Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with … · tal activities, including pre-attentional sensory gating, attention,learningandmemory,problemsolving,plan-ning,reasoningandjudgment,understanding,knowing

Journal of Alzheimer’s Disease 33 (2013) 547–658DOI 10.3233/JAD-2012-121537IOS Press

547

Review

Cognitive Enhancers (Nootropics). Part 2:Drugs Interacting with Enzymes

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

Accepted 30 August 2012

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

Keywords: Alzheimer’s disease, cognitive enhancers, donepezil, enzymes, galantamine, memory, rivastigmine

1. INTRODUCTION

As of August 29, 2012, there are 26,677 entries inPubMed under the term cognitive enhancers, 26,680entries under the term nootropic and 242 entries underthe term cognition enhancers. Scifinder lists 5,105references under the research topic nootropic, 535references under the term cognitive enhancer, and9,780 references for cognition enhancers. The Thom-son Reuters Pharma database lists 1,106 drugs asnootropic agents or cognition enhancers and gives zeroresults under the term cognitive enhancer. The termnootropics was coined by the father of piracetam Cor-neliu Giurgea in 1972/1973 [1, 2], NOOS = mind andTROPEIN = toward.

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

Nootropics are drugs to treat cognition deficits,which are most commonly found in patients sufferingfrom Alzheimer’s disease (AD), schizophrenia, stroke,attention deficit hyperactivity disorder, or aging. MarkJ. Millan and 24 eminent researchers [3] presented anexcellent overview on cognitive dysfunction in psy-chiatric disorders in the February 2012 issue of NatureReviews Drug Discovery and defined cognition as “asuite of interrelated conscious (and unconscious) men-tal activities, including pre-attentional sensory gating,attention, learning and memory, problem solving, plan-ning, reasoning and judgment, understanding, knowingand representing, creativity, intuition and insight, spon-taneous thought, introspection, as well as mental timetravel, self awareness and meta cognition (thinking andknowledge about cognition)”.

Since a first review in 1989 on “Families of Cogni-tion Enhancers” by Froestl and Maıtre [4], substantialprogress has been made in the understanding of

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548 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes

the mechanism(s) of cognitive enhancers. Therefore,we propose a new classification to assign cognitionenhancing drugs to 19 categories:

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

(Part 3)5. Drugs interacting with Heat Shock Proteins

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

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

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

(Part 3)10. Drugs interacting with Transcription Factors

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

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

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

16.2. Inhibitors of serum amyloid P componentbinding (Part 3)

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

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

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

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

In Part 1, drugs interacting with receptors weredescribed [5]. In Part 2, we describe drugs interact-ing with enzymes and in Part 3, drugs interacting withtargets 3 to 10 and compounds and preparations ofcategories 11 to 19.

2. DRUGS INTERACTING WITH ENZYMES

Researchers have been investigating drugs inter-acting with a wide variety of enzymes in order to

identify valuable cognition enhancers. These enzymesare:

2.1 Drugs interacting with Acetyl- & Butyryl-cholinesterase (AChE & BChE)2.1.1. Drugs inhibiting AChE and other biolog-

ical targets2.1.1.1. Dual AChE inhibitors and

AChE receptor ligands2.1.1.2. Dual AChE and amyloid-�

inhibitors2.1.1.3. Dual AChE inhibitors and

antioxidants2.1.1.4. Dual AChE and �-secretase-1

or �-secretase inhibitors2.1.1.5. Dual AChE inhibitors and cal-

cium channel blockers2.1.1.6. Dual AChE inhibitors and

cannabinoid receptor antago-nists

2.1.1.7. Dual AChE and fatty acidamide hydrolase inhibitors

2.1.1.8. Dual AChE inhibitors and his-tamine H3 receptor antagonists

2.1.1.9. Dual AChE and monoamineoxidase inhibitors

2.1.1.10. Dual AChE inhibitors andmetal chelators

2.1.1.11. Dual AChE inhibitors and N-methyl-D-aspartic acid recep-tor channel blockers

2.1.1.12. Dual AChE inhibitors andplatelet activating factor antag-onists

2.1.1.13. Dual AChE and serotonin trans-porter inhibitors

2.1.1.14. Dual AChE and sigma receptorinhibitors

2.2 Drugs interacting with �-Secretase2.3 Drugs interacting with �-Secretase2.4 Drugs interacting with �-Secretase

2.4.1. �-Secretase Inhibitors2.4.2. �-Secretase Modulators2.4.3. Inhibitors of �-Secretase Activating

Protein2.4.4. Notch Pathway Inhibitors

2.5. Drugs interacting with �-Hexosaminidase2.6. Drugs interacting with 11�-Hydroxysteroid

Dehydrogenase2.7. Drugs interacting with Calpain2.8. Drugs interacting with Carbonic Anhydrase2.9. Drugs interacting with Caspases

W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes 549

2.10. Drugs interacting with Catechol-O-methyl-transferase

2.11. Drugs interacting with Cathepsin2.12. Drugs interacting with Cholesterol 24S-

hydroxylase (CYP46A1)2.13. Drugs interacting with Cyclooxygenase2.14. Drugs interacting with D-Amino Acid

Oxidase2.15. Drugs interacting with Glutaminyl Cyclase2.16. Drugs interacting with Glyceraldehyde-3-

Phosphate Dehydrogenase2.17. Drugs interacting with Glycogen Synthase

Kinase-3�2.18. Drugs interacting with Guanylyl Cyclase2.19. Drugs interacting with Heme Oxygenase2.20. Drugs interacting with Histone Deacetylase2.21. Drugs interacting with HMG-CoA Reductase2.22. Drugs interacting with Insulin-degrading

Enzyme2.23. Drugs interacting with Kinases ( /=GSK-3� and

/= PKC)2.24. Drugs interacting with Kynurenine Mono-

Oxygenase and Kynurenine Transaminase II2.25. Drugs interacting with 5-Lipoxygenase2.26. Drugs interacting with Monoamine Oxidase2.27. Drugs modulating O-linked N-Acetylgluco-

saminidase2.28. Drugs interacting with Peptidyl-prolyl cis-trans

Isomerase D2.29. Drugs interacting with Phosphodiesterases2.30. Drugs interacting with Phospholipases A2 and

D22.31. Drugs interacting with Plasminogen Activator

Inhibitor2.32. Drugs interacting with Poly ADP-Ribose Poly-

merase2.33. Drugs interacting with Prolyl Endo Peptidase2.34. Drugs interacting with Prostaglandin D & E

Synthases2.35. Drugs interacting with Protein Kinase C2.36. Drugs interacting with Protein Tyrosine Phos-

phatase2.37. Drugs interacting with Rac1 GTPase2.38. Drugs interacting with Ras Farnesyl Trans-

ferase2.39. Drugs interacting with S-Adenosylhomo-

cysteine Hydrolase2.40. Drugs interacting with Sirtuin2.41. Drugs interacting with Steroid sulfatase2.42. Drugs interacting with Transglutaminase2.43. Drugs interacting with Ubiquitin Carboxyl-

terminal Hydroxylase (Usp14).

2.1. Drugs interacting with Acetyl- andButyrylcholinesterase

Since the publication of the cholinergic hypothe-sis of AD by Bartus et al. in 1982 [6], tremendousefforts have been undertaken to find either selectiveacetylcholine receptor agonists (described in Part 1)or acetylcholinesterase (AChE) inhibitors [7–15]. Thehistory of the cholinergic hypothesis was traced back[16]. In retrospect, the latter approach (i.e., AChEinhibitors) turned out to be more successful than the bigefforts to find selective acetylcholine receptor agonists.

Tacrine (tetrahydroaminoacridine, Cognex;Warner-Lambert, Pfizer) was approved by the Foodand Drug Administration (FDA) in 1993 and waslaunched in 1995 for the treatment of AD. It potentlyblocks butyrylcholinesterase (BChE) (IC50 = 47 nM)and AChE (IC50 = 190 nM) [17]. Tacrine has a shorthalf-life (2–3 hours) and must be administered 4times a day. The major problem is its severe, thoughreversible, hepatotoxicity [17, 18].

Donepezil (Aricept; E2020; co-developed by Eisaiand Pfizer, Fig. 1) was approved by the FDA in Novem-ber 1996 and was launched in the US in January1997 for the treatment of mild-to moderate AD. InOctober 2006, FDA approval for the treatment ofsevere AD was granted. It potently blocked AChE(IC50 = 23 nM), whereas blockade of BChE was 320times weaker (IC50 = 7,420 nM) [17]. The Japaneseinventors disclosed values of IC50 = 5.7 nM for AChEand IC50 = 7,140 nM for BChE (factor 1250) [19].Donepezil interacts with the active site of AChE and theperipheral anionic site of the enzyme [20]. Its long ter-minal disposition half-life of 70 hours supports once-daily administration [18]. Interestingly, the two enan-tiomers of donepezil racemize rapidly in vivo [21, 22].

The sales for donepezil reported by Eisai for 2011totaled USD 1.853 billion (Thomson Reuters Pharma,update of August 24, 2012).

2,301 publications on donepezil are listed inPubMed (as of August 29, 2012).

For the synthesis and medicinal chemistry ofdonepezil, see [19, 23], for an efficient process forlarge-scale synthesis of donepezil [24, 25], and formolecular modeling of donepezil [26, 27].

Many preclinical and mechanistic reviews have beenpublished [28–37]. Interestingly, donepezil eliminatedthe suppressive effects of amyloid-� (A�)42 on long-term potentiation (LTP) in rat hippocampal slices [38,39]. Synergistic effects of donepezil and the 5-HT4receptor agonist RS-67333 on the object recogni-tion were observed in mice [40]. Pharmacokinetic


Fig. 1. Launched acetylcholinesterase inhibitors.

considerations for donepezil dosing strategies werepresented [41].

There is extensive literature available on clinical trialresults; see (in chronological order) [42–66]. Broaderconsiderations of higher doses of donepezil in thetreatment of mild, moderate, and severe AD were com-municated recently [67], in particular on the questionof the case of the 23 mg dose [68]. For the effectsof donepezil on levels of cholinesterases in the cere-brospinal fluid (CSF) of AD patients, see [69].

For safety and tolerability of donepezil, see [70–72],for pharmaco-economics [73–81].

Donepezil significantly improved abilities in dailylives of young adults with Down syndrome [82] andin female Down syndrome patients [83], whereas inchildren with Down syndrome of age 10–17 years,donepezil did not show any benefit versus placebo [84].

Donepezil was used for the treatment of patientswith Parkinson’s disease [85–87] and for the treatmentof memory impairment in multiple sclerosis patients[88].

Many galenical forms have been developed.Donepezil hydrochloride fine granule formulation waslaunched in Japan in September 2001. Donepezil rapid

oral disintegration tablet was launched in Japan in July2004 and in the US in June 2005. Donepezil oral jellyformulation was launched in Japan in December 2009.Donepezil oral sustained release high-dose (23 mg)tablet formulation was launched in the US in August2010. The US NDA donepezil once weekly transder-mal formulation in collaboration with Teikoku Seiyakuwas submitted in June 2010. A dry syrup formulationadministered by suspending the dry syrup in wateris in pre-registration in Japan. A fast dissolving oralfilm strip formulation in collaboration with AppliedPharma Research and Labtec is in clinical evaluation,as is donepezil oral rapid disintegration film in col-laboration with Kyukyu Pharmaceuticals. Donepeziltransdermal patch with Labtec, donepezil hydrochlo-ride transdermal patch with Nitto Denk and Kowa, andNAL-8812, a 3-day patch formulation co-developedwith NAL Pharmaceuticals are in preclinical evalua-tions, as is the Immediate Suspension encapsulation byALRISE Biosystems. NAL-8817 is an orally dissolv-ing film formulation of donepezil using the BIO-FXfast-onset oral cavity drug delivery system technologyin preclinical evaluation (Thomson Reuters Pharma,update of May 31, 2012).


Deuterated donepezil is investigated by the com-pany Deuteria Pharmaceuticals for the potentialtreatment of AD (Thomson Reuters Pharma, updateof August 10, 2012).

Donepezil + memantine (ADS-8704, Arimenda;Adamas Pharmaceuticals), a once-daily fixed dosecombination extended release formulation, is currentlytested in Phase II clinical trials. In May 2012, the FDAapproved Phase III studies in an end-of-Phase II meet-ing. First clinical results were presented [89] (ThomsonReuters Pharma, update of July 5, 2012).

Rivastigmine (Exelon, SDZ-ENA-713; SDZ-212-713; ENA-713; Novartis, Fig. 1) is a potent BChEinhibitor (IC50 = 37 nM). It blocks AChE with anIC50 = 4,150 nM, a factor of 112 times less than BChE[17]. It forms a carbamoylated complex with the active-site serine inactivating it for about 10 hours producinga “pseudo-irreversible” inhibition. For an excellentreview on the neurobiology of BChE, see [90, 91].

Rivastigmine was launched for the treatment of mildto moderate AD in 2000 in the EU and the US and in2010 in Japan. It was approved for the treatment ofmild to moderately severe dementia associated withidiopathic Parkinson’s disease. Rivastigmine transder-mal patch was launched in the EU in 2007 and in Japanin 2011 in collaboration with the Japanese licensee OnoPharmaceuticals.

Sales for rivastigmine for 2011 were USD 1.067billion representing a 6% increase on 2010 (ThomsonReuters Pharma, update of August 24, 2012).

There are currently 1,181 publications on rivastig-mine listed in PubMed (as of August 29, 2012).

Several syntheses of rivastigmine were published[92–96].

Excellent papers on the preclinical characterizationof rivastigmine were communicated [97–102].

Extensive literature exists on the clinical trialresults of rivastigmine in AD (in chronological order)[103–112]. Rivastigmine at doses of up to 12 mg/dayhad useful efficacy in patients with mild-moderatedementia of the Alzheimer type. Reports from largerPhase III studies confirmed these findings. The b.i.d.administration is the more efficacious regimen and hadcomparable tolerability to the t.i.d. regimen.

Rivastigmine was evaluated for the treatment ofdementia in Parkinson’s disease [113–120]. Oralrivastigmine 3–12 mg/day for 24 weeks was signif-icantly more effective than placebo in amelioratingcognitive and functional decline, including attentionaldeficits, in patients with Parkinson’s disease demen-tia. Rivastigmine was also effective in patients withdementia with Lewy bodies. Benefits were seen on tests

of attention, working memory, and episodic secondarymemory [121]. Rivastigmine was successfully appliedfor the treatment of vascular dementia [122–125],for treatment of hallucinations in Creutzfeldt-Jakobdisease [126], and memory deficits induced by elec-troconvulsive therapy [127].

For safety and tolerability of rivastigmine, see [50,74, 128]; for pharmaco-economics [78, 80, 129].

Many reviews exist on results of clinical trialsusing the rivastigmine transdermal patch [130–154]describing enhanced tolerability and significantly lessside effects.

NAL-8822 (NAL Pharmaceuticals) is a one-daypatch formulation of rivastigmine using its Bio-D3transdermal drug delivery system technology in pre-clinical evaluation (Thomson Reuters Pharma, updateof May 31, 2012).

Galantamine (Razadyne, Reminyl, Nivalin;Janssen Pharmaceutica, part of Johnson & Johnson,Shire and Takeda under license from Sanochemia;Fig. 1) is an alkaloid extracted from the bulbs of theAmaryllidaceae family that include daffodils and thecommon snowdrop (Galanthea woronowii [155]). Itblocks AChE (E.C. 3.1.1.7) with an IC50 of 800 nMand BChE (E.C. 3.1.1.8) with an IC50 of 7,320 nM[17]. Galantamine was launched in 2001 for thetreatment of mild to moderate AD in Europe and theUS and in March 2011 in Japan. In 2005, Johnson& Johnson launched an extended release capsuleformulation.

The sales of galantamine in 2011 for Johnson &Johnson were USD 470 million, for Shire USD 40 mil-lion, and for Takeda USD 34 million (Thomson ReutersPharma, update of August 27, 2012).

There are currently 1,602 publications on galan-tamine (and galanthamine) listed in PubMed (as ofAugust 29, 2012).

To a small extent, galantamine is still produced fromsnowdrops [156, 157]. However, chemical syntheseshave taken over. A technical process for an efficientnine-step procedure, which affords (−)-galanthaminein 12% overall yield, was presented by Sanochemia[158]. The synthetic schemes from academic laborato-ries were not scaled up [159–163].

The pharmacological characterization of galan-tamine was described in depth [164–175]. Galan-tamine weakly inhibited hERG channels [176].

Interestingly, galantamine not only blocks AChEand BChE, but also acts as a positive allosteric mod-ulator of nicotinic acetylcholine receptors enhancingthe concentrations of acetylcholine in the brain by asecond mechanism [177–182].


The pharmacokinetics of galantamine werereported [183–187].

Many publications described the clinical trial resultsof galanthamine in AD (in chronological order)[188–201 [1]]. Galantamine improved and stabilizedcognitive performance, activities of daily living, andbehavioral symptoms over the course of 6 months,and its efficacy and tolerability are comparable withthose of other AChE inhibitors (rivastigmine anddonepezil). Galantamine proved to be one of the stan-dard first-line medications for mild-to-moderate AD.For galantamine in Parkinson’s disease, see [201];in schizophrenic patients [202]; in vascular dementia[203].

For safety and tolerability, see [72]; for pharmaco-economics [78, 80, 204]. The historical developmentof galantamine as a clinically used drug was tracedback [205].

