December 2009 in the US. Data onthe enhancement of cognitive function in vivo werecommunicated [476] (Thomson Reuters Pharma,update of October 24, 2013).

Velusetrag (TD-5108, Theravance, South San Fran-cisco, CA; Fig. 18) is in Phase I trials for AD in theUS in July 2010. In January 2013 a proof-of-conceptPhase II trial in gastroparesis in the US and in Italywas initiated. Its in vitro pharmacological profile waspublished [477]. Another potential use is treatment ofgastrointestinal motility disorders [478, 479] (Thom-son Reuters Pharma, update of May 27, 2014).


AAT-009 (RQ-00000009, RQ-9; AskAt, followingits spin-out from RaQualia, Chita-Gun, Aichi-Ken,Japan and Pfizer) is a selective 5-HT4 receptor partialagonist for the treatment of AD. A Phase I study wasinitiated in Japan in August 2008, a second Phase Istudy in February 2013 (Thomson Reuters Pharma,update of January 2, 2014). The structure was notdisclosed.

SUVN-D1003019, SUVN-1004028, SUVN-D1108121, SUVN-D4010, and orally bioavailableSUVN-D1104010 (Suven Life Sciences, Hyder-abad, India) are selective 5-HT4 receptor agonistsfor the treatment of MCI, cognition, and AD. A4-hydroxyquinolinone with good oral exposure, brainpenetration, moderate clearance, good half-life in rats,and efficacy in in vivo cognition tests was presentedat the 243rd ACS Meeting in San Diego March 2012(Fig. 18). Preclinical data on SUVN-D1104010 werepresented at the Alzheimer’s Association InternationalConference in Vancouver, July 14–19, 2012 [273].In November 2013 preclinical studies in AD wereongoing (Thomson Reuters Pharma, update of May26, 2014).

GSK terminated the development of the 5-HT4antagonist PET ligand 11C-SB-207145 (Fig. 18;Thomson Reuters Pharma, update of December 4,2013). The ligand is still extensively used for brainimaging of 5-HT4 receptors in academic settings[480–484]. Also the tritiated ligand 3H-SB-207145is frequently used for 5-HT4 receptor binding studies[485, 486].

The development of TD-8954 (Theravance; [476,487–489]) for the indication AD was terminated,but development for the treatment of gastrointesti-nal motility disorders is continuing (Thomson ReutersPharma, update of May 27, 2014).

1.35.5. 5-HT6 receptor antagonistsThe topic 5-HT6 receptors and AD was reviewed

[490]. Their role in modulating brain neurochemistrywas described [491].

Idalopirdine (Lu AE58054; LY-483518; SGS-518; Lundbeck, Valby, DK under license from Lilly;Fig. 19) was in Phase II clinical development sinceNovember 2009. Lundbeck and Otsuka Pharmaceuti-cal Co., Tokyo have concluded a license agreement

Fig. 19. 5-HT6 receptor antagonists.


to co-develop and co-commercialize Lu AE58054. InOctober 2013 the first of four Phase III trials wasinitiated; the Phase III program will enroll approxi-mately 3,000 patients and assess Lu-AE58054 (10 to60 mg) combined with donepezil. The primary end-points will be ADAS-cog, activities of daily living, andthe Clinical Global Impression of Change Scale. Threestudies were started: NCT01955161: Study of LuAE58054 in patients with mild to moderate AD treatedwith donepezil (STARSHINE), NCT02006641: LuAE58054 in patients with mild to moderate AD treatedwith donepezil (STARBEAM) and NCT02006654:Lu AE58054 in patients with mild to moderate ADtreated with an acetylcholinesterase Inhibitor (STAR-BRIGHT) (Thomson Reuters Pharma, update of May15, 2014).

AVN-101 (Avineuro Pharmaceuticals, San Diego,CA and Avineyro, Russian Federation under licensefrom Alla Chem LLC, Hallandale Beach, FL) is a 5-HT6 receptor antagonist for the potential treatment ofAD and anxiety. Phase II clinical trials were initiated inFebruary 2010 for AD and anxiety (Thomson ReutersPharma, update of May 29, 2014). The structure wasnot disclosed.