Johnson & Johnson developed and launched Raza-dyne ER (Reminyl XL), an extended release capsuleformulation, in April 2005 in the US. Patientstreated with the extended release formulation hadbetter overall Alzheimer’s Disease Assessment Scale(ADAS-cog/11) scores than the placebo group after sixmonths (Thomson Reuters Pharma, update of March21, 2012).

NAL-8801 (NAL Pharmaceuticals) is a one daypatch formulation of galantamine using the Bio-D3transdermal drug delivery system technology in pre-clinical evaluation (Thomson Reuters Pharma, updateof May 31, 2012).

Memogain (GLN-1062; Galantos Pharma) is a pro-drug, the benzoyl ester, of galantamine administered asan intranasal formulation. Memogain has a more than15 times higher bioavailability in the brain than thesame dose of galantamine. It is cleaved enzymaticallyto galantamine [206]. It is in Phase I since November2011 (Thomson Reuters Pharma, update of December28, 2011).

Huperzine A (Cerebra; Shanghai Institute of Mate-ria Medica; Fig. 1) is a natural Lycopodium alkaloidfound in extracts from Huperzia serrate [207]. It waslaunched in China for the treatment of AD in 1995. Thedrug is administered in low oral doses of 0.1 mg fourtimes a day. Huperzine A blocked AChE with an IC50of 82 nM and BChE with an IC50 of 74.43 �M [208,209]. (−)-Huperzine A is 35-fold more potent that (+)-Huperzine A (Ki = 6.2 nM and 210 nM, respectively[210]), corroborating earlier Ki values of 8 nM and300 nM [211]. Molecular modeling studies revealedthat huperzine A binds to the bottom of the bindingcavity of AChE with its ammonium group interacting

with Trp-84, Phe-330, Glu-199, and Asp-72 (catalyticsite) and to the opening of the gorge with its ammo-nium group interacting with Trp-279 (peripheral site)[212]. Tyr-337 is essential for inhibition of recombi-nant human AChE by huperzine A [213]. The X-raystructures of Torpedo californica AChE complexedwith (+)-huperzine A and (−)-huperzine B was pre-sented [214].

Currently huperzine A is produced in large scalefrom natural sources, in particular from Phlegmariu-rus squarrosus, a member of the Huperziaceae [215],although several chemical synthesis schemes wereworked out [208, 216–222]. A large-scale syntheticroute resulted from a joint venture by process chemistsof Shasun Pharma (UK and India), Rhodia Pharma(USA), and Debiopharm (Switzerland) [223].

There are currently 358 publications on huperzineA listed in PubMed (as of August 29, 2012).

Excellent reviews on the pharmacology ofhuperzine A have been published (in chronologicalorder) [224–230]. In particular, the neuroprotec-tive effects of huperzine A have been investigatedin great detail, e.g., protective effects against A�-associated neurotoxicity [231–235]. Huperzine A dosedependently increased secretory amyloid-� proteinprecursor (A�PP) release suggesting a modulatoryeffect of huperzine A on �-secretase activity [236,237]. These findings were confirmed independently[238, 239]. This mechanism seems to play viaWnt/�-catenin signaling. Chronic administration ofhuperzine A to double transgenic mice led to anincrease in ADAM10 and a decrease in �-secretase-1and A�PP695 protein levels [240]. Recently huperzineA was also evaluated in triple transgenic mice con-firming the improvement of cognitive performanceand the non-amyloid pathway activation [241].

Reviews on results of clinical trials of huperzine Awere published [242–244]. A Phase II clinical studyin 210 AD patients treated with either placebo, 200 �gbid, or 400 �g bid of huperzine A (70 patients per arm)showed no effect in the 200 �g group, but huperzineA 400 �g bid showed a 2.27 point improvement inADAS-cog at 11 weeks versus a 0.29 decline in theplacebo group (p = 0.001) [245] (Thomson ReutersPharma, update of February 20, 2012).

The company Xel Pharmaceuticals (Draper, Utah) isdeveloping the once-weekly sustained release transder-mal patch formulation XEL-001HP. This formulationis currently tested in a Phase I clinical trial inChina since September 2008. Xel Pharmaceuticalsis also investigating the sustained release topical gelformulation XEL-001HG in preclinical evaluation


(both Thomson Reuters Pharma, update of March 14,2012).

Novartis chemists synthesized novel analogues ofhuperzine A. The program was terminated [246].

WIN-026 (INM-176, KR-WAP-026; WhanIn underlicense from Scigenic & Scigen Harvest) is an AChEinhibitor with antioxidant and anti-A� properties con-taining a 95% extract of Angelica gigas Nakai in thepre-registration phase [247]. In June 2008, a PhaseIII clinical trial for the treatment of AD was initi-ated, which was completed by May 2011. The resultswere submitted to the Korean FDA. Launch is expectedfor the second half of 2012. The memory ameliorat-ing effects of INM-176 in mice were described [248](Thomson Reuters Pharma, update of May 30, 2012).

Posiphen (the (+)-enantiomer of phenserine, QRPharma under license from TorreyPines Therapeutics,Fig. 2) is in Phase II clinical trials for the oral treat-ment of AD since June 2009. It was effective to lowerA� levels in cell cultures and in mice [249]. Interest-ingly, posiphen also blocked the expression of brain�-synuclein [250, 251]. Posiphen is a candidate drug tolower CSF A�PP, A� peptide, and tau levels in humans[252] (Thomson Reuters Pharma, update of July 25,2012).

Shen Er Yang (Changchun Huayang HighTechnology Co Ltd., Shanghai, Fig. 2) is atablet formulation of 1,2,3,4,5,6,7,8-octohydro-9-phenylacetamidoacridine, a dual cholinesteraseinhibitor in Phase II clinical trials since March 2011(Thomson Reuters Pharma, update of April 18, 2012).

Methanesulfonyl fluoride (SeneXta under licensefrom the University of Texas at El Paso, Fig. 2) is anAChE inhibitor in Phase I clinical trials for AD andpost-stroke cognitive impairment. A Phase II clinicaltrial for AD was planned for 2011. For the inhibitionof BChE by methanesulfonyl fluoride, see [253]; forthe inhibition of AChE [254]. Learning and memoryenhancing effects were described [255–258]. A reporton a double-blind, placebo-controlled study of safetyand efficacy in 5 men and 10 women (60–82 years) withMini-Mental State Examination (MMSE) scores of9–24, who had senile dementia of the Alzheimer type,was published. Methanesulfonyl fluoride improvedcognitive performance as measured by the MMSE,ADAS-cog, Global Deterioration Scale, and the Clin-ical Interview Based Impression of Change [259](Thomson Reuters Pharma, update of June 28, 2012).

There are currently many cholinesterase inhibitorsin preclinical evaluation (in alphabetical order):

Bisnorcymserine (QR Pharma, under license fromTorreyPines Therapeutics; Fig. 2) is a dual BChE and

A�PP inhibitor. An IND was cleared by the FDA inDecember 2010. The inhibition of serum BChE bybisnorcymserine was reported [260]. For the crystalstructure of the complex, see [261] (Thomson ReutersPharma, update of July 25, 2012).

Bis-(7)-tacrine (Mayo Foundation; Fig. 2) wasone of the first homodimers reported in the lit-erature with increased potency as AChE inhibitor(IC50 = 0.4 nM with significantly less affinity to BChE(IC50 = 390 nM, selectivity for AChE is a factor of 980)[262]. For a more detailed description of bis(7)-tacrine,see section 2.1.1.5. Dual AChE inhibitors and calciumchannel blockers.

FS-0311 (Shanghai Institute for Materia Medica;Fig. 2) is a bis-huperzine B derivative with similarpotency for the inhibition of AChE as donepezil buthigher potency than huperzines A and B. It antago-nized cognitive deficits induced by scopolamine or bytransient brain ischemia [263].

Huprines (tacrine-huperzine A hybrids, Fig. 2)were presented by scientists of the University ofAutonoma de Barcelona [264–269] and independentlyfrom the University of Hong Kong [270]. French sci-entists also significantly contributed to novel huprinederivatives [271–273].

The best characterized huprines are huprine-X(3-chloro-9-ethyl), huprine-Y (3-chloro-9-methyl,see Fig. 2), and huprine-Z (3-fluoro-9-methyl). Theyare very potent AChE inhibitors with Ki values of0.026 nM for huprine-X and 0.033 nM for huprineY versus 31 nM for tacrine, 1.1 nM for donepezil,and 4.6 nM for huperzine A [267]. Other scientistsmeasured IC50 values of 0.78 nM for (±)-huprine-Y and 4.58 nM for (±)-huprine-Z in human AChEpreparations [274]. (±)-Huprine-X is an agonist atM1 muscarinic acetylcholine receptors (Ki = 338 nM)and at M2 mAChRs (Ki = 4.66 �M) [275]. The bind-ing of huprine-X to Torpedo californica AChE wasresolved in an X-ray structure at 2.1 A resolution[276]. Huprine-X facilitated learning and memory inthe Morris water maze [277]. Chronic treatment ofTg2576 (A�PPswe) mice and of 3xTgAD mice with0.12 �mol/kg huprine-X i.p. for 21 days caused a sig-nificant reduction of insoluble A�40 by 40% (p < 0.05)in the hippocampus of 3xTgAD mice while showingno effect in A�PPswe mice [278]. Additional data onhuprine X in triple transgenic mice were disclosedrecently [241].

Another way to create huperzine A-tacrine hybridsis to link the primary amino group of huperzine A to theprimary amino group of tacrine with methylene groups[279]. The best compounds showed Ki values against


Fig. 2. Acetylcholinesterase inhibitors in development or in preclinical evaluation.

human AChE of 6.4 nM versus 0.026 for huprine-X.A group of Spanish and Italian scientists describedhuprine-tacrine heterodimers [280, 281].

Dimerization of an inactive fragment of huperzineA led to bis-(12)-hupyridone (Hong Kong Univer-sity, Fig. 3) displaying an IC50 = 52 nM versus 115 nMfor huperzine A [282]. The tether length of 12-13

methylene groups is consistent with simultaneousbinding to both the catalytic and the peripheral siteof AChE (see Fig. 5). Bis-(12)-hupyridone may alsoact via �7 nicotinic acetylcholine receptors [283].

NP-0336 (Noscira) is a BChE inhibitor in preclinicalevaluation (Thomson Reuters Pharma, update of July19, 2011). The structure was not communicated.


Fig. 3. Acetylcholinesterase inhibitors in preclinical evaluation II.

Fig. 4. Dual acetylcholinesterase and muscarinic M2 ACh receptor blocker.

SPH-1285 (Sanochemia Pharmazeutika, formerlyWaldheim Pharmazeutika; Fig. 3 shows SPH-1286)is a neuroprotective derivative of galantamine for thepotential treatment of glaucoma (Thomson ReutersPharma, update of January 3, 2012).

The most potent AChE inhibitor is the moleculesyn-1 (Fig. 3) with Kd of 77 fM synthesized at theScripps Research Institute linking a tacrine part viaclick chemistry to a phenanthridium unit. The tacrinepart is binding to the catalytic site (see Fig. 5), the


Fig. 5. Indole-tacrine heterodimers binding simultaneously to thecatalytic and the peripheral anionic site of acetylcholinesterase[381]. With permission from ACS Publications.

phenanthridium piece is located at the peripheral site(see Fig. 5) [284].

Many new scaffolds for AChE inhibitors werediscovered recently, such as benzoxazolinones [285],indolizinoquinoline [286], isoindoline-1,3-diones[287], pyrrolo isoxazol benzoic acid derivatives [288],pyrrolo thiazoles [289], quinazolines [290], andquinoline derivatives [291] acting as AChE inhibitors.Also tacrin-ferulic acid-nitric oxide (NO) donortrihybrides were presented [292].

Excellent reviews describe quantitative structureactivity relationships (QSAR) [293, 294], virtualscreening techniques [295], and the use of support vec-tor machines for a classification of AChE inhibitors[296]. High throughput screening and molecularmodeling for novel AChE inhibitors was discussed[297].

The development of many AChE inhibitors wasterminated (in alphabetical order) of amiridin (ipi-dacrine hydrochloride; Nikken Chemicals [298–300]),AP-2238 (University of Bologna [301–303]), BZYX(Zhejiang University), CI-1002 (Parke-Davis, nowPfizer), CHF-2822 and CHF-2957 (Chiesi), EN-101(an orally active 20-base antisense oligonucleotidedirected against an AChE sequence; Amarin underlicense from Yissum [304]), eptastigmine (MF-201;

Mediolanum [305–309], ER-127528 (Eisai), F-3796(Pierre Fabre), FR-152558 (Fujisawa), galantamineliposomal (Sanochemia), ganstigmine (CHF-2819;Chiesi [310–315], Hoe-065 (Hoechst, now sanofi[316–318], HP-290 (Hoechst, now sanofi), icopezil(CP-118954; Pfizer [319]), JES-9501 (dehydroevo-diamine hydrochloride, DHED; Jeil Pharmaceuticalsin collaboration with Seoul Univ.), LB-1003 (LifelikeBiomatic), metrifonate (BAY-a-9826, ProMen; Bayer[320–324]; MF-268 and MF-8615 (Mediolanum),MHP-133 (Medical College of Georgia), mimopezil(DEBIO-9902, ZT-1; Debiopharm under license fromthe Shanghai Institute of Materia Medica; a once–dailyprodrug, a Schiff base of huperzine A with 2-hydroxy-3-methoxy-5-chloro-benzaldehyde [319], NP-7557(Nastech [325]), NXX-066 (Astra), P26 (Phy-topharm), P-10358, P-11012, P-11149, and P-11467(Hoechst Marion Roussel, now sanofi), phenserineand (-)-phenserine (Axonyx under license from NIH,Daewoong Pharmaceuticals [326–329], of controlledrelease and transdermal formulations of physostig-mine (Forest Laboratories, Lohmann Therapie Sys-teme [330–332], protexia (PEG-rBChE; PEGylatedrecombinant human butyryl-cholinesterase; PharmA-thene under license from Nexia Biotechnologies; aprotein produced in the milk of goats in a pegylatedformulation; the development as post-exposure therapyfor chemical nerve agent, currently in Phase I trials, isongoing [333, 334]), Ro-46-5934 (Roche; a dual AChEinhibitor and M2 muscarinic acetylcholine receptorantagonist), RS-1439 (Sankyo; a dual AChE and sero-tonin re-uptake inhibitor), S-9977 (Servier; a dualAChE and serotonin re-uptake inhibitor), SDZ-ENX-792 (Sandoz, now Novartis), SM-10888 (Sumitomo[335–337]), SPH-1359 (Sanochemia), stacofylline(S-9977; Servier [338–341]), suronacrine (HP-128;Hoechst, now sanofi [342, 343]), T-82 (SS Pharmaceu-tical, a subsidiary of Boehringer Ingelheim and Arena[344, 345]), tolserine (Axonyx under license fromNIH [346–349], UCB-11056 (UCB), velnacrine (HP-029; Hoechst, now sanofi [350, 351]), of zanapezil(TAK-147; Takeda [352, 353] and of zifrosilone(MDL-73745, Hoechst Marion Roussel, now sanofi[354–356]).

2.1.1. Drugs inhibiting AChE and otherbiological targets

Tremendous efforts have been undertaken to com-bine AChE inhibition and interaction with multipletargets thought to be responsible for AD pathogenesisto create “multi-target-directed ligands” [357–370].


2.1.1.1. Dual AChE inhibitors and AChE receptorligands. Caproctamine (University of Bologna;Fig. 4) is a potent AChE inhibitor (Ki = 104 nM) anda competitive M2 muscarinic acetylcholine receptorantagonist (Kb = 410 nM) [371].

MHP-133 (Medical College of Georgia; Fig. 4) is anAChE inhibitor interacting with M1 muscarinic acetyl-choline, 5-HT4 and I2 imidazoline receptors [372,373].

Ro-46-5934 (Hoffmann-La Roche, Fig. 4) is a dualAChE inhibitor and M2 AChR antagonist for thepotential treatment of AD. The development was dis-continued [374].

An attempt to combine tacrine and xanomeline ledto hybride compounds displaying potent acetyl andBChE inhibition (pIC50’s of 8.2 and selectivity ratioof 1.0). The hybrids did not bind as agonists to theorthosteric muscarinic acetylcholine M1 receptor butas antagonists to an allosteric site of the M1 AChRthereby reducing the amount of acetylcholine [375].

2.1.1.2. Dual AChE and amyloid-β inhibitors. AChEcolocalizes with A� peptide deposits in the brainsof AD patients and promoted A� fibrillogenesis byforming stable AChE-A� complexes. AChE boundthrough its peripheral site to the A� nonamyloidogenicform and acted as a pathological chaperone inducinga conformational transition to the amyloidogenic form[376–380].

One approach is to design ligands binding to boththe catalytic as well as to the peripheral anionic site ofAChE inhibitors (Fig. 5) [381].

After first attempts [301, 302, 371, 382–384] animportant breakthrough was achieved with NP-61.

NP-61 (NP-0361; Noscira, previously Neu-ropharma) is a once-daily dual binding site AChE andA� secretion inhibitor currently in Phase I clinicaltrials for the treatment of AD. The structure wasnot disclosed, but is probably a combination of6-chloro-tacrine (binding to the catalytic binding site)linked via a methylene bridge from the primary amineto the amide nitrogen of indole propionamide bindingat the peripheral binding site [381]. Key biologicaldata on NP-61 were published: inhibition of AChE:IC50 = 20 pM, inhibition of BChE: IC50 = 2.9 nM,inhibition of A�40 aggregation with human AChE inthe thioflavin T test: IC50 = 2 �M, inhibition of A�40aggregation without AChE in the thioflavin T test:49% at 100 �M [385, 386]. NP-61 was able to reversecognitive impairment tested in the Morris water mazeand to reduce plaque load in cortex and hippocampusof 6 month-old human A�PP (Swedish mutation)

transgenic mice treated once daily by oral gavagefor three months (the doses were not communicated)(Thomson Reuters Pharma, update of May 10, 2012).

IDN-5706, a hyperforin derivative, decreased thecontent of AChE associated with different types of A�plaques in 7-month-old double A�PPSWE/PS1 trans-genic mice after treatment with IDN 5706 for 10 weeks[387]. See also Part 3, Chapter 13. Natural Products.

IQM-622 (Neuroscience Group and CSIC, Madrid;Fig. 6) significantly decreased the brain A� depositsafter treatment of A�PP/PS1 mice for four weeks. Itpromoted the degradation of intracellular A� in astro-cytes and protected against A� toxicity in culturedastrocytes and neurons (chemistry: [388]; biology:[389]).

This is an area of research with numerous novelcontributions presenting new piperidinium-type com-pounds [390], new piperidine derivatives [391],donepezil-type inhibitors [392], novel pyrano[3,2-c]quinoline-6-chlorotacrine hybrids [393], pyridinyli-dene hydrazones [394], novel bis(7)-tacrine derivatives[395], hybrid compounds combining donepezil andAP2238 [303], heterodimers of enantiopure huprineX or Y and donepezil-type derivatives [396],2,4-disubstituted pyrimidine derivatives [397, 398],novel triazole-containing berberine derivatives [399],huprine-tacrine heterodimers [400, 401], isaindigo-tone derivatives [402], and oxoisoaporphine-basedinhibitors [403]. Berberine derivatives act as multi-functional agents of antioxidant, inhibitors of AChE,BChE, and A� aggregation [404].

Bisnorcymserine (QR Pharma, under license fromTorreyPines Therapeutics; see Fig. 2) is a dual BChEand A�PP inhibitor.

2.1.1.3. Dual AChE inhibitors and antioxidants.Lipocrine (University of Bologna; Fig. 6) is a com-bination of 6-chlorotacrine with �-lipoic acid [405].It has been shown that �-lipoic acid is an universalantioxidant [406–408], which protected rat corticalneurons against cell death induced by A�. Lipocrineinhibited AChE with an IC50 of 0.25 nM and BChEwith 10.8 nM within 1 minute. It inhibited the aggre-gation of A� with an IC50 of 45 �M and showedsignificant antioxidant activity against formation ofreactive oxygen species in SH-SY5Y cells after treat-ment with tert.-butyl hydroperoxide at 5 �M (p < 0.01),10 �M (p < 0.001), and 50 �M (p < 0.001) [409].

Memoquin (University of Bologna; Fig. 6) is acombination of the polyamine amide caproctamine[371] showing AChE and M2 muscarinic ACh recep-tor blocking properties with a 1,4-benzoquinone


Fig. 6. Dual acetylcholinesterase inhibitors with amyloid-� inhibitor, antioxidant, BACE-1 inhibitor, and calcium channel blocker activities.

functionality derived from coenzyme Q or idebenoneas a radical scavenger [366, 410, 411]. It inhibitedAChE with an IC50 of 1.55 nM, human AChE-inducedaggregation of A�40 with an IC50 of 28.3 �M andA�42 self-aggregation with an IC50 of 5.93 �M.NAD(P)H:quinone oxidoreductase 1 (NQO1) is theenzyme responsible for the regeneration and mainte-nance of the CoQ-reduced state. Memoquin is a goodsubstrate for NQO1 with a Km of 12.7 �M. In addition,memoquin also effectively blocked �-secretase-1 withan IC50 of 108 nM. The compound reduced the num-ber of A� plaques in transgenic AD11 mice after oraladministration and rescued behavioral deficits in anobject recognition test in transgenic AD11 mice [412].

Introduction of methyl groups in the �-position ofthe terminal benzylamine moieties (Fig. 6; Memoquin,R = Me, both in (R)-configuration) led to an improvedderivative (inhibition of AChE with IC50 of 0.5 nM;inhibition of human AChE-induced aggregation ofA�40 with IC50 of 9.34 �M [413, 414].

Combination of the 2,5-diamino-benzoquinonescaffold with curcumin derived substituents is anotherway to multitarget-directed ligands [415].

Dual-acting drugs with extremely potent AChEinhibiting activity and antioxidant properties were pre-sented [416]. Hybrides between 6,8-dichlorotacrineand melatonin showed an IC50 of 8 pM againsthuman AChE and potent peroxyl radical absorbance


capacities of 2.5-fold the value of Trolox in the oxygenradical absorbance capacity assay using fluorescein(ORAC-FL). Full experimental details were pro-vided [417]. N-acylamino-phenothiazines are selectiveBChE inhibitors and protected neurons against exoge-nous and mitochondrial free radicals [418, 419]. Acombination of tacrine and ferulic acid was described[420] as were novel piperazine derivatives [421].Berberine derivatives act as multi-functional agents ofantioxidant, inhibitors of AChE, BChE, and A� aggre-gation [422].

2.1.1.4. Dual AChE and β-secretase-1 or γ-secretaseinhibitors. Memoquin (University of Bologna, Fig. 6)is a potent inhibitor of AChE with an IC50 of 1.55 nMand of �-secretase-1 with an IC50 of 108 nM (see pre-vious section 2.1.1.3.).

Coumarin derivatives are also dual human AChEand �-secretase-1 inhibitors [423]. Inhibitions ofAChE with IC50 of 180 nM and of �-secretase-1 withIC50 of 150 nM were measured.

Researchers from the Shanghai Institute of Mate-ria Medica presented a dual inhibitor of AChE:IC50 = 1.83 �M and of �-secretase-1: IC50 = 0.567 �M[424].

A tacrine-chromene derivative with cholinergic,antioxidant, A� reducing, and BACE1 inhibitingproperties showed the following values: AChE:IC50 = 75 nM, BChE: IC50 = 1 nM, �-secretase-1:IC50 = 2.8 �M [425]. Quinoxaline-based hybrid com-pounds with AChE, histamine H3 receptor, and�-secretase-1 inhibitory activities were described[426].

Galantamine-based hybrid molecules with AChE,BChE, and �-secretase inhibiting activities have beenpresented recently [427].

2.1.1.5. Dual AChE inhibitors and calcium chan-nel blockers. Bis(7)-tacrine (Mayo Foundation, seeFig. 2), first synthesized in 1996 [262], is a verypotent AChE inhibitor (IC50 = 0.4 nM) with signifi-cantly less affinity to BChE (IC50 = 390 nM, selectivityfor AChE by a factor of 980). Bis(7)-tacrine wasextensively characterized. It reversed AF64A-induceddeficits in navigational memory in rats [428]. It pro-tected against ischemic injury in primary culturedmouse astrocytes [429]. It reduced hydrogen peroxide-induced injury in rat pheochromocytoma cells [430]. Itshowed inhibitory action on N-methyl-D-aspartic acid(NMDA) receptors with an IC50 of 0.763 �M [431].Bis(7)-tacrine significantly reduced the augmentationof (L-type) high-voltage activated inward calcium

currents induced by A� [432]. For an excellent review,see [433].

ITH-4012 (TK-19; CSIC Madrid; Fig. 6) is anAChE inhibitor with an IC50 of 0.8 �M [434]. It causedan elevation of the cytosolic concentration of Ca2+in fura 2-loaded bovine chromaffine cells from con-centrations of 10 to 250 nM, which was related to theinduction of protein synthesis relevant for cell survival.This cytoprotective action of ITH-4012 was reversedby the protein synthesis inhibitor cycloheximide.

ITH-12118 (CSIC Madrid; Fig. 6), a tacripyrine,combines tacrine and a L-type voltage-dependent cal-cium channel blocker of the nimodipine type. Thesynthetic work was described in [435, 436] and theextensive biological characterization in [437] show-ing that ITH12118 could be a paradigmatic multitargetcompound having selective brain effects with smallerperipheral side effects. Additional chemical and phar-macological studies were published [438].

The development of NP-34 (or NP-04634; Noscira,formerly Neuropharma), a natural product derivedfrom the marine sponge Aplysina cavericola with cal-cium channel blocking and AChE inhibiting propertieswas terminated [439].

2.1.1.6. Dual AChE inhibitors and cannabinoid recep-tor antagonists. CB1 receptor antagonists increasedACh release in certain brain areas including corti-cal regions and the hippocampus [440]. The CB1antagonist scaffolds of diaryl-pyrazolines and diaryl-imidazoles [441, 442] were combined with tacrine.Compound 20 (Solvay, now Abbott, Fig. 7) displayedan IC50 of 316 nM for acetylcholinesterase and a Ki

of 48 nM for CB1 receptors. The Ki for CB2 receptorswas >1 �M [443].

2.1.1.7. Dual AChE & fatty acid amide hydro-lase inhibitors. In regions of A�-enriched neuriticplaques an increased activity of the enzyme fattyacid amide hydrolase (FAAH) was selectively demon-strated [444]. Inhibitors of FAAH may regulateendocannabinoid signaling and may counteract neu-roinflammation. First dual cholinesterase and FAAHinhibitors were synthesized at the University ofBologna [445]. One carbamate derivative (shown inFig. 7) displayed IC50’s of 50 nM for FAAH, 74.9 nMfor human AChE, and 1.57 nM for human BChE.

MIQ-001 (Meta-IQ Aps) is a fatty acid metabolisminhibitor for the potential treatment of AD. A PhaseI healthy volunteer study was performed with dosesfrom 6 to 100 mg/day starting in February 2010. Noside-effects were observed. Meta-IQ generated excel-


Fig. 7. Dual acetylcholinesterase & fatty acid amide hydrolase inhibitor, dual acetylcholinesterase inhibitor & cannabinoid, and histamine H3receptor antagonists.

lent preclinical data showing efficacy in restoration ofshort and long term memory in an AD mouse model(Thomson Reuters Pharma, update of June 25, 2012).The structure was not communicated.

The development of AMR-109 (Amarin Corp.,ultra-pure eicosapentanoic acid), a modulator ofomega-3 fatty acids, was terminated. For the neu-roprotective effects of eicosapentenoic acid againstA� induced impairment of LTP and memory, see[446–448]. For a review on polyunsaturated farry acidsas cognitive enhancers see [449].

2.1.1.8. Dual AChE inhibitors and histamine H3 recep-tor antagonists. FUB833 (Freie University of Berlin;Fig. 7) is a potent AChE inhibitor (IC50 = 2.6 nM),BChE inhibitor (IC50 = 8.8 nM), hH3 receptor antag-onist (Ki = 0.33 nM) inhibiting also histamine N-methyltransferase (HMT with IC50 = 48 nM) [450].

University of Parma medicinal chemists describedpotent dual non imidazole histamine H3 receptor antag-onists and AChE inhibitors [451]. Quinoxaline-based

hybrid compounds with AChE, histamine H3 receptor,and �-secretase-1 inhibitory activities were described[452].

2.1.1.9. Dual AChE and monoamine oxidaseinhibitors. Increased monoamine oxidase (MAO) Bactivity was found in AD brains [453]. A combinationof AChE and of MAO B inhibitors in one moleculewas attempted already in 1996 [454, 455]. Thebreakthrough was achieved with Ladostigil.

Ladostigil (TV-3326; Avraham Pharmaceuticalsunder license from Yissum Research Development,a wholly owned company of the Hebrew Universityof Jerusalem; Fig. 8) combines the carbamate moietyof the BChE inhibitor rivastigmine with the propar-gylamine pharmacophore of the MAO-B inhibitorsselegiline and rasagiline. Ladostigil is more potentagainst BChE (IC50 = 1.7 �M) than against AChE(IC50 = 51 �M). It is a central nervous system (CNS)-selective inhibitor of MAO-A and MAO-B withlittle inhibition of liver and small intestine MAO.


Fig. 8. Dual acetylcholinesterase and monoamine oxidase inhibitor or metal chelator properties.

Propargylamines are irreversible inhibitors of MAO,therefore the long-term daily administration results ina cumulative effect. 50 �mol/kg given daily for 7 and14 days inhibited both MAO-A and MAO-B by >60%.80% inhibition of the brain enzymes was achieved witha dose of 75 �mol/kg given once daily for 2 weeks[456]. Ladostigil was extensively characterized [357,457–472].

Ladostigil is currently in Phase IIb clinical trialsin 190 patients in Europe since December 2010 forthe oral treatment of AD. In February 2012 a PhaseII trial was initiated in Israel and Europe in patientssuffering from mild cognitive impairment (Thom-son Reuters Pharma, update of May 18, 2012). Seealso section 2.26. Drugs interacting with MonoamineOxidase.

Spanish medicinal chemists described potent dualcholinesterase and MAO inhibitors [473–475].

2.1.1.10. Dual AChE inhibitors and metal chelators.HLA20A (Technion Haifa; Fig. 8) is a combinationof an 8-hydroxy-quinoline metal chelator, which wascarbamoylated at the 8-hydroxy function to interactwith AChE as does rivastigmine [476, 477]. Inhibitionof AChE was measured with IC50’s of 0.5 �M and forBChE with 42.58 �M. Interaction with AChE readilycleaved the carbamoyl moity to release the chelatorreadily forming complexes with FeSO4 and CuSO4.The prochelator is nontoxic to human SH-SY5Y cellsat 25 or 50 �M. A recent review described the field ingreat detail [478].

Novel indanone derivatives were designed as AChEinhibitors and metal-chelating agents [479].

2.1.1.11. Dual AChE inhibitors and N-methyl-D-aspartic acid receptor channel blockers. Carbacrine(University of Bologna, Fig. 9), a potent AChEinhibitor (IC50 = 2.15 nM), and weak inhibitor ofBChE (IC50 = 296 nM), blocked AChE-induced A�aggregation to 58% at 100 �M and A� self-aggregation to 36% at 50 �M and inhibited NMDAreceptors with an IC50 of 0.74 �M. It is a noncompeti-tive open-channel blocker. In the ORAC test carbacrinewas a good antioxidant (IC50 = 0.07 �M), more potentthan trolox [480].

University of Jena researchers presented bivalent�-carbolines as dual AChE inhibitors and NMDAreceptor blockers such as compound 22b (Fig. 9):IC50 = 0.5 nM for AChE, 5.7 nM for BChE, and 1.4 �Mfor the NMDA receptor, respectively [481].

Bis(7)-tacrine (Mayo Foundation, Fig. 2, see sec-tion 2.1.1.5. Dual AChE inhibitors and calciumchannel blockers) inhibited NMDA receptors with anIC50 of 763 nM [431].

2.1.1.12. Dual AChE inhibitors & platelet acti-vating factor antagonists. PMS-777 (University ofParis 7-Denis Diderot and Shanghai Jiao TongUniversity; Fig. 10), synthesized in 1996 [482,483], is a tetrahydrofuran derivative, which inhibitedAChE (IC50 = 2.48 �M), BChE (IC50 = 4.47 �M), andacted as platelet factor antagonist (IC50 = 12.5 �M)[484–490]. It inhibited A�-induced human neurob-lastoma SH-SY5Y cell apoptosis in a concentrationdependent manner. It decreased reactive oxygenspecies up to 32%, NO production up to 5 times,and TNF� release by 33% (Thomson Reuters Pharma,update of June 20, 2012).


Fig. 9. Dual acetylcholinesterase inhibitors and NMDA receptor blocker.

PMS-1339 (University of Paris 7-Denis Diderotand Shanghai Jiao Tong University; Fig. 10) is anovel piperazine derivative, which inhibited AChE(IC50 = 4.4 �M) and BChE (IC50 = 1.09 �M), A�aggregation (recombinant human AChE-induced:IC50 = 45.1 �M), and acted as platelet factor antago-nist (IC50 = 332 nM) [491] (Thomson Reuters Pharma,update of June 20, 2012).

2.1.1.13. Dual AChE and serotonin transporterinhibitors. RS-1259 (BGC-20-1259; BRG underlicense from Daiichi Sankyo; Fig. 10) is a dual inhibitorof AChE (IC50 = 101 nM) and of the serotonin trans-porter (IC50 = 42 nM). It significantly ameliorated theage-related short-term memory impairment at a dose of1 mg/kg in rats 24-25 months of age [492]. At 2 mg/kgRS-1259 was also effective in recovering from memorydeficits. For the design, synthesis and structure-activityrelationships see [493–495]. Its development was ter-minated.

2.1.1.14. Dual AChE and sigma receptor inhibitors.SP-04 (Samaritan Pharmaceuticals; Fig. 10) is aninhibitor of AChE and of sigma-1 receptors. For syn-thesis and biological evaluation, see [496] (ThomsonReuters Pharma, update of March 23, 2011).

The development of igmesine (JO-1784; Jouveinal,now Pfizer) was terminated. See Part 1, Chapter 1.28,Drugs interacting with Sigma receptors.