AVN-211 Avineuro Pharmaceuticals, San Diego,CA, and Avineyro, Russian Federation under licensefrom Alla Chem LLC, Hallandale Beach, FL) isanother 5-HT6 receptor antagonist in Phase II clinicaltrials for the potential treatment of cognitive symp-toms in schizophrenia since June 2009. In February2011 results from the double-blind, Phase IIa trial in50 patients showed the trial met its primary efficacyendpoints and AVN-211 was safe and well tolerated.In July 2013 a Phase IIb schizophrenia trial was ini-tiated (Thomson Reuters Pharma, update of May 29,2014). The structure was not disclosed.

SAM-760 (PF-05212377, WYE-103760; Wyeth,now Pfizer; Fig. 19) was in Phase I clinical trials forthe treatment of AD since October 2009. In January2013 a placebo-controlled, randomized, double-blind,18-week, Phase II trial was initiated to assess the safetyand efficacy of SAM-760 in patients with mild-to-moderate AD (n = 342) with existing neuropsychiatricsymptoms on a stable dose of donepezil (ThomsonReuters Pharma, update of May 16, 2014).

ABT-354 (SLV-354; Abbvie, North Chicago, IL fol-lowing its acquisition of Solvay’s pharmaceutical busi-ness) is a 5-HT6 receptor modulator in Phase I clinicaltrials since February 2010 in the UK. In March 2012another Phase I trial began in schizophrenia patients(n = 22) in the US (Thomson Reuters Pharma, update ofMay 29, 2014). The structure was not communicated.

AVN-322 (Avineuro Pharmaceuticals, San Diego,CA and Avineyro, Moscow, Russia under license fromAlla Chem LLC, Hallandale Beach, FL) was in Phase Iclinical trials for the treatment of AD since June 2009.In October 2013 a new Phase I study was initiated inRussia (Thomson Reuters Pharma, update of May 29,2014). The structure was not disclosed.

SUVN-502 (Suven Life Sciences, Hyderabad,Fig. 19), an orally active 5-HT6 receptor antagonist,which increases extracellular levels of acetylcholineand glutamate, is in Phase I clinical trials for the treat-ment of cognitive disorders in AD, attention deficienthyperactivity, PD, and schizophrenia since June 2008in Switzerland and since November 2013 in the US(Thomson Reuters Pharma, update of May 26, 2014).

SYN-114 and SYN-120 (Biotie Therapies, Basel,Switzerland, formerly Synosia Therapeutics underlicense from Roche, Basel, Switzerland) are currentlyboth in Phase I clinical trials for the treatment of cog-nitive disorders since January 2007 and March 2009in the US, respectively (Thomson Reuters Pharma,updates of August 24, 2012 and May 27, 2014, respec-tively). The structures were not disclosed.

There are many 5-HT6 receptor antagonists in pre-clinical evaluation (in alphabetical order):

AVN-457, AVN-458 and AVN-492 (Avineuro Phar-maceuticals, San Diego, CA) are drugs for the potentialtreatment of cognitive disorders (Thomson ReutersPharma, update of May 30, 2014). The structures werenot disclosed.

BVA-101 and BVA-601 (Biovista, Charlottesville,VA) are novel formulations of latrepirdine (dimebon)for the potential oral treatment of multiple sclerosis andof epilepsy, respectively (Thomson Reuters Pharma,updates of November 28, 2012 and of November 29,2012, respectively).

SEL-103 (Selvita Life Sciences Solutions, Krakow,PL) is a program of 5-HT6 receptor inhibitors for thepotential treatment of AD and related cognitive disor-ders (Thomson Reuters Pharma, update of March 13,2014). No structures were communicated.

5-HT6 receptor antagonists (Abbvie, NorthChicago, IL; Fig. 19) are evaluated for the potentialtreatment of cognitive deficits in patients with AD andschizophrenia. The medicinal chemistry was described[492]. The effects to ameliorate scopolamine-inducedmemory deficits in object recognition and object loca-tion tasks in Wistar rats were reported [493] (ThomsonReuters Pharma, update of January 4, 2013).

5-HT6 receptor antagonists (Proximagen, Lon-don, UK, a subsidiary of Upsher-Smith Laboratories,Maple Grove, MN, under license from Swedish


Orphan Biovitrum, Stockholm) are evaluated for thepotential treatment of cognitive disorders includingcognitive disorders in PD. By March 2012 in vivo stud-ies had demonstrated high brain penetration and goodoral activity in a novel object recognition test (Thom-son Reuters Pharma, update of April 16, 2014). Nostructures were communicated.