2.2. Drugs interacting with alpha-secretase

�-Secretase cleaves A�PP at the Lys16-Leu17bond within the A� sequence to generate the sol-uble N-terminal A�PP fragment (sA�PP�) and themembrane bound CTF83 (carboxy-terminal fragmentof 83 residues in length) thus precluding the forma-tion and subsequent deposition of A�. The activationof the �-secretase processing of A�PP as a thera-peutic approach in AD was reviewed [497–501]. Theactivation of �-secretase is controlled by the pro-tein phosphorylation signal transduction pathway ofprotein kinase C (PKC). A review on �-, �-, and�-secretases in AD was published [502].

Etazolate (EHT-0202; SQ-20009; Exonhit; Fig. 10)is an orally active phosphodiesterase (PDE) 4 inhibitorand anxiolytic GABAA receptor modulator. Etazolatedose-dependently increased the secreted levels of non-amyloidogenic sA�PP� in cortical neurons of ratsthus shifting A�PP processing toward the �-secretasepathway [503]. Etazolate improved the memory perfor-mance in aged rats [504]. The results of the first PhaseII 3-month, randomized, placebo-controlled, double-


Fig. 10. Two dual acetylcholinesterase & platelet-activating factor, one acetylcholinesterase & serotonin transporter, one acetylcholinesteraseand sigma-1 receptor inhibitor(s) and an �-secretase activator.

blind study in AD patients were reported [505]. Thedrug was shown to be safe and well tolerated (ThomsonReuters Pharma, update of September 13, 2011).

Bryostatin-1 (Blanchette Rockefeller Neuro-sciences Institute) is a naturally occurring PKCactivator isolated from the Californian marine bry-ozoan Bugula neritina. Bryostatin-1 increased brainlevels of sA�PP� and reduced brain A�40 levels,which may be explained by activation of �-secretase[499, 506]. In February 2012, the Institute waspreparing to initiate clinical trials in neurologicaldisorders. Chemistry and biology of bryostatins wasreviewed [507] (Thomson Reuters Pharma, updateof February 24, 2012). See also section 2.35. Drugsinteracting with Protein Kinase C.

NP-17, NP-21, NPM-01, NPM-05B1, and NPM-05B2 (Noscira) are orally available �-secretaseactivators of marine origin for the potential treatmentof AD (Thomson Reuters Pharma, updates of July 27,2011). The structures were not communicated.

Many compounds shifted A�PP processing towardthe �-secretase pathway in in vitro experiments, such

as muscarinic acetylcholine receptor agonists, MAO-B inhibitors, statins, non-steroidal anti-inflammatorydrugs (NSAIDs), neuropeptides such as PACAP,estrogen, and others [499]. However, the benefit forAD patients in clinical trials was (so far) disappointing.

2.3. Drugs interacting with beta secretase

In the amyloidogenic pathway, A�PP is firstcleaved by �-secretase (BACE1, EC 3.4.23.46 [508,509]) between residue methionine 671 and asparticacid 672 to release a 100 kDa N-terminal fragmentsA�PP and a 12 kDa membrane bound CFT99,which is subsequently cleaved by �-secretase withinthe transmembrane region to form C-terminal A�peptides ranging from 38 to 43 residues. �-secretasewas cloned simultaneously by five groups in 1999 andearly 2000: at Amgen [510, 511]; at Elan [512], atPharmacia & Upjohn, now Pfizer [513], at GSK [514],and at the Oklahoma Medical Research Foundation[515]. It is a 501 amino acid protein with two active


site motifs at amino acids 93-96 and 289-292. Itis structurally related to renin, cathepsins D and E,pepsinogens A and C, and the retroviral asparticproteases [516, 517]. The �-secretase-1 gene wasdescribed [518] as was the cell biology, regulation,and inhibition of �-secretase [519]. For the enzymaticactivities of �-secretase-1 and �-secretase-2 (BACE2;EC 3.4.23.45) in AD, see [520]. �-secretase-1 isalso required for myelination and correct bundling ofaxons by Schwann cells [521, 522].

An X-ray crystal structure of �-secretase-1 boundto the octapeptidic inhibitor OM99-2 was published[523, 524]. Apo and inhibitor complex structures of�-secretase-1 at the resolution of 1.75 A were deter-mined [525]. X-ray crystal structures of �-secretase-1bound to a macrocyclic peptidomimetic [526] and toa spiropiperidine iminohydantoin were communicated[527], as was the crystal structure of an active form of�-secretase-1 [528].

�-secretase-1 knockout mice are healthy despitelacking the primary �-secretase activity in the brain[529, 530]. �-secretase-1 null mice are rescued fromA�-dependent hippocampal memory deficits [531].

A rare gene mutation in the A�PP was identifiedin an Icelandic population by scientists of deCodegenetics, which protects against AD and age-relatedcognitive decline. This A673T mutation is directlyadjacent to the cleavage site of �-secretase (methionine671 and aspartic acid 672) [532]. For a commentary,see [533].

In view of the importance of the amyloid hypothesisfor AD, it is not surprising that many pharmaceu-tical companies embarked on medicinal chemistryprograms to discover �-secretase inhibitors (in alpha-betical order): Actelion, Allosterix, ALSP, Amgen,Archer Pharmaceuticals, Astellas, Astex Therapeutics,AstraZeneca, BACE Therapeutics, Boehringer Ingel-heim, Bristol Myers Squibb, CoMentis (company ofProf. Jordan Tang), Critical Outcome Technologies, DeNovo Pharmaceuticals, DuPont Pharma, Elan, EnvoyTherapeutics, Evotec, Genetics Company, Glaxo-SmithKline, IntelliHep, JADO Technologies, Johnson& Johnson, Kyoto University, LG Life Sciences,Ligand Pharmaceuticals, Lilly, Locus Pharmaceuti-cals, Medivir, Merck, NasVax, Noscira, Novartis,Pfizer, ProMediTech, Roche, Samada Research, sanofi,Schering-Plough, Senex Biotechnology, Shionogi,Sibia, Sunesis Pharmaceuticals, Takeda, Trans-TechPharma, Vertex Pharma, Vitae Pharmaceuticals, andWyeth. In addition, there are numerous excellentpapers by competent synthetic organic chemists andmolecular modelers working at universities. The prob-

lems of �-secretase inhibitors are mostly due to theirpeptidomimetic structures displaying high molecularweight, high polar surface area, low oral bioavail-ability, metabolic instability, low blood brain barrierpenetration, and susceptibility to P-glycoprotein trans-port out of the brain.

There are many interesting reviews on the phar-macology and medicinal chemistry of �-secretaseinhibitors (in chronological order): 2001: [534–536]2002: [537–543], 2003: [544–547], 2004: [548–550],2005: [551, 552], 2006: [553–557], 2007: [558–560],2008: [517, 561–563], 2009: [508, 564–569], 2010:[570–574], 2011: [575–578], 2012: [579–581].

LY-2886721 (Eli Lilly) was in two Phase I clini-cal trials since June 2010 (n = 50) and December 2010(n = 60) in the US. The studies were completed inOctober 2010 and in April 2011, respectively. In April2012 a randomized, double-blind, placebo-controlled,Phase I/II study (NCT01561430) was initiated inpatients with mild cognitive impairment due to AD(expected n = 129) in the US and is scheduled to com-plete in December 2013. For medicinal chemistry, see[582–586] (Thomson Reuters Pharma, update of July27, 2012). The structure was not communicated.

CTS-21166 (ASP-1702, ATG-Z1; Astellas Pharmaand CoMentis) is a �-secretase-1 inhibitor in Phase Iclinical trials since June 2007. In 48 volunteers, thedrug was safe and well tolerated (Thomson ReutersPharma, update of July 10, 2012). The structure wasnot communicated.

E-2609 (Eisai) is a �-secretase inhibitor in PhaseI clinical trials since December 2010 in the US inhealthy young and elderly volunteers (n = 48). Thetrial was completed in May 2012. Multiple-ascendingoral doses of E-2609 (25 to 400 mg for 14 days)were studied at a single site in the US in this ongoingtrial in healthy human volunteers of 50 to 85 yearsof age (both genders). The drug was safe and welltolerated with minor adverse effects. Reductions ofA� in CSF and plasma were demonstrated followingboth single and repeated administrations (ThomsonReuters Pharma, update of August 07, 2012). Thestructure was not communicated.

HPP-854 (TTP-854; High Point Pharmaceuticals,a spin-out from TransTech Pharma) is a �-secretaseinhibitor in Phase I clinical trials since November 2009(Thomson Reuters Pharma, update of April 5, 2012).The structure was not communicated.

MK-8931 (SCH-900931; Schering-Plough, nowMerck; Fig. 11) is an inhibitor of �-secretase inPhase I clinical trials since October 2009 (n = 40).In April 2012 data were presented from a two-part,


Fig. 11. Beta-secretase inhibitors.


randomized, double-blind, placebo-controlled singlerising-dose study (n = 40). Single doses of MK-8931from 2.5 to 550 mg were well-tolerated [587]. Formedicinal chemistry, see [548, 588–593] (ThomsonReuters Pharma, update of August 13, 2012).

For further documentation on the impressive�-secretase-1 inhibitor research program ongoing atMerck see (in chronological order): [594–621 [2]].

At the occasion of the 244th ACS meeting inPhiladelphia Merck presented a bicyclic iminohete-rocycle compound (Fig. 11) with an optimizedthiadiazine subunit with high affinity for �-secretase.

RG-7129 (Roche from a research collaboration withSiena Biotech) is a small molecule �-secretase (BACE)inhibitor in Phase I development since September2011 (Thomson Reuters Pharma, update of August 8,2012). The structure was not communicated. See alsothe interesting papers [621, 622].

Several �-secretase inhibitors of known structure arein preclinical evaluation (in alphabetical order):

Amgen (presumably AC-3; AMG-0683; Fig. 11)investigated series of 2-aminoquinolines and 2-aminopyridines as �-secretase-1 inhibitors [623].Hydroxy-ethylamine containing �-secretase inhibitorswere described very recently [624, 625] (ThomsonReuters Pharma, update of July 31, 2012).

AZ-13 (Astex Pharmaceuticals and AstraZeneca;Fig. 11) at 50, 75, 100, or 300 mmol/kg achieved aconcentration-dependent decrease in A�40, A�42, andsA�PP levels in brain and plasma of C57BL/6 mice.For medicinal chemistry, see [626–629] (ThomsonReuters Pharma, update of August 2, 2012).

Bristol-Myers Squibb (Fig. 11) is investigating aseries of 7-aza-indole compounds with IC50 values of10 nM against BACE-1 and 800 nM against BACE-2. For medicinal chemistry, see [630–635] (ThomsonReuters Pharma, update of August 8, 2011).

Elan (Fig. 11) presented data on hydroxyethylamine�-secretase-1 inhibitors with IC50 values against�-secretase-1 of 12 nM and an ED50 value of 2.1 nMin a HEK-293 cellular assay. For medicinal chemistry,see [636–643] (Thomson Reuters Pharma, update ofAugust 13, 2012).

Johnson & Johnson (presumably JNJ-715754,Fig. 11) is evaluating compounds from a seriesof aminopiperazines with an IC50 of 40 nM in a�-secretase-1 enzymatic assay, of 28 nM for hA�42,and 25 nM for hA�Total. Many medicinal chem-istry papers were communicated [644–649] (ThomsonReuters Pharma, update of January 18, 2012).

KMI-008, KMI-358, KMI-370, KMI-420,KMI-429, KMI-574, KMI-1027, and KMI-1303

(Kyoto Pharmaceutical University) are potent BACE1inhibitors [650–665]. KMI-429 (Fig. 12) is a�-secretase 1 inhibitor with enhanced cell membranepermeability (IC50 = 3.9 nM). KMI-574 (Fig. 12)is a �-secretase inhibitor produced by substitutingthe side chain of KMI-429 with a bioequivalentmaterial to enhance blood-brain barrier permeability(IC50 = 5.6 nM). KMI-1027 (Fig. 12) is a low molecu-lar weight �-secretase inhibitor with enhanced in vivoenzyme stability and blood-brain barrier permeability(IC50 = 50 nM). KMI-1303 (Fig. 12) is a �-secretase1 inhibitor with higher affinity for active site pockets(IC50 = 9 nM). The structures were obtained fromthe Wako Online Catalog, Research for Alzheimer’sDisease, edition November 2011.

L-655240 (Merck, Fig. 12) is a thromboxane A2antagonist, which was re-discovered as a BACE1inhibitor with IC50 of 4.47 �M by Chinese authors[666].

Novartis (Fig. 11) investigated a series of cyclicsulfoxide hydroxyethylamine �-secretase-1 inhibitors.The compound reduced CSF and brain A�40 levels ina dose-dependent manner and showed good efficacyat a 10 fold lower dose, when co-administered withthe CYP3A4 inhibitor ritonavir in various animal mod-els. For medicinal chemistry, see [667–671]. (ThomsonReuters Pharma, update of July 5, 2011).

TAK-070 (University of Tokyo under license fromTakeda) is a �-secretase and A� aggregation inhibitor(Thomson Reuters Pharma, update of June 8, 2012).The structure was not communicated.

WAY-258131 (Wyeth, now Pfizer; Fig. 11) inhibited�-secretase-1 with an IC50 value of 10 nM and reducedA�40 with an IC50 value of 20 nM. For medicinalchemistry, see [672–689] (Thomson Reuters Pharma,update of August 15, 2012).

Several companies have �-secretase-1 inhibitorsin preclinical development, whose structures werenot communicated (in alphabetical order): Allosterix,BACE Therapeutics, Boehringer Ingelheim, EnvoyTherapeutics [690], Evotec [691, 692], Il DongPharma (Seoul), IntelliHep (heparinoid �-secretaseinhibitors), LG Life Sciences [693], ProMediTech,Samada Research, Vitae Pharmaceuticals in collabo-ration with Boehringer Ingelheim and the TechnicalUniversity of Munich [694, 695].

A dual �-secretase-1 inhibitor and metal chelatorwas described [696].

Dual �7 nicotinic acetylcholine receptor activa-tors and �-secretase-1 inhibitors are investigated ina program at the University of Maryland (ThomsonReuters Pharma, update of February 24, 2012).


Fig. 12. Beta-secretase inhibitors II.


JADO Technologies synthesized a membrane-anchored version of a �-secretase transition-stateinhibitor by linking it to a sterol moiety. This inhibitorreduced enzyme activity much more efficiently thandid the free inhibitor in cultures cells and in vivo [697].

BBS-1 BACE inhibitor mAb vaccine (NasVaxunder license from Ramot at Tel Aviv University) isinvestigating a vaccine based on its lead mAb candidateBBS-1 (blocking �-site-1), which inhibits the abilityof �-secretase-1 to cleave A�PP (Thomson ReutersPharma, update of July 30, 2011).

Antibodies directed against the �-secretase cleav-age site of A�PP were described [698, 699].

Brain-targeted BACE1 antibody (Genentech,Roche Holding) is a bi-specific antibody against�-secretase-1 and the transferrin receptor to allowtranscytosis across the blood-brain barrier [700, 701](Thomson Reuters Pharma, update of May 14, 2012).This technique was pioneered by W. M. Pardridge ofUCLA [702–708].

Excellent papers on �-secretase-1 inhibitors fromuniversities were presented (in alphabetical order oftheir location): Mahidol University Bangkok [709,710], University of Darmstadt [711], TU Dresden[712], University of Duisburg-Essen [713], GwangjuInstitute of Science and Technology Korea [714],Linkoping University [715]; University of Liverpool[716, 717], University of Marseille [718], Max-Planck-Institut fur Biochemie Martinsried [719], Universityof Montreal [720–722], Technical University Munich[695], Peking University [723], University of Pisa[724–726], Purdue University [536, 559, 561, 727,728], Sapienza University Rome [729], Shanghai Insti-tute of Materia Medica [730, 731], Shujitsu University[732], Stockholm University [733–735], Universityof South Florida Tampa [736], University of Tokyo[665], SISSA-ISAS Trieste [737], CNRS Valbonne[738, 739], and Uppsala University [740–743].

Excellent papers on theoretical calculations on�-secretase-1 inhibitors were presented (in chrono-logical order) 2001: [744], 2003: [644], 2004: [645,646, 745], 2005: [746, 747], 2006: [748–751], 2007:[752–754], 2008: [755, 756], 2009: [757, 758], 2010:[759–765], 2011: [766–771], 2012: [772–778].

Several companies or institutions seem to have aban-doned the search for novel �-secretase-1 inhibitors,such as Actelion, De Novo, the Genetics Co (Callisto-Gen), Ligand, Locus Pharmaceuticals, Medivir [779],Noscira, and Plexxikon.

The development of allosteric peptide BACE-1inhibitors (Allosterix), of ARC-050 (Archer Phar-maceuticals), AZD-3839 (AstraZeneca [780, 781]),

BACE inhibitors (BACE Therapeutics, Evotec,Samada Research, and ProMediTech/LG Life Sci-ences), GRL-8234 (Oklahoma Medical ResearchFoundation [782]), GSK-188909 (GSK [783–791]),LY-2811376 (Lilly [792]), SIB-1281 (Sibia), of TAK-070 (Takeda [793, 794]), and of TC-1 (Merck underlicense from Sunesis [795, 796]) was terminated.

2.4. Drugs interacting with gamma-secretase

�-secretase is an aspartyl protease that cleavesits substrates within the transmembrane region in aprocess termed regulated-intramembrane-proteolysis(RIP). The enzyme consists of four protein compo-nents: presenilin 1 or 2, which contains the catalyticdomain, nicastrin, Aph-1 (anterior pharynx-1), andPen-2 (presenilin enhancer-2) in a 1 : 1:1 : 1 ratio [797].It is hypothesized that the free N-terminus of a �-secretase substrate first binds to the ectodomain ofnicastrin (a 709 amino acid type 1 membrane glyco-protein), which may facilitate its interaction with thedocking site on presenilin followed by relocation to theactive site on presenilin, where it is cleaved [798–812].�-secretase cleaves A�PP transmembrane domain in aprogressive stepwise manner at the �, ζ, and �-sites,resulting in A� species of varying length. This step-wise cleavage may occur via two different routes. Theyinitiate with the formation of A�49 and A�48 andthen proceed via the cleavage at approximately everythree residues, i.e., every helical turn of the substrate.The two product lines are �49-ζ46-�43-�40 and �48-ζ45-�42. Further cleavage will subsequently generatethe other isoforms A�39, A�38, and A�37, of whichA�38 results from the product line containing A�42[813–816]. The mechanism of �-secretase dysfunctionin familial AD was addressed [817].

�-secretase also cleaves other protein substrates,e.g., Notch, Jagged, and Nectin 1� [818–821].�-secretase cleavage of Notch leads to the release of thesmaller cytosolic fragment NICD (Notch intracellulardomain) important in signal transduction pathways. �-secretase inhibitors that are not Notch-sparing maycause severe gastrointestinal toxicity and interferewith the maturation of B- and T-lymphocytes in mice[822–827]). Note that A�PP interacts with Notchreceptors [828].

The first proof that �-secretase inhibitors reducedA� peptide levels in the brain was published alreadyin 2001 by Elan scientists [829].

In view of the importance of the amyloid hypothesisfor AD, it is not surprising that many pharmaceu-tical companies embarked on medicinal chemistry


programs to discover �-secretase inhibitors andmodulators (in alphabetical order): Archer Pharmaceu-ticals, AstraZeneca, Bristol-Myers Squibb, Cellzome,Eisai, Elan, EnVivo Pharmaceuticals, Harvard Med-ical School, Intra-Cellular Therapies, Janssen, Lilly,Merck, Myriad Genetics, NeuroGenetic Pharmaceuti-cals, Ortho-McNeill, Pfizer, Roche, TorreyPinesThera-peutics and Wyeth (now Pfizer). There are many highlyinteresting publications on medicinal chemistry andpharmacology of �-secretase inhibitors and modu-lators reviewed (in chronological order) 2002: [539,830–834]; 2003: [835]; 2004: [836, 837]; 2005: [838,839]; 2006: [556, 557, 840–843]; 2007: [819]; 2008:[844]; 2009: [809, 845–847]; 2010: [848, 849]; 2011:[577, 850]; 2012: [851, 852].

A review on the molecular modeling and the designof �-secretase inhibitors was presented [607].

Many excellent reviews on the therapeutic poten-tial of �-secretase inhibitors and modulators werepublished [850, 853–863].

2.4.1. Gamma-secretase inhibitorsAvagacestat (BMS-708163; Bristol-Myers Squibb;

Fig. 13) is an orally active �-secretase inhibitor thatselectively inhibited A� production. A Phase II trialin 200 AD patients was initiated in February 2009;a second Phase II trial in 270 prodromal AD (mildcognitive impairment) patients over a period of 104weeks was initiated in May 2009. First reports on thetolerability profile, pharmacokinetic parameter, andpharmacodynamics markers were published [864–866[3]]. A sensitive and selective LC-MS/MS method fordetermination of avagacestat in plasma and CSF waspresented [866]. For medicinal chemistry and phar-macology, see [867, 878] (Thomson Reuters Pharma,update of August 10, 2012).

NIC5-15 (Humanetics under license from theMount Sinai School of Medicine, Fig. 13) is the naturalproduct D-pinitol, which inhibits the formation of A�plaques and inhibits �-secretase. In July 2009 encour-aging Phase IIa data of the study NCT00470418 werereported (Thomson Reuters Pharma, update of January19, 2012).

E-2212 (Eisai), a �-secretase inhibitor, is in PhaseI clinical evaluation since January 2010 (n = 91). Thestructure of E-2212 was not communicated. E-2212replaces the abandoned �-secretase modulator E-2012(Thomson Reuters Pharma, update of March 15, 2011).

(−)-GSI-1 (L-685,458; SCH-900229; Merck;Fig. 13) has an EC50 value of 15 mg/kg in a rat modeland displayed excellent oral pharmacokinetics. GSI-1lowered A�40 plasma concentration. By August 2011,

Phase I trials had begun. For the extensive medicinalchemistry see [879–902] (Thomson Reuters Pharma,update of May 04, 2012).

Several �-secretase inhibitors are currently in pre-clinical evaluation (in alphabetical order):

Harvard Medical School scientists are investigat-ing a series of Notch-sparing �-secretase inhibitors forthe potential treatment of AD (one structure shownin Fig. 13). One of the compounds (AD-1068) has anIC50 value of 9 nM against A�42 and an IC50 value of1.8 �M for Notch. For medicinal chemistry (early workwas performed in part at the University of Tennessee),see [903–911]. An excellent review was published in2010 [848]. It appears that the development was termi-nated recently (Thomson Reuters Pharma, update ofJune 25, 2012).

MRK-560 (SCH-1375975; Schering-Plough, nowMerck; Fig. 13) reduced A� plaque deposition with-out evidence of notch-related pathology in the Tg2576mouse [912–915]. For medicinal chemistry, see [885,916–919, 895, 896, 920–927] (Thomson ReutersPharma, update of November 24, 2011).

NGP-555 (NeuroGenetic Pharmaceuticals, Fig. 14)has an IC50 for A� of 8.3 nM. It reduced levels ofA�42 in brain and plasma at doses up to 100 mg/kg p.o.Chronic treatment with 50 mg/kg for 7 months signifi-cantly reduced the percentage area of plaques in mousebrains. There was no evidence of Notch-mediated GItoxicity [928]. A potential follow-up compound may beNGP-328, whose structure was not disclosed (Thom-son Reuters Pharma, update of June 4, 2012).

Pepscan Therapeutics is investigating a series ofpeptide-based �-secretase inhibitors for the potentialtreatment of AD (Thomson Reuters Pharma, update ofApril 1, 2011). The structures were not communicated.

Pfizer (Fig. 14) presented a novel �-secretaseinhibitor containing a bicyclo-[1.1.1]-pentanyl moietywith an IC50 of 0.178 nM being equipotent to avagace-stat (IC50 = 0.196 nM) [929]. For additional medicinalchemistry papers from Pfizer, see [930–935] (ThomsonReuters Pharma, update of July 30, 2012).

RO-02 (Roche; Fig. 14) inhibited enzyme activ-ity with an A�42 inhibition IC50 value of 500 nM.For medicinal chemistry, see [936] (Thomson ReutersPharma, update of July 20, 2011).

Large �-secretase inhibitor research programs werealso ongoing at Amgen [937] and at Elan, see[938–947].

Excellent papers on �-secretase inhibitors from uni-versities were presented (in chronological order) 2001:[948, 949]; 2004: [950, 951]; 2005: [952]; 2006: [953,954]; 2009: [955, 956]; 2010: [957]; 2012: [958, 959].


Fig. 13. �-secretase inhibitors.

Excellent papers on theoretical calculations on�-secretase inhibitors have been presented (in chrono-logical order) [960–967].

Critical Outcome Technologies is investigatingorally available, dual �- and �- secretase inhibitors(Thomson Reuters Pharma, update of June 24,2011).

The development of several �-secretase inhibitorswas terminated, of ARC-069 (Archer Pharmaceu-ticals, Roskamp Institute), begacestat (GSI-953;WAY-210953; PF-5212362; Wyeth, now Pfizer [809,968–974]), BMS-299897 (Bristol-Myers Squibb;[975–978]), BMS-433796 (Bristol-Myers Squibb[869, 979]), E-2012 (Eisai), ELND-006 and ELND-007 (both Elan [944–946, 980, 981]; GSI-136 (Wyeth,now Pfizer [982]), MK-0752 (Merck; in Phase II for thetreatment of cancer, but terminated for the indicationof AD [983]); PF-03084014 (Pfizer; in Phase I for thetreatment of cancer, but terminated for the indicationof AD [984–987]), RO-4929097 (RG-4733; Roche,for the indication breast cancer [988–993]), sema-gacestat (LY-450,139; Eli Lilly [931, 932, 994–1010])and of SR-973 (DuPont/Scios, now Bristol-MyersSquibb).

2.4.2. Gamma-secretase modulatorsA �-secretase modulator interacts with allosteric

binding sites at the protease complex shifting the pro-teolytic processing of A�PP toward higher productionof shorter A� species such as A�38 at the expense ofthe highly toxic A�42 isoform. Impairment of Notchprocessing and signaling was not observed [1011].Reviews on �-secretase modulators were presented (inchronological order) 2005: [1012]; 2006: [556, 557,1013]; 2007: [1014, 1015]; 2008: [833, 1016–1019];2010: [821]; 2011: [1020, 1021]; 2012: [1022–1024].

Tarenflurbil (MPC-7869; (R)-flurbiprofen, Flur-izan, Myriad Genetics, Loma Linda University;Fig. 14) is a COX inhibitor and �-secretase modu-lator that selectively reduced the levels of A�42 invivo [1025, 1026]). The IC50 values for the inhibi-tion of COX-1 are 44 �M, of COX-2 : 123 �M, and ofA�42: 280 �M [1027]. Chronic administration of R-flurbiprofen attenuated learning impairments in trans-genic A�PPswe mice [1028]. Tarenflurbil upregulatednerve growth factor and brain-derived neurotrophicfactor protecting both human neuroblastoma cell linesand primary neurons from cytotoxicity associated withexposure to A�42 or hydrogen peroxide [1029].


Fig. 14. �-secretase inhibitors and modulators.

Tarenflurbil was tested in a Phase II study in 210patients with doses of 400 mg and 800 mg twice perday or placebo for 12 months. Patients with mild AD inthe 800 mg tarenflurbil group had lower rates of declinethan those in the placebo group concerning activitiesof daily living. In patients with moderate AD 800 mgtarenflurbil twice a day had no significant effects onADCS-ADL and ADAS-cog [1030].

Tarenflurbil was tested in a Phase III study in 1,684patients, of which 1,046 completed the trial. Taren-flurbil had no beneficial effect on the co-primaryoutcomes for ADCS-ADL and for ADAS-cog [1031];for commentaries see [1032–1034] (Thomson ReutersPharma, update of August 24, 2012).

With the termination of the development oftarenflurbil, the NO-releasing flurbiprofen derivativeHCT-1026 (NicOx) was also stopped.

CHF-5074 (Chiesi Farmaceutici; Fig. 14) showed aconcentration dependent inhibitory activity on A�42secretion (IC50 = 40 �M). At 300 �M, an inhibitoryeffect was detected on COX-1 (–40%), but not onCOX-2 [1035]. It is devoid of Notch-interfering activi-ties in vitro [1036]. Treatment of 6 months old hA�PPtransgenic mice for 6 months significantly reduced

the number of plaques in cortex and hippocampus,whereas ibuprofen did not reduce A� burden [1037].CHF-5074 treatment of Tg2576 mice from 6 to 15months of age resulted in a significant attenuation ofthe neurogenesis impairment in hippocampus [859,1038]. For the reduction of the accumulation of hyper-phosphorylated tau, see [1039], for the restorationof hippocampal plasticity in Tg2576 mice [1040]and for the effects in a mouse model of scrapie[1041].

CHF-5074 was tested in a double-blind, placebo-controlled Phase I ascending oral dose study in 48healthy males with 200, 400, and 600 mg/day for 14days (n = 12 each per dose level and 12 receivingplacebo). The drug was well tolerated. In March 2011,a Phase II trial was initiated in the US and in Italy(n = 96). Trial completion is expected for July 2012(Thomson Reuters Pharma, update of July 23, 2012).

EVP-0962 (EnVivo Pharmaceuticals) is a �-secretase modulator in Phase I clinical evaluation sinceJune 2011 in healthy volunteers. By June 2012, thePhase I trial was completed (Thomson Reuters Pharma,update of August 14, 2012). Its structure was not com-municated.


Several �-secretase modulators are currently in pre-clinical evaluation (in alphabetical order):

Amgen (Fig. 15) presented preclinical data on anovel �-secretase modulator at the occasion of the41st SFN Meeting in Washington in November 2011(Thomson Reuters Pharma, update of December 6,2011).

AZ-4800 (AstraZeneca; Fig. 15) at 75, 150, and300 �mol/kg caused a dose dependent decrease ofbrain A�42 1.5 hours after administration to C57mice (Thomson Reuters Pharma, update of April 1,2011). For medicinal chemistry, see [1042, 1043].AstraZeneca scientists described the detailed phar-macological evaluation of the �-secretase modulatorsAZ3303 and AZ1136 (both Fig. 16) [1044, 1045]. Thesecond-generation �-secretase modulators have differ-ent modes of action regarding Notch processing [1046](Thomson Reuters Pharma, update of July 4, 2012).

BIIB-042 (Biogen Idec; Fig. 15) is a �-secretasemodulator, which significantly reduced brain A�42 lev-els in CF-1 mice and in Fisher rats and plasma A�42levels in cynomolgus monkeys. For medicinal chem-istry, see [1047, 1048] (Thomson Reuters Pharma,update of March 27, 2012).

GSM-2 (Merck UK [1049], Fig. 15), as was inves-tigated by scientists of Astellas [1050], significantlyameliorated memory deficits in Tg2576 mice and didnot affect normal cognition in wild-type mice. In con-trast �-secretase inhibitors avagacestat (BMS-708163)and semagacestat (LY-450139) on subchronic dosingimpaired normal cognition in 3 month old Tg2576mice.

GSM-10h (GSK, Fig. 15) is an orallyactive piperidine-derived �-secretase modulator[1051–1054]. GSK is also investigating �-secretasemodulators derived from pyridazines (Fig. 15 [1055])and from pyridines (Fig. 15) [1056] (ThomsonReuters Pharma, update of January 13, 2012).

Janssen described a novel series of bicyclic hetero-cycles as potent �-secretase modulators [1057].

Merck (Fig. 16) is investigating �-secretase mod-ulators with fused 5,6-bicyclic heterocycles. The bestcompound had an IC50 of 122 nM for the inhibitionof A�42 and exhibited good selectivity over overall�-secretase inhibition (IC50 ratio of 38 fold). In rats,the compound reduced A�42 in the CSF by 26%after 3 hours at 30 mg/kg p.o. Medicinal chemistrywas described [1058–1063]. Important mechanisticinsights were contributed [1064] (Thomson ReutersPharma, update of August 15, 2012).

Merck (Fig. 16) presented a new series of triazoleanalogues, which inhibited A�42 and A�40 with IC50

values of 0.2 and 2.06 �M, respectively, and showeda hERG interaction of IC50 > 10 �M [1065, 1066].In a third series, Merck scientists presented pyridoneand pyridazone heterocycles as �-secretase modulators[1067].

Pfizer medicinal chemists presented novel dihy-drobenzofuran amides as orally bioavailable, centrallyactive �-secretase modulators [1068] (ThomsonReuters Pharma, update of July 30, 2012).

Roche presented novel �-secretase modulators at theoccasion of the Alzheimer’s Association InternationalConference in Paris, France, July 16–21, 2011. Onecompound (Fig. 16) had an A�42 EC50 value of 0.1 �Mand demonstrated dose-dependent efficacy in trans-genic A�PPswe mice. CSF A�42 levels were reducedin non-transgenic rats for longer than 8 hours. A goodpharmacokinetic profile was seen (Thomson ReutersPharma, update of July 27, 2012).

SPI-014, SPI-1802, SPI-1810, and SPI-1865(Satori Pharmaceuticals, Figure 16) are �-secretasemodulators reducing the levels of A�42 without alter-ing total A� levels in cell lines and in animal modelsof AD (Thomson Reuters Pharma, update of July 31,2012). The structures were not communicated.

TorreyPines Therapeutics presented a novel class ofaminothiazoles as �-secretase modulators. Compound3 (Fig. 16) displayed an IC50 for A�42 of 5 nM [1069].

Excellent papers on �-secretase modulators fromuniversities were presented from the TU Darmstadt[1070–1074], the University of Duesseldorf [1075],Emory University [1076], from the Mayo Clinic[1077], the Memorial Sloan-Kettering Cancer Center[1078–1080], the University of Munich [1081, 1082],and the University of Tokyo [1083].

Excellent papers on theoretical calculations on�-secretase modulators were presented from the Uni-versity of Duesseldorf [1084], the MassachusettsGeneral Hospital [1085–1087], and Vanderbilt Univer-sity [1088].

Dual modulators of �-secretase and peroxisomeproliferator-activated receptor � (PPAR�) werepresented to produce compounds with IC50 (A�42) of5.1 �M and EC50 (PPAR�) of 6.6 �M [1089, 1090].

The development of JNJ-4018677 and JNJ-42601572 (Janssen, formerly Ortho-McNeil Pharma-ceuticals under license from Cellzome) [1091] wasdiscontinued.

2.4.3. Inhibitors of gamma-secretase activatingprotein

�-secretase activating protein (GSAP) interactsboth with �-secretase and its substrate, the A�PP


Fig. 15. �-secretase modulators.