SUVN-507 (Suven Life Sciences, Hyderabad;Fig. 19) is a 5-HT6 receptor antagonist (Ki = 1.3 to1.6 nM) for the treatment of schizophrenia, MCI andAD in preclinical development. Other compoundsin preclinical evaluation are SUVN-501, SUVN-504,SUVN-901, SUVN-976, and SUVN-A60203. SUVN-504 is evaluated as drug for the potential treatmentof obesity and metabolic disorders including diabetes.SUVN-512 was presented as a novel 5-HT6 receptorantagonist with drug like properties at the Alzheimer’sAssociation International Conference in Boston, July17, 2013 in Abs P4-305 (Thomson Reuters Pharma,update of April 11, 2014).

Novel chemical classes of 5-HT6 receptor antago-nists, i.e., aryl aminosulfonamide derivatives with aKb of 0.02 nM were reported by medicinal chemists atSuven, as were N1-arylsulfonyl-3-piperazinyl indolederivatives with a Ki of 3.4 nM [494–501].

The development of SB-742457 (GSK; [502–506])was terminated.

1.36. Sigma receptors

The accumulation of the sigma-1 receptor iscommon to neuronal nuclear inclusions in various neu-rodegenerative diseases [507].

Anavex-2-73 (AVex-2-73; AN-2; Anavex Life Sci-ences, Vancouver, BC; Fig. 20), a sigma-1 receptoragonist, is currently in a Phase I AD trial since Marchof 2011 [508]. Sigma-1 receptor agonists like Anavex2-73 are involved in cellular survival by regulating andstabilizing a key cell stress sensor [509]. Blockade oftau hyperphosphorylation and A�1-42 generation wasreported [510] (Thomson Reuters Pharma, update ofMay 29, 2014).

ANAVEX PLUS (Anavex Life Sciences, Van-couver, BC) is a combination of Anavex-2-73 anddonepezil for the potential treatment of AD. In January2014 clinical development with the Roskamp Insti-tute (Sarasota, FL) was planned (Thomson ReutersPharma, update of May 29, 2014).

Anavex-1-41 (Anavex Life Sciences, Vancouver,BC; Fig. 20) is a potential back-up compound[511–513] (Thomson Reuters Pharma, update of May19, 2014).

Epigen Biosciences (San Diego, CA) is investigatingligands to sigma-1 receptors that regulate nitric oxideproduction for the potential treatment of AD (Thom-son Reuters Pharma, update of February 13, 2014).Structures were not communicated.

Fabomotizole (Afobazol, CM-346, SM-346, GRN-014; Pharmstandard through its subsidiary IBCGenerium, Moscow; Fig. 20) is a neuroprotective pan-sigma receptor agonist for the potential treatmentof ischemic stroke and neurodegenerative conditionsincluding AD. The drug was launched in Russia in2005 as an OTC mild anxiolytic. The drug modulatesneuronal responses to A�25-35 [514, 515] (ThomsonReuters Pharma, update of May 20, 2014).

MC-116 (M’s Science, Kobe) is a sigma receptoragonist for the potential treatment of major depressionand CNS diseases including AD (Thomson ReutersPharma, update of February 28, 2013). The structurewas not communicated.

(±)-PPCC (University of Trieste; Fig. 20), a novelsigma-1 receptor ligand, displayed anti-amnesic prop-erties on cognitive dysfunction induced by selectivecholinergic lesions in rats [516].

SOM Biotech SL (Barcelona) is investigating arepurposed formulation of an undisclosed sigma-1agonist, for the potential treatment of amnesia and AD(Thomson Reuters Pharma, update of December 24,2013). The structure was not communicated.

A novel PET radioligand for imaging of sigma-1receptors 18F-FTC-146 (Stanford University, Fig. 20)was presented [517, 518].

The development of (–)-MR22 (University ofMessina; [519–521]) was terminated.

1.37. Somatostatin receptor agonists

The roles of neuropeptides including somatostatinwere discussed [216].