Fig. 16. �-secretase modulators and a Notch pathway inhibitor.

carboxy-terminal fragment (A�PP-CTF). ReducingGSAP concentrations in cell lines decreased A�concentrations, hence GSAP may be a new thera-peutic target for AD [1092]. For a commentary, see[1093]. The immunohistochemical characterization of

�-secretase activation protein expression in AD brainswas described [1094]; the purification and characteri-zation of human GSAP [1095].

IC-200155 (Intra-Cellular Therapies) is a com-pound that decreases A� levels in the brain by


Fig. 17. One 11� hydroxysteroid dehydrogenase inhibitor, three calpain and one cathepsin B inhibitor(s).

interacting with GSAP (Thomson Reuters Pharma,update of February 24, 2012). The structure was notcommunicated.

2.4.4. Notch pathway inhibitorsAGT-0031 (AxoGlia Therapeutics; Fig. 16) is an

inhibitor of the Notch pathway, which is involved inastrocyte differentiation and inflammatory activationfor the potential treatment of multiple sclerosis andAD (Thomson Reuters Pharma, update of February29, 2012).

2.5. Drugs interacting with beta hexosaminidase

The first report of short-term memory deficits in amurine model of lysosomal storage diseases includingSandhoff disease was described [1096].

Amicus Therapeutics is investigating smallmolecule pharmacological chaperones that bind to andactivate the lysosomal enzyme beta-hexosaminidasefor the potential oral treatment of AD. Thesecompounds lowered the levels of GM2 and GM3gangliosides associated with A� aggregation (Thom-

son Reuters Pharma, update of March 28, 2012). Nostructures were communicated.

2.6. Drugs interacting with 11 betahydroxysteroid dehydrogenase

The topic 11�-hydroxysteroid dehydrogenase type1 (11�-HSD-1), brain atrophy, and cognitive declinewas reviewed [1097, 1098]. 11�-HSD1 expression wasenhanced in the aged mouse hippocampus and causedmemory impairment [1099]. Enhanced hippocampalLTP and spatial learning was found in 11�-HSD1knockout mice [1100, 1101]. Partial deficiency orshort term inhibition of 11�-HSD1 improved cognitivefunction in aged mice [1102, 1103]). Inhibition of 11�-hydroxysteroid dehydrogenase by carbenoxolone (100mg three times per day) improved cognitive functionin elderly men [1104].

ABT-384 (Abbott Laboratories) is in a double-blind safety/efficacy Phase II trial since May 2010 inpatients (n = 260) with mild to moderate AD in the UK.Despite being safe, well tolerated and tested at dosesassociated with full inhibition of brain 11�-HSD-1activity, it did not induce symptomatic improvement in


mild to moderate AD during the 12-week trial period.Therefore the trial was terminated (Thomson ReutersPharma, update of July 18, 2012). The structure ofABT-384 was not communicated.

KR-1-2 (Korea Research Institute of ChemicalTechnology) suppressed cortisol by inhibiting 11�-hydroxysteroid dehydrogenase type 1. The drug isintended for the treatment of glaucoma and demen-tia (Thomson Reuters Pharma, update of February 27,2012).

UE-1961, UE-2811 (Fig. 17) and UE-2343 (Univ.of Edinburgh in collaboration with Argenta Discovery)are inhibitors of 11�-hydroxysteroid dehydrogenase1 (11�-HSD1) for the potential treatment of age-related cognitive disorders, such as memory loss[1102]. UE-2343 showed cognition enhancement inaged transgenic Tg2576 mice after one month of treat-ment in a passive avoidance test and a significantreduction of their A� plaque load (Thomson ReutersPharma, update of March 15, 2012). Another classof 11�-HSD1 inhibitors, i.e., 1,5-substituted 1H tetra-zoles, was described [1105].

2.7. Drugs interacting with calpain

The mechanistic involvement of the calpain-calpastatin system in AD neuropathology wasreviewed [1106]. Calpain inhibitors for the treatmentof AD were discussed [1107, 1108]. Over-activatedcalpain caused a down-regulation of cAMP-dependentprotein kinase in AD brain [1109]. Neuronal over-expression of the endogenous inhibitor of calpains,calpastatin, in a mouse model of AD reduced A�pathology [1110].

A-705253 (Abbott, formerly Knoll; Fig. 17) isan orally active calpain inhibitor for the potentialtreatment of AD. A-705253 significantly reducedcholinergic neurodegeneration caused by A� in adose-dependent manner in rats [1111–1117]. It alsoprevented stress-induced tau hyperphosphorylation invitro and in vivo [1118, 1119] (Thomson ReutersPharma, update of May 16, 2011).

ABT-957 (Abbott) is a calpain inhibitor for thepotential treatment of neurological disorders includ-ing AD (Thomson Reuters Pharma, update of March2, 2012). The structure was not communicated.

AK-295 (CX-295, Vasolex; AxoTect under licensefrom Cortex Pharmaceuticals using technologylicensed from Alkermes, Fig. 17) attenuated motor andcognitive deficits following experimental brain injuryin the rat [1120] (Thomson Reuters Pharma, update ofFebruary 9, 2012).

SNJ-1945 (Senju Pharmaceutical; Fig. 17) is apotent calpain inhibitor for the potential oral treat-ment of age-related macular degeneration, retinopathy,and optic neuritis. Preclinical data were reported[1121–1124]. Medicinal chemistry papers were con-tributed [1125–1128] (Thomson Reuters Pharma,update of April 18, 2012).

The development of calpain inhibitors BDA-410 (Mitsubishi-Tokyo Pharmaceuticals), CEP-3122(Cephalon, now Teva), EP-475 (University of Ten-nessee), MDL-28170 (Hoechst Marion Roussel, nowsanofi [1129–1131]), and of TH-3501 (University ofVirginia) was terminated.

2.8. Drugs interacting with carbonic anhydrase

Carbonic anhydrase dysfunction impaired cognitionand was associated with mental retardation, AD, andaging [1132].

The Blanchette Rockefeller Neurosciences Insti-tute is investigating phenylalanine compounds actingas carbonic anhydrase activators for the potentialtreatment of attention deficit disorders and memoryproblems in AD (Thomson Reuters Pharma, update ofFebruary 16, 2012).

2.9. Drugs interacting with caspases

Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases, are a family ofcysteine proteases that play essential roles in apoptosis(programmed cell death), necrosis, and inflammation.For a review on caspase-6 and neurodegeneration,see [1133]; for the role of caspases in AD, see[1134–1138].

NWL-117 (New World Laboratories) is an irre-versible inhibitor of active caspase-6 for thepotential treatment of AD (Thomson Reuters Pharma,update of July 18, 2012). The structure was notcommunicated.

2.10. Drugs interacting withCatechol-O-methyltransferase (COMT)

The topic COMT, cognition, and psychosis wasreviewed [1139–1141]. The potential role of COMTinhibitors for the treatment of cognitive deficits asso-ciated with schizophrenia was described [1142, 1143].

Tolcapone (Tasmar; Roche, launched in 1997)improved cognition and cortical information process-ing in normal human subjects [1144]. Tolcapone andEntacapone (Comtan; Orion in collaboration with


Novartis launched in 1999) blocked fibril formation of�-synuclein and A� and protected against A�-inducedtoxicity [1145].

The company Cerecor is investigating COMTinhibitors for the potential treatment of schizophreniaincluding cognition (Thomson Reuters Pharma, updateof April 12, 2012). Structures were not communicated.

2.11. Drugs interacting with cathepsin

Reduction of cathepsin B in transgenic miceexpressing human wild-type A�PP resulted in sig-nificantly decreased brain A� [1146, 1147]. Highercathepsin B levels were found in plasma of AD patientscompared to healthy controls [1148].

Aloxistatin (E-64d; AB-007; ALP-496; ALSP;Fig. 17) is an inhibitor of cathepsin B for the poten-tial treatment of AD and traumatic brain injury[1149–1152]. Aloxistatin was previously evaluated forthe treatment of Duchenne muscular dystrophy byTaisho Pharmaceuticals, but the development was ter-minated (Thomson Reuters Pharma, update of June 29,2012).

Acetyl-L-leucyl-L-valyl-L-lysinal (ALSP) is a cys-teine protease inhibitor, which caused a significantreduction in brain A� and �-secretase activity byapproximately 50% after i.c.v. administration of0.06 mg/g brain weight/day for 28 days [1153] (Thom-son Reuters Pharma, update of June 28, 2012).

The development of CEL-5A (University of Cali-fornia at Irvine; a cathepsin D inhibitor) and cystatinC (New York University/Nathan Kline Institute, a cys-teine protease inhibitor) was terminated.

2.12. Drugs interacting with cholesterol24S-hydroxylase (CYP46A1)

Abnormal induction of the cholesterol-catabolicenzyme CYP46 in glial cells of AD patients wasalready recognized in 2001 by researchers at theKarolinska Institute [1154], followed by [1155–1157].It was shown that polymorphism in the cholesterol24S-hydroxylase gene (CYP46A1) associated withthe ApoE�3 allele increased the risk of AD andof mild cognitive impairment [1158, 1159]. Simi-lar results were obtained in elderly Chinese subjects[1160, 1161]. CYP46A1 functional promotor haplo-types decipher genetic susceptibility to AD [1162].Reviews were published [1163, 1164]. The crystalstructure of the enzyme was elucidated [1165]. ThecDNA cloning was described by scientists from the

University of Texas [1166], who generated also KOmice [1167].

AAV-CYP46A1 (INSERM in collaboration withsanofi) is an adeno-associated virus gene ther-apy encoding cholesterol 24-hydroxylase (CYP46A1gene) for the potential injectable treatment of AD.Reduced A� peptides, amyloid deposits, and trimericoligomers were observed in A�PP23 mice. Signifi-cant improvements in cognitive function assessed bythe Morris water maze were also seen in Tau22 mice[1168] (Thomson Reuters Pharma, update of June 6,2012). See also Part 3, Chapter 4 Drugs interactingwith Gene Expression.

2.13. Drugs interacting with cyclooxygenase(COX)

COX (EC 1.14.99.1) is an enzyme that is responsi-ble for the formation of prostaglandins, prostacyclin,and thromboxane. NSAIDs exert their effects throughinhibition of COX. Oligomers of A�1-42 induced theactivation of COX-2 in astrocytes [1169].

Epidemiological studies have documented a reducedprevalence of AD among users of NSAIDs [1170,1171, 1026, 1172–1178]).

In the Rotterdam study, 6,989 subjects 55 yearsof age or older were analyzed for the associa-tion of NSAIDs use and AD. The relative riskof AD was 0.95 in subjects with short-term use(1 month) of NSAIDs, 0.62 in subjects withintermediate-term use (1 to 24 months), and 0.20in those with long-term use (more than 24 months)[1179]. Several clinical trials using indomethacin,diclofenac/misoprostol, naproxen, nimesulide, cele-coxib, and rofecoxib showed no benefit for ADpatients, reviewed by [1177]. The ADAPT researchgroup could not show a prevention of AD dementiain a clinical trial using naproxen and celecoxib [1180,1181].

The NSAIDs ibuprofen, indomethacin, and sulindacsulfide preferentially decreased the highly amyloido-genic A�42 peptide [1172]. This effect was notmediated by inhibition of COX, but by an allostericmodulation of �-secretase [1064] and by a change inpresenilin 1 conformation [1182]. A list of compoundsdecreasing the formation of A�42 peptide comprisingdiclofenac, (R)-flurbiprofen, fenoprofen, ibuprofen,indomethacin, meclofenamic acid. and sulindac waspresented [1183]. NSAIDs dose-dependently destabi-lized preformed A� fibrils in vitro [1184, 1185]. Theseeffects were also shown in transgenic mice in vivo[1025, 1177].


A�42-lowering NSAIDs constitute the foundingmembers of the new class of �-secretase modulators[1186], vide supra section 2.4.2.

2.14. Drugs interacting with D-amino acidoxidase

The therapeutic potential of D-amino acid oxidase(DAAO) inhibitors was described [1187]. Several sus-ceptibility genes for psychiatric disorders have beenidentified, among others G72, which is the D-aminoacid oxidase activator [1188–1191].

AS-2651816-00 (Astellas Pharma) is a novel DAAOinhibitor for the potential treatment of schizophreniawith an IC50 of 1.5 nM against human DAAO (Thom-son Reuters Pharma, update of August 24, 2012). Itis a 3-hydroxy-pyridazin-4(1H)-one, but the precisestructure was not communicated.

Eisai following the acquisition of MGI Pharmawas investigating DAAO inhibitors to enhance theactivity of D-serine. The compound 6-chlorobenzo[d]isoxazol-3-ol (CBIO) showed an IC50 of 200 nM. Itsdevelopment was terminated. Also the development ofDAAO inhibitors of Merck and Pfizer and of SEP-227900 (Sunovion) was terminated.

2.15. Drugs interacting with Glutaminyl Cyclase

Glutaminyl cyclase (QC) is an enzyme that catalyzesthe formation of pyroglutamic peptides or proteinsfrom a N-terminal glutamine residue. Human QC canperform in parallel the conversion of a N-terminal glu-tamate of a peptide to a pyroglutamated peptide. WhenA� is cleaved between amino acids 2 and 3, a pep-tide with a N-terminal glutamate is formed, which iscyclized by QC to the N-terminal pyroglutamate. Thistransformation renders the molecule more hydropho-bic and increases its aggregation velocity [1192–1197].Hence a QC inhibitor could prevent the formationof this species [1198–1204]. Secondary glutaminyl-cyclase inhibitor interactions were presented [4].

PBD-150 (Probiodrug; Fig. 18) is a potent inhibitorof human glutaminyl cyclase (IC50 = 17 nM) andtotally inhibits formation of A�3,11-(pE)40,42 in cellculture at 1 �M (Thomson Reuters Pharma, update ofFebruary 24, 2012).

A second generation of compounds was evaluated,in which the 1-propyl imidazole residue was replacedby the more rigid benzimidazole.

PQ-912 (Probiodrug) is a potent QC inhibitor inPhase I clinical studies with single- and multipleascending dose, blinded, placebo-controlled, random-

ized in healthy volunteers (n = 100). First resultsshowed that oral administration of PQ-912 was safeand well tolerated with relevant therapeutic levels inblood and CSF (Thomson Reuters Pharma, update ofJanuary 4, 2012). The structure of PQ-912 was notcommunicated.

2.16. Drugs interacting withglyceraldehyde-3-phosphate dehydrogenase

A proteomics analysis of the AD hippocampalproteome showed an increase of the levels of glyc-eraldehyde 3-phosphate dehydrogenase [1205]. Adecrease of the activity of cerebral glyceraldehyde-3-phosphate dehydrogenase in different animal modelsof AD was observed [1206].

Omigapil (SNT-317, TCH-346, CGP-3466; San-thera under license from Novartis; Fig. 18) is an orallybioavailable glyceraldehyde 3-phosphate dehydroge-nase modulator with anti-apoptotic properties for thetreatment of Parkinson’s disease and amyotrophic lat-eral sclerosis in Phase I clinical trials [1207–1221](Thomson Reuters Pharma, update of April 11,2012).

2.17. Drugs interacting with glycogen synthasekinase-3β (GSK-3β)

GSK-3� (EC 2.7.11.26, 47 kDa) is a ser-ine/threonine protein kinase ubiquitously expressedand involved in many cellular signaling pathwaysplaying a key role in the pathogenesis of AD. Itis probably the link between A� and tau patholo-gies. A� activates GSK-3� through impairment ofphosphatidyl-inositol-3/Akt signaling. A�-activatedGSK-3� induced hyperphosphorylation of tau, neu-rofibrillary tangle formation, neuronal death, andsynaptic loss (all found in AD brains). GSK-3�induced memory deficits in vivo. Crucial is thephosphorylation at serine 9. The cited papers arelisted in chronological order: 1999: [1222]; 2002:[1223–1225]; 2004: [1226–1228]; 2005: [1229]; 2006:[1230–1232]; 2007: [1233, 1234]; 2008: [1235–1240];2009: [1241–1243]; 2010: [1244, 1245]; 2011:[1246–1252]; 2012: [1253–1260].

GSK-3� was crystallized and the crystal structurewas resolved [1261, 1262]. 3D-QSAR studies werereported [1263, 1264]. Ligand-based virtual screeningwas elucidated [1265]. Scoring functions were applied[1266].

Tideglusib (NP-12, NP-031112; Nypta; Noscira,previously known as Neuropharma; Fig. 18) is the


Fig. 18. A glyceraldehyde 3-phosphate dehydrogenase modulator, a glutaminyl cyclase inhibitor, 10 glycogen synthase-3� and one HDACinhibitor.


lead compound of a series of orally active thiadia-zolidinediones, potent inhibitors of GSK-3 [1267]. APhase IIb clinical trial in AD patients was initiated inSpain, Germany, Finland, and the UK in April 2011.In January 2012, randomization of patients (n = 308)was completed in the double-blind trial. Preliminaryresults are expected by the end of 2012. In Decem-ber 2009, a Phase II trial for progressive supranuclearpalsy was initiated in the US and in Europe. Enrollmentwas completed in October 2010 (n = 125). The drugwas granted orphan status for progressive supranuclearpalsy in November 2009. First positive results of aclinical pilot study were reported [1268]. (ThomsonReuters Pharma, update of July 23, 2012).

There are currently many GSK-3� inhibitors in pre-clinical evaluation (in alphabetical order):

AX-9839 (ActivX Biosciences, Kyorin Pharmaceu-ticals, Fig. 18) is an inhibitor of GSK-3� for thepotential treatment of diabetes, AD, and various CNSdisorders [1269] (Thomson Reuters Pharma, update ofApril 18, 2012).