1.38. Sortilin receptor inhibitors

Sortilin is a type I membrane receptor belongingto the vacuolar protein sorting 10 protein (VPS10P)family of sorting receptors [346], that also includesSorLa and SorCS1,2 and 3 [522]. Previously, sor-tilin was known as the neurotensin receptor 3[523]. Sortilin binds to and promotes �-cleavage ofA�PP and is responsible for ApoE-mediated cel-lular uptake and degradation of extracellular A�[524–526]. Significantly increased levels of sortilinwere found in human AD brains and in 6-monthold Swedish-A�PP/PS1dE9 transgenic mice [527].


Fig. 20. Sigma-1R agonists and antagonists, a sortilin R and a TNF-� inhibitor.

BACE1 retrograde trafficking is regulated by thecytoplasmic domain of sortilin [528]. ExtracellularA� oligomers act as sortilin ligands [529]. In addi-tion, genetic variants in the sortilin-related receptor(SORL1) and the sortilin-related vacuolar proteinsorting 10 (VPS10) domain-containing receptor 1(SORCS1) are associated with increased risk of late-onset AD [530].

AF-38469 (Lundbeck, Valby, DK; Fig. 20) is anorally bioavailable sortilin receptor inhibitor with anIC50 of 330 nM [531]. An X-ray crystal structure ofthe sortilin-AF-38469 protein-inhibitor complex waspublished [532] (Thomson Reuters Pharma, update ofMarch 11, 2014).

1.39. Sphingosine-1-phosphate receptor modulators

Sphingolipids are critical players in AD [533].Plasma sphingomyelins are associated with cognitiveprogression in AD [534]. The pathological roles ofceramide and its metabolites in metabolic syndromeand AD were described [576].

ABT-363 (AbbVie, North Chicago, IL) is asphingosine-1-phosphate receptor 5 (S1P5) modulatorfor the potential treatment of neurological disordersincluding AD (Thomson Reuters Pharma, update of

January 3, 2013). Another S1P1/S1P5 receptor mod-ulator ABT-413 is evaluated in Phase I clinical trialsfor the treatment of multiple sclerosis and rheumatoidarthritis since June 2011 (Thomson Reuters Pharma,update of January 4, 2013). Neither structure wascommunicated.

Fingolimod (FTY720; Novartis and MitsubishiTanabe Pharma, Osaka, launched in 2010) attenu-ated A�42 induced impairment of spatial learning andmemory in rats [535] via increased BDNF expressionin neurons [536]. It showed neurorestorative effectsin a rat model of AD in direct comparison withmemantine [537]. Fingolimod increased BDNF lev-els and ameliorated A�-induced memory impairment[538] (Thomson Reuters Pharma, update of January 7,2014).

Siena Biotech is investigating S1P) antagonists forthe potential treatment of neurodegenerative diseasesincluding AD and Huntington’s disease, inflamma-tion, and fibrosis (Thomson Reuters Pharma, update ofOctober 1, 2012). Structures were not communicated.

1.40. Tachykinin receptor antagonists

The roles of neuropeptides including the tachykininsystem were discussed [216].


1.41. Tumor necrosis factor receptor 1/2 inhibitors

125I-A�1-40 binds specifically to TNFR1 in SH-SY5Y cells with a Kd of 0.42 nM [539]. A combinationof data on plasma TACE activity, sTNFRs, and A� withthe presence of the ApoE �4 allele may provide a novelbiomarker [540].

NK-001 (NP-1; Neurokine Pharmaceuticals, Van-couver, BC) is a repurposed form of the TNF�-blocking agent etanercept, 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 [541, 542]. A rapid cognitive improvementfollowing perispinal etanercept administration (Tren-delenburg positioning) to 15 probable-AD patientstreated once weekly for 6 months was reported[543–545]. See also the commentary [546]. In Decem-ber 2010 the drug was in Phase II development inCanada for the potential treatment of neurocognitiveimpairment following coronary artery bypass graftsurgery (Thomson Reuters Pharma, update of August19, 2013).

3,6′-Dithiothalidomide (Fig. 20), a small moleculeinhibitor for TNF-� prevented cognitive deficits in atriple transgenic mouse model of AD [547–550].

PD-2015, PD-2016 and PD-2024 (P2D Bio-science, Cincinnati, OH) are small molecule TNF�inhibitors. They are thalidomide analogues. A signifi-cant improvement (by 24%) in the Morris water mazeperformance was observed in mice administered PD-2015 at a 100 mg/kg dose. The working memory in theradial arm maze task and the ability to construct a nestwere improved by 42 and 17%, respectively (Thom-son Reuters Pharma, update of February 26, 2014).The structures were not communicated.