CG-9, CG-701338, CG-701446, and CG-701448(Crystal Genomics) are lead compounds from a seriesof GSK-3 inhibitors for the potential treatment of can-cer, AD, and schizophrenia (Thomson Reuters Pharma,update of May 02, 2012). The structures were not com-municated.

CP-70949 (Pfizer; Fig. 18) is a selective inhibitorof GSK-3� in preclinical evaluation [1270] (ThomsonReuters Pharma, update of July 11, 2011).

Dual GSK-3�/casein kinase 2 modulators (Uni-versity of Illinois at Chicago) are investigated for thepotential treatment of Alzheimer’s disease. (ThomsonReuters Pharma, update of September 20, 2012). Struc-tures were not communicated.

GSK-3� inhibitors (Pfizer, Fig. 18) investigated aseries of oxazole derivatives. The shown compoundhad an IC50 of 5 nM and a more than 100-fold selec-tivity against all other kinases and met safety criteria(Thomson Reuters Pharma, update of Aug. 28, 2012).

JI-7263 (Jeil Pharmaceuticals) is the lead compoundfrom a series of GSK-3� inhibitors for the poten-tial treatment of AD and amyotrophic lateral sclerosis(Thomson Reuters Pharma, update of May 7, 2012).The structure was not communicated.

Mitsubishi-Tanabe (Fig. 18) presented a potentGSK-3� inhibitor at the AIMECS 11 meeting in Tokyowith an IC50 of 12 nM (Thomson Reuters Pharma,update of January 24, 2012).

NNI-362 (NNI-AD; NeuroNascent) is a multikinaseand GSK-3� modulator inhibiting several tau phos-phorylation sites. Other orally active compounds that

stimulate neuron formation are NNI-X01, NNI-C, andNNI-251 (Thomson Reuters Pharma, update of July19, 2012). The structures were not communicated.

NP-101020 (Noscira) is a GSK-3� inhibitor for thepotential treatment of AD (Thomson Reuters Pharma,update of January 12, 2012). The structure was notcommunicated.

SN-2127 (AstraZeneca, Fig. 18) is one of severalGSK-3� inhibitors in evaluation by AstraZeneca asare SN-2568, SN-3728, and others (Thomson ReutersPharma, update of April 4, 2012).

Takeda (Fig. 18) presented a very potent GSK-3�inhibitor with IC50 of 2 nM. After oral administra-tion a significant reduction of tau phosphorylation wasobserved in aged JNPL3 mice [1271–1273]; Thom-son Reuters Pharma, update of January 04, 2012). Thecompound MMBO (Fig. 18) decreased tau phosphory-lation and ameliorated cognitive deficits in a transgenicmodel of AD [1274]).

TWS-119 (Scripps Research Institute; Fig. 18) isa compound that can induce neurogenesis in murineembryonic stem cells. The target of TWS-119 wasshown to be GSK-3� by affinity-based and biochemi-cal methods [1275].

VP1.15 (CSIC Madrid and University of Toronto,Fig. 18) is a dual GSK-3 and PDE7 inhibitor acting asan antipsychotic and cognitive enhancer in C57BL/6Jmice [1276, 1277].

Extensive programs to identify GSK-3� inhibitorshave been ongoing at AstraZeneca [1226, 1278–1280],at ChemDiv [1281], at GSK (e.g., SB-415286 andothers [1282–1287]), at GVK Biosciences [1288], atJohnson & Johnson [1289–1292], at Kemia [1293], atLilly [1294–1296], at Roche [1297], at Vertex [1298]),and at Yuyu in collaboration with CrystalGenomics[1299].

Potent GSK-3� inhibitors were described byresearchers at universities (in alphabetical order oftheir location): University of Athens [1300], UniversityAutonoma de Barcelona [1301], Technical Universityof Braunschweig [1302], University of Caen [1303,1304], University of Illinois at Chicago [1305–1310],Technical University of Darmstadt [1311, 1312, 1312],Martin-Luther University Halle [1313], University ofLa Rochelle [1314], University of Leuven [1231,1239–1241], CSIC Madrid [1315–1318], Universityof Louisiana at Monroe [1319], CNRS/Institut CurieOrsay [1320], Peking University [1321], Indian Insti-tute of Technology Roorkee [1322], Korea Institute ofScience and Technology Seoul [1323], Fudan Univer-sity Shanghai [1324], and the University of Talca, Chile[1325].


SAR studies on GSK-3� inhibitors were publishedby researchers at the Technical University Darmstadt,University of Naples, University of Leuven, and TelAviv University [1326].

The Broad Institute is investigating ATP noncompet-itive and allosteric inhibitors of GSK-3� (ThomsonReuters Pharma update of June 3, 2011).

DM-204 (DiaMedica following its acquisition ofSanomune) is a monoclonal antibody that inhibitsGSK-3� (Thomson Reuters Pharma update of June 15,2012).

The development of AR-A014418 (AstraZeneca)was terminated [1226, 1278–1280] as was NP-103(Noscira) and UDA-680 (SAR-502250; MitsubishiPharma and sanofi). Also the development ofPropentofylline (HWA 285; Hoechst Werke Albert,now sanofi) for AD and for vascular dementia has beenterminated after results of the 72 week propentofyllinelong-term use (PLUS) clinical trial showed no treat-ment differences between the propentofylline-treatedgroup and the placebo-treated group [1327–1331].Propentofylline attenuated tau hyperphosphorylationby reducing the activated form of GSK-3� and byincreasing the inactivated form of GSK-3� [1332].Propentofylline is also a potent inhibitor of PDEs(see section 2.29.). The development of SAN-161(Sanomune, a subsidiary of DiaMedica), SB-216763(SmithKline Beecham, now GSK [1333], and the XD-4000 series (Xcellsyz, Lonza group) was terminated.

2.18. Drugs interacting with guanylyl cyclase

Soluble guanyl cyclase may be required foremotional learning and for both reference andworking memory [1334]. A selective irreversibleinhibitor of soluble guanyl cyclase, i.e., 1H-[1,2,4]-oxadiazole[4,3-a]-quinoxaline-1-one at doses of 5, 10,and 20 mg/kg impaired retention for the passive avoid-ance task in rats. Activation of soluble guanyl cyclaseand cGMP formation in the brain represents one ele-ment of effective neuroprotective pathways mediatedby NO [1335]. The design and synthesis of nomethi-azoles as NO-chimeras for neurodegenerative therapywas described [1336].

sGC-1016 (sGC Pharma) is a sustained-release NOmimetic for the potential treatment of AD in Phase Iclinical trial, which was completed in July 2012 show-ing high bioavailability (Thomson Reuters Pharma,update of July 17, 2012). The structure was not com-municated.

GT-715 and GT-1061 (Cita NeuroPharmaceuticals,Vernalis) were prototypes of engineered NO mimetics,

which activated soluble guanylyl cyclase and increasedcGMP formation. They improved task acquisition incognitively impaired animals and in the 6-OHDAmodel of Parkinson’s disease [1337–1341]. The devel-opment of both compounds was terminated.

2.19. Drugs interacting with heme oxygenase

Glial heme oxygenase-1 expression in AD and mildcognitive impairment was reviewed [1342–1346].

OB-28 (Osta Biotechnologies) is a hemeoxygenase-1 inhibitor for the potential injectabletreatment of AD showing statistically significantimprovement in behavioral deficits in double trans-genic (A�PPSWE/PS1dE9) mice (n = 103) aftertreatment with 15 or 30 mg/kg/day for 4 months(Thomson Reuters Pharma update of August 6, 2012).The structure of OB-28 was not communicated.

2.20. Drugs interacting with histone deacetylase(HDAC)

An in depth overview shows how to target “the cor-rect” HDAC(s) to treat cognitive disorders [1347]. Theroles of HDAC inhibition in neurodegenerative condi-tions were discussed [1348]. The role of HDAC6 inAlzheimer’s disease was discussed [1349]. The loss ofHDAC5 impaired memory function [1350].

EVP-0334 (EnVivo under license from Methyl-Gene) is developing the orally active HDAC inhibitoras a cognition enhancer for the potential treatmentof AD. A Phase I clinical trial was started in May2009 and finished in May 2010. Phase II trial areunderway since November 2011. Medicinal chemistrypapers were published [1351, 1352] (Thomson ReutersPharma, update of August 10, 2012).

4-Phenylbutyrate (Digna Biotech SL) amelioratedcognitive deficits and reduced tau pathology in anAD mouse model [1353–1355], reduced A� plaques,and rescued cognitive behavior in AD transgenic mice[1356, 1357]. The drug is in Phase I clinical trials forthe potential treatment of AD since April 2010 (Thom-son Reuters Pharma update of May 30, 2012).

Other HDAC inhibitors are currently in preclinicalevaluation (in alphabetical order):

CHDI-390576 and CHDI-00381817 (HDAC4inhibitors) are investigated by the CHDI Foundation incollaboration with BioFocus DPI (Thomson ReutersPharma update of August 10, 2012). The structureswere not disclosed.

Crebinostat (Harvard Medical School, Fig. 18)is a novel HDAC inhibitor and enhancer of CREB-


regulated transcription and modulator of chromatin-mediated neuroplasticity [1358].

KAR-3010, KAR-3084, and KAR-3166 (KarusTherapeutics) are HDAC6 inhibitors for the poten-tial oral treatment of immune and inflammatorydisease including AD (Thomson Reuters Pharmaupdate of July 05, 2012). The structures were notdisclosed.

LB-201 and LB-205 (Lixte Biotechnology) aredrugs that target HDAC and prevent the degradationand restore the activity of glucocerebrosidase for thepotential treatment of neurological disorders such asGaucher’s disease [1359] (Thomson Reuters Pharmaupdate of April 05, 2012). The structures were notdisclosed.

Dual PKC activators and HDAC inhibitors weredescribed [1360].

The development of EHT-0205 (ExonHit) wasterminated.

2.21. Drugs interacting with HMG-CoA reductase

The enzyme 3-hydroxy-3-methyl-glutaryl-CoAreductase (EC 1.1.1.88) is the rate-controlling enzymeof the mevalonate pathway, which produces choles-terol and other isoprenoids. It is the target of thestatins (or HMG-CoA reductase inhibitors). In alarge study comprising 9,844 participants at agesfrom 40 to 45 years the risk of AD was evaluated inrelation to cholesterol levels. The analyses revealedthat cholesterol levels >220 mg/dL were a significantrisk factor for AD [1361]. See also the review [1362].

A lower prevalence of probable AD in a cohort ofpatients taking lovastatin or pravastatin between 60and 73% (p < 0.001) lower than the total patient popu-lation or compared with patients taking other medica-tions typically used for the treatment of hypertension orcardiovascular disease was found [1363–1367]. Excel-lent reviews were provided [1368–1375]. The linkbetween altered cholesterol metabolism and AD wasdescribed [1376]. Statins, risk of dementia, and cogni-tive function were discussed [1377].

Statins can shift A�PP processing to the non-amyloidogenic �-secretase pathway, e.g., simvastatin,which in addition prevented neuroinflammation andoxidative stress [1378, 1379], atorvastatin, which inaddition prevented neuroinflammation [1380, 1381]and lovastatin, which in addition stimulated the upreg-ulation of �7 nicotinic acetylcholine receptors [1382,1383]. A�40 blocked cerebral perivascular sympa-thetic �7-nAChRs, which was prevented by statinssuch as mevastatin and lovastatin [1384, 1385].

Pitavastatin attenuated celecoxib- and streptozotocin-induced experimental dementia [1386]. Atovastatinand pitavastatin reduced senile plaque and phospho-rylated tau in aged A�PP mice [1387, 1388].

These promising biological results in experimentalanimals were not confirmed in extensive clinical trials.Only a slight reduction of cognitive decline in a largestudy including 3,334 participants was found [1389].A post hoc analysis from three double-blind, placebo-controlled, clinical trials of galantamine in patientswith AD was done [1390]. Patients were divided intofour treatment groups, statin plus galantamine (n = 42),statin alone (n = 50), galantamine alone (n = 614),and placebo (n = 619). Galantamine was associatedwith a significant beneficial effect on cognitive sta-tus (p < 0.001). The use of statins did not produce asignificant beneficial effect (p = 0.083).

A proof-of-concept randomized controlled trial ofAtorvastatin (Lipitor, Pfizer, launched in 1996) indi-cated a trend for symptomatic benefit in mild tomoderate AD patients [1391–1393]. But the largeLEAD (Lipitor’s effect in Alzheimer’s Dementia)study in 640 patients, who were randomized to atorvas-tatin 80 mg/day or placebo for 72 weeks followed bya double-blind, 8-week atorvastatin withdrawal phasedid not show a significant benefit for cognition asmeasured by ADAS-cog (p = 0.26) or for global func-tion as measured by ADCS-Clinical Global Impressionof Change (p = 0.73) compared with placebo [1394,1395]).

Pravastatin (Pravachol, Mevalotin; DaiichiSankyo, launched in 1989) was evaluated in PROS-PER (Prospective Study of Pravastatin in the Elderlyat Risk) in 5,804 participants at six different timepoints. No difference in cognitive decline was foundin patients treated with pravastatin compared toplacebo (p > 0.05). During a three year follow-upperiod no effect on cognitive decline was observed[1396].

Simvastatin (Zocor, MK-0733; Merck launchedin 1989) was evaluated in a 406 patient Phase IIIstudy conducted by the National Institute of Aging.Patients were treated with 20 mg simvastatin per dayfor six weeks and with 40 mg/day simvastatin foran additional 18 months. Simvastatin lowered lipidlevels, but had no effect on change of ADAS-cogscore or on secondary outcome measures [1397–1403].Chronic simvastatin treatment rescued cognitive func-tion in a transgenic mouse model of AD and enhancedLTP in the CA1 region of the hippocampus in slicesfrom C57BL/56 mice via inhibition of farnesylation[1404–1406].


Fig. 19. One HMG-CoA-reductase, 7 kinase and one kynurenine aminotransferase II inhibitor(s).

NST-0037 (Neuron BioPharma; Fig. 19) is a nat-ural small molecule HMG-CoA-reductase inhibitor,which also has neuroprotective, antioxidant, andanti-convulsive activity. The synthesis was described

[1407]. Potential follow-up compounds are NST-0005and NST-0060, whereas the development of NST-0021was terminated (Thomson Reuters Pharma, update ofJune 13, 2012).


2.22. Drugs interacting with insulin-degradingenzyme

The role of insulin-degrading enzyme in AD wasdiscussed [1408, 1409]. The expression and functionalprofiling of insulin-degrading enzyme in elderly andAD patients was reported [1410] as was the character-ization in human serum [1411].

The company Inventram is investigating insulin-degrading enzyme activators for the potential treatmentof type 2 diabetes and AD (Thomson Reuters Pharma,update of April 20, 2012). No structures were commu-nicated.

2.23. Drugs interacting with Kinases ( /= GSK-3β

and /= PKC)

Advances in the development of kinase inhibitortherapeutics for AD were presented [1412]. Note-worthy is that acetyl-L-carnitine (ST-200, Nicetile,Zibren; launched by Sigma-Tau in Italy in 1985 andin South Korea in 1995 as a memory enhancer) ame-liorated spatial memory deficits induced by inhibitionof phosphoinositol-3-kinase and PKC [1413]. Alsoclioquinol seems to operate in a similar way [1414].

Masitinib (AB-1010, AB Science; Fig. 19) is aninhibitor of c-kit, Lyn and PDGF-R kinases. It wasevaluated in a Phase II clinical trial as an adjuncttherapy to cholinesterase inhibitor and/or memantinein 26 patients with mild-to-moderate AD versusplacebo (n = 8). The masitinib treated patients showedimprovements in MMSE scores, the ADAS-Cog andthe Alzheimer’s Disease Cooperative Study Activitiesof Daily Living Inventory with statistical significancebetween treatment arms at week 12 and/or week24 (p = 0.016 and 0.030, respectively) [1415]. InSeptember 2010, EMA approved a pivotal Phase IIItrial in 300 AD patients to assess safety and efficacy of6 mg/kg/day masitinib over 24 weeks. The biologicalcharacterization was described [1416] (ThomsonReuters Pharma, update of August 10, 2012). Numer-ous other kinase inhibitor therapeutics are currentlyin preclinical evaluation (in alphabetical order):

AIK-2, AIK-2a, AIK-2c, and AIK-21 (AllinkyBiopharma) are non-ATP-competitive MAP kinaseinhibitors for the potential treatment of cerebrovascu-lar stroke and AD (Thomson Reuters Pharma, updateof October 28, 2011). The structures were not commu-nicated.

Beta carboline alkaloids (Translational GenomicsResearch Institute) including harmol (Fig. 19) inhibitdual specificity tyrosine phosphorylation regulated

kinase 1A (DYRK1A) and tau phosphorylation(IC50 = 90 nM). (Thomson Reuters Pharma, update ofJune 8, 2012).

Cadeprin (group S8A serine protease) antagonistsare investigated by researchers from the Universitiesof Strathclyde and Glasgow [1417] (Thomson ReutersPharma, update of May 3, 2012).

Casein kinase 1δ inhibitors (Proteome Sciences),such as PS-110 and PS-278, are investigated for thepotential treatment of AD. (Thomson Reuters Pharma,update of July 2, 2012). Structures were not commu-nicated.