TNFR1 NAMs (Addex Therapeutics) are investi-gated for the potential oral treatment of rheumatoidarthritis, psoriasis, AD and multiple sclerosis (Thom-son Reuters Pharma, update of April 7, 2014).

TNFR2:Fc fusion protein (UCB, Brussels, Bel-gium) is a s.c. formulation of an anti-TNF� agent forthe potential treatment of AD [551] (Thomson ReutersPharma, update of October 26, 2012).

1.42. Vitamin D receptors

Epidemiological studies suggested that vitamin Dinsufficiency increased the risk of AD. Low serum vita-min D concentrations were observed in AD patients[552, 553]. The role of vitamin D in AD and possiblegenetic and cell signaling mechanisms were discussed

[554]. Reviews on vitamin D, cognition, and dementiawere presented [555, 556, 577]. Vitamin D supplemen-tation restored suppressed synaptic plasticity in AD[578]. The major mediator of vitamin D’s actions is thevitamin D receptor. A� suppressed the expression ofthe vitamin D receptor gene [557]. The current knowl-edge was compiled in a recent review [558]. VitaminD3-enriched diet correlated with a decrease of A�plaques in the brains of A�PP transgenic mice [559].1�,25-Dihydroxyvitamin D3 and resolving D1 retunethe balance between A� phagocytosis and inflamma-tion in AD patients [560]. Combination of memantineand vitamin D prevented axon degeneration inducedby A� and glutamate [561].

The level of vitamin D-binding protein (DBP) isincreased in the CSF of patients with AD. DBP inter-acted with A� and suppressed A�-mediated pathology[562].

CONCLUSIONS

With the launch of the NMDA receptor channelblocker Memantine for the treatment of moderate tosevere AD in 2002, a valuable medication was addedto four acetylcholinesterase inhibitors launched previ-ously (see Part 2 [7]). The medical team of Merz underHans Jorg Mobius and the many collaborating clini-cians deserve full credit for an important breakthroughfor the benefit of AD patients.

So far, the development of 14 Phase III com-pounds interacting with receptors for the potentialtreatment of AD was discontinued, i.e., of alvameline,cevimeline, milameline, sabcomeline and xanome-line (M1 mAChR agonists), dehydroepiandrosterone(androgen receptor agonist), fasoracetam, nebracetam,and nefiracetam (piracetam analogues), neramex-ane (NMDA receptor channel blocker), rosiglitazone(PPAR� agonist), xaliproden (5-HT1A receptor ago-nist), lecozotan (5-HT1A receptor antagonist), andlatrepirdine (5-HT6 receptor antagonist).

Three compounds interacting with receptors arecurrently in Phase III clinical trials for the poten-tial treatment of AD: encenicline (EVP-6124; �4�2nAChR agonist), pioglitazone (PPAR� agonist), andidalopirdine (Lu AE58054; 5-HT6 receptor antago-nist). First results can be expected in 2017 only.

There are currently 17 compounds interacting withreceptors in Phase II clinical trials for the potentialtreatment of AD: MK-7622 (M1 mAChR agonist),ispronicline and pozanicline (�4�2 nAChR ago-nists), ABT-126 and GTS-21 (�7 nAChR agonists),


tozadenant (adenosine receptor A2A antagonist),ORM-12741 (�2C adrenoceptor antagonist), dronabi-nol (cannabinoid receptor agonist), phyto-�-SERM,(ER-� agonist), HT-2157 (galanin-3 receptor antag-onist), S-38093 (histamine H3 receptor antagonist),MSDC-0160 (PPAR� sparing agonist), TTP-488(RAGE antagonist), PRX-3140 (5-HT4 receptor ago-nist), AVN-101, AVN-211, SAM-760, AVN-101,AVN-211 and SAM-760 (5-HT6 receptor antago-nists). In view of the duration of a clinical developmentin this indication it will take past 2020 until one of thesecompounds will make it to the market.

DISCLOSURE STATEMENT

Authors’ disclosures available online (http://www.j-alz.com/disclosures/view.php?id=2195).

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Cognitive Enhancers (Nootropics). Part 1: Drugs ...€¦ · The present review covers the evolution of research in this ﬁeld through March 2014. Keywords: Alzheimer’s disease,