CDK5/p25 inhibitors (Pfizer) are investigated forthe potential treatment of AD. A novel pyrrolo[3,2-b]pyridine derivative (Fig. 19) displayed low nMpotency. (Thomson Reuters Pharma, update of April14, 2011).

CZC-25146 (GSK, following its acquisition ofCellzome) is leucine-rich repeat kinase 2 (LRRK2)inhibitor for the potential treatment of Parkinson’s dis-ease. [1418] (Thomson Reuters Pharma, update of June1, 2012).

Dasatinib (Bristol-Myers Squibb, launched 2006), aSrc tyrosine kinase inhibitor, attenuated A� associatedmicrogliosis in a murine model of AD [1419].

DYRK-1 alpha protein kinase inhibitors (ArrienPharmaceuticals) are evaluated for the potentialtreatment of Alzheimer’s disease and Down syndrome.(Thomson Reuters Pharma, update of April 24, 2012).Structures were not communicated.

DYRK-1 alpha protein kinase inhibitors (CarnaBiosciences) is a program in the stage of lead optimiza-tion. (Thomson Reuters Pharma, update of March 16,2012). Structures were not communicated.

FRAX-120, FRAX-355, and FRAX-486 (Afraxis)showed IC50 values of 23, 58, and 14 nM for p21-activated kinase. The drugs have a potential for thetreatment of fragile X syndrome, autism, schizophre-nia, and AD (Thomson Reuters Pharma, update ofAugust 14, 2012). Structures were not communicated.

G-2019S (Zenobia Pharmaceuticals in collabora-tion with Johns Hopkins University) is a LRRK2inhibitor for the potential treatment of Parkinson’s dis-ease (Thomson Reuters Pharma, update of March 13,2012). The structure was not communicated.

Hydroxy-fasudil (Fig. 19, Asahi Kasei PharmaCorp.), a rho kinase (ROCK) inhibitor, improvedspatial learning and working memory in rats ina water radial-arm maze [1420]. ROCK inhibitionled to an increase of Rac1 activity and to anactivation of PKCζ which in turn phosphorylatedKIBRA involved in the formation of memory [1421].


ROCK inhibition prevented tau hyperphosphorylation[1422].

KIBRA pathway modulators (Amnestix Inc., awholly owned subsidiary of SYGNIS Pharma) offer anew genetic link to cognition that may benefit patientssuffering from AD. For the association of KIBRA andlate onset AD, see [1423], for enhancement of cog-nition in anxiety disorders [1424] (Thomson ReutersPharma, update of August 14, 2012).

LDN-22684 (Sirtris Pharmaceuticals) is a LRRK2inhibitor for the potential treatment of Parkinson’s dis-ease [1425] (Thomson Reuters Pharma, update of June17, 2011). The structure was not communicated.

LRRK2 inhibitors (Arrien Pharmaceuticals) areinvestigated for the potential oral treatment ofParkinson’s disease (Thomson Reuters Pharma,update of May 18, 2012). The structures were notcommunicated.

LRRK2 inhibitors (Genentech, Fig. 19) are inves-tigated for the potential treatment of Parkinson’sdisease. The medicinal chemistry was described[1426]. (Thomson Reuters Pharma, update of June 26,2012). The lead structure was communicated.

LRRK2 inhibitors (Genosco, Oscotec Inc.) areinvestigated for the potential treatment of Parkinson’sdisease (Thomson Reuters Pharma, update of April 20,2012). The structures were not communicated.

LRRK2 inhibitors (Oncodesign Biotechnology)are investigated for the potential treatment of cancerand CNS diseases including Parkinson’s disease(Thomson Reuters Pharma, update of April 2, 2012).The structures were not communicated.

LRRK2 inhibitors (Origenis GmbH) are investi-gated for the potential treatment of Parkinson’s disease(Thomson Reuters Pharma, update of May 11, 2012).The structures were not communicated.

LRRK2 inhibitors (Pfizer) are investigated for thepotential treatment of Parkinson’s disease (ThomsonReuters Pharma, update of June 20, 2012). The struc-tures were not communicated.

LRRK2 inhibitors (Vernalis/Lundbeck) are inves-tigated for the potential treatment of Parkinson’sdisease (Thomson Reuters Pharma, update of May 02,2012). The structures were not communicated.

MARK inhibitors (microtubule affinity regulat-ing kinase; Medical Research Council Technology,MRCT) are investigated for the inhibition of tau phos-phorylation (Thomson Reuters Pharma, update of June1, 2012).

MARK3 inhibitors (microtubule affinity regulat-ing kinase 3, CDC25-associated kinase-1; Merck) arein preclinical evaluation for the potential treatment of

AD. The pyrazolo[1,5-a]pyridine compound (Fig. 19)showed t1/2’s in rat, dog, and Rhesus monkey of 3.5,2.3, and 1.4 hours, respectively (Thomson ReutersPharma, update of April 14, 2011).

Minokine (MW01-2-069A-SRM; NorthwesternUniversity; Fig. 19) is a p38 MAP kinase inhibitor forthe potential oral treatment of neurodegenerative dis-eases including AD (Thomson Reuters Pharma, updateof April 27, 2011).

NNI-351 (NNI-depression, NNI-DS, Neu-roNascent; Fig. 19) is an orally active compoundpreventing stress-induced neurogenesis reductionvia inhibition of dual specificity tyrosine-phosphorylation-regulated kinase 1 alpha (DYRK-1�)protein (Thomson Reuters Pharma, update of March22, 2012).

P-005 (NB Health Laboratory) is a small moleculehighly selective kinase inhibitor for the potential treat-ment of AD (Thomson Reuters Pharma, update ofDecember 23, 2011). The structure was not commu-nicated.

Protein kinase inhibitors (ManRos Therapeutics)are evaluated as AD medication (Thomson ReutersPharma, update of February 24, 2011). The structureswere not communicated.

SEL-103 (Selvita Life Sciences Solutions) is a pro-gram in collaboration with Orion Corporation, EspooFinland, to investigate novel, orally bioavailable andhighly selective small molecules for the potentialtreatment of multiple cognitive disorders includingAD (Thomson Reuters Pharma, update of July 4,2012).

SEL-141 (Selvita Life Sciences Solutions) is a pro-gram targeting kinases involved in tau phosphorylationfor the potential treatment of AD, Down syndrome, andcognitive disorders. Focus is on DYRK1A (ThomsonReuters Pharma, update of July 4, 2012). Structureswere not communicated.

Sorafenib, a small molecular inhibitor of tyro-sine protein kinases (VEGFR and PDGFR) and ofraf restored working memory in A�PPSWE transgenicmice [1427].

TTT-3002 (TauTaTis) is a multi-targeted kinaseinhibitor that can inhibit the LRRK2 gene and tumorgrowth for the potential treatment of Parkinson’s dis-ease, AD, and cancer. (Thomson Reuters Pharma,update of January 25, 2012). The structure was notcommunicated.

URMC-099-C (Califia, the University of NebraskaMedical Center and the University of Rochester) is aninhibitor of mixed lineage kinase-3 for the treatmentof HIV-associated neurocognitive disorder (Thomson


Reuters Pharma, update of June 5, 2012). The structurewas not communicated.

Inhibitors of the protein kinase c-raf1, such as GW-5074 and ZM-336372, protected cortical cells againstA� toxicity [1428].

The development of AIKb2 (Allinky Biopharma;a MAP kinase inhibitor), BA-1001 (BioAxone; arho kinase inhibitor [1429]), GW-5074 (GSK, a c-raf1 inhibitor), ORS-1006 (Arrien Pharmaceuticals, aLRRK2 inhibitor), Pan-MLK inhibitors (Cephalon,now Teva), PLX-3397 (Plexxikon, a subsidiary of Dai-ichi Sankyo; an oral small-molecule dual Fms/kit andFlt3-ITD inhibitor; a Phase II trial for the treatmentof acute myelogenous leukemia continues), RS-4073(Daiichi Sankyo; a potentiator of TrkA and Mapkinase activation), SB-203580 (SmithKline Beecham,now GSK; a protein kinase and cytokine suppressionbinding protein (CSBP)/p38 inhibitor [1430], SCIO-323 (Scios, a p38 kinase inhibitor), SRN-003-556(SIRENADE Pharmaceuticals; an ERK2 inhibitor),and of ZK-808762 (University of Gottingen; aserine protease and Factor Xa inhibitor) wasterminated.

2.24. Drugs interacting with kynureninemono-oxygenase and kynureninetransaminase II

The kynurenine metabolism in AD was described[1431]. Reduction of kynurenic acid formationenhanced hippocampal plasticity and cognitivebehavior [1432]. Crystal structure-based selective tar-geting of kynurenine aminotransferase II for cognitiveenhancement was discussed [1433].

CHDI-003940246 and CHDI-00340246 (Evotec incollaboration with the CHDI Foundation) are kynure-nine mono-oxygenase inhibitors for the potentialtreatment of Huntington’s disease (Thomson ReutersPharma, update of January 10, 2012). The structureswere not communicated.

PF-04859989 (Pfizer, Fig. 19) is an inhibitor ofkynurenine (oxoglutarate) aminotransferase II for thepotential treatment of schizophrenia [1434] (ThomsonReuters Pharma, update of March 21, 2012).

2.25. Drugs interacting with 5-lipoxygenase

The enzyme 5-lipoxygenase (5-LO) catalyzes theconversion of arachidonic acid to 5-hydroxy-peroxy-eicosatetraenoic acid (5-HPETE) and subsequentlyto 5-hydroxy-eicosatetraenoic acid (5-HETE), whichare metabolized to different leukotrienes [1435]. The

group of Domenico Pratico found that A� depositionin brains of Tg2576 mice lacking 5-LO was reducedby 64 to 80%, suggesting that pharmacological inhibi-tion of 5-LO could provide a novel therapy for AD[1436]. Additional investigations showed that 5-LOregulated the formation of A� by activating the cAMP-response element binding protein (CREB), which inturn increased transcription of the �-secretase complex[1437, 1438].

In a Letter to the Editor of Annals of Neurology,Kenji Hashimoto [1439] suggested to test minocy-cline, which protected PC12 cells against NMDA-induced injury via inhibiting 5-lipoxygenase activation[1440].

Minocycline (Wyeth, now Pfizer and Takedalaunched in 1999) is a second generation tetracy-cline that effectively crosses the blood brain barrier.It improved cognitive impairment in AD models[1441]. It provided protection against A�25-35 inducedalterations of the somatostatin signaling pathway[1442, 1443]. It reduced microglial activation [1444,1445] and A�-derived neuroinflammation [1446].It recovered MTT-formazan exocytosis impaired byA� [1447]. Minocycline inhibited �-secretase-1 ina transgenic model of AD-like amyloid pathology[1448]. It reduced the development of abnormal tauspecies in models of AD [1449–1451]. Minocyclineimproved negative symptoms in patients with earlyschizophrenia [1452].

A new class of 5-lipoxygenase inhibitors was com-municated recently [1453].

2.26. Drugs interacting with monoamine oxidase

Recent efforts of medicinal chemists to exploreligands targeting MOAs were reviewed [1454]. Apatent-related survey on new MOA inhibitors was pub-lished [1455]. The changes of MAO A and B in ADwere elucidated [1456] as was the platelet MAO Bactivity in dementia [1457].

Ladostigil (TV-3326; Avraham Pharmaceuticalsunder license from Yissum Research Development, awholly owned company of the Hebrew University ofJerusalem; see Fig. 8) is a dual acetylcholine esteraseand MAO inhibitor currently in Phase II clinical tri-als in 190 patients in Europe since December 2010(Thomson Reuters Pharma, update of May 18, 2012).See section 2.1.1.9. Dual AChE and MAO inhibitors.

RG-1577 (RO-4602522; EVT-302; Roche underlicense from Evotec) is an orally active, selective,and reversible MAO-B inhibitor. The company wasplanning to start a Phase II trial in patients with AD


in the second half of 2012 (Thomson Reuters Pharma,update of August 8, 2012). Its structure was notcommunicated.

OG-45 (Oryzon Genomics) is a dual MAO-Binhibitor and lysine specific demethylase-1 inhibitor.(Thomson Reuters Pharma, update of April 16, 2012).Its structure was not communicated.

VAR-10200 (HLA-20; Varinel; Fig. 20) is a dualiron-chelating agent and MAO-B inhibitor for thepotential treatment of age-related macular degener-ation [1458] (Thomson Reuters Pharma, update ofFebruary 24, 2012).

VAR-10300 (M-30; Varinel, Technion and theWeizmann Institute of Science; Fig. 20) combinesthe iron-chelating properties of 8-hydroxy-quinolinewith the MAO inhibitor moiety of rasaglinine [470,1459–1465] (Thomson Reuters Pharma, update of May15, 2012).

Rasagiline (TVP-1012; (R)-enantiomer; Azilect;marketed by Teva and Lundbeck; Fig. 20) proved to bea very valuable drug for the treatment of Parkinson’sdisease with sales in 2011 of USD 290 million reportedby Teva and USD 221 million reported by Lundbeck.Rasagiline was extensively characterized (in chrono-logical order) [1466–1478]. The effects of rasagiline oncognitive deficits in cognitively-impaired Parkinson’sdisease patients were evaluated [1479]. A�PP process-ing properties of rasagiline were described [1480].Rasagiline improved learning and memory in younghealthy rats [1481]. In July 2004 Eisai initiated PhaseII clinical trials in the US for the treatment of AD, lateralso in combination with donepezil. In March 2008development for the indication AD was discontinued(Thomson Reuters Pharma, update August 29, 2012).

Safinamide (FCE-26743; NM-1015, PNU-151774E; Zambon under license from Newron, whoacquired the rights from Pharmacia and Upjohn,now Pfizer; Fig. 20) is a potent MAO B inhibitor(IC50 = 98 nM; MAO A: IC50 = 580 �M, selectivityindex: 5,918 for the potential treatment of Parkinson’sdisease and AD [1482]. The first synthesis wasdescribed in 1998 [1483] followed by the solid-phasesynthesis [1482]. The enantiomeric separation ofsafinamide was disclosed [1484]. The biologicalcharacterization was described in detail [1485–1487].Several reviews were published [1488–1490]. PhaseIII trials in early Parkinson’s disease patients beganin June 2004. An expert opinion on safinamide inParkinson’s disease was published [1491]. A PhaseIII trial in AD patients was abandoned in late 2007(Thomson Reuters Pharma, update of August 21,2012).

The development of many other MAO inhibitorsfor the indication AD was terminated, of bifemelane(MCI-2016; SON-216; Sosei under license from Mit-subishi [1492, 1493]), EVT-301 (Evotec under licensefrom Roche), EXP-631 (Bristol-Myers Squibb),4-fluoroselegiline (Chinoin, now sanofi), HT-1067(Helicon Therapeutics), indantadol (Vernalis underlicense from Chiesi), lazabemide (Ro 19-6327; Roche[1494–1496]), milacemide (GD Searle, now Pfizer[1497–1499]), NW-1772 (Newron Pharmaceuticals),PF-9601N (University of Autonoma de Barcelona),Ro-41-1049 (Roche), SL-25.1188 and SL-34.0026(both sanofi) and of YY-125 (Yuyu Inc.).

2.27. Drugs modulating O-linkedN-acetylglucosaminidase (O-GlcNAcase;OGA)

O-GlcNAcase is the enzyme that plays a role inthe removal of N-acetylglucosamine groups from ser-ine and threonine residues in both the nucleus andthe cytoplasm of cells [1500, 1501]. O-GlcNAcasemay compete with phosphorylation of the same ser-ine or threonine residues. Studies to elucidate thebinding mode were carried out by [1502, 1503].O-GlcNAcylation directly regulates core componentsof the pluripotency network [1504].

Alectos Therapeutics/Merck are investigatingO-GlcNAcase modulators (Thomson Reuters Pharmaupdates of July 5, 2012).

GlcNAcstatin (University of Dundee in collabo-ration with Aquapharm Biodiscovery; Fig. 20) is amarine natural product for the potential treatment ofAD [1505, 1506]. For an efficient and versatile synthe-sis of GlcNAcstatin derivatives, see [1507] (ThomsonReuters Pharma, update of January 23, 2012).

NButGT (Seoul National University; Fig. 20),a specific inhibitor of O-GlcNAcase, reduced A�production by lowering �-secretase activity both invitro and in vivo. O-GlcNAcylation takes place at theS708 residue of nicastrin, a component of �-secretase[1508] = [5]. The synthesis was described by chemistsof the Simon Fraser University [6].

SEG-4 (Summit Corporation) inhibited OGA withIC50 and Ki values of 10 and 72 nM, respectively. Thecompound significantly reduced tau phosphorylation(Thomson Reuters Pharma, update of August 2, 2012).The structure was not communicated.

Thiamet-G (Simon Fraser University) is apotent inhibitor of human O-GlcNAcase (Ki = 21 nM;Fig. 20) and efficiently reduced phosphorylation oftau at Thr231, Ser396, and Ser422 in both rat cor-


Fig. 20. Four monoamine oxidase and three O-linked N-acetylglucosaminidase inhibitors.

tex and hippocampus [1509–1512]. For commentariessee [1513, 1514]. Acute thiamet G treatment led toa decrease in tau phosphorylation at Thr181, Thr212,Ser214, Ser262/Ser356, Ser404, and Ser409 and anincrease in tau phosphorylation at Ser199, Ser202,Ser396, and Ser422 in mouse brain, probably via stim-ulation of GSK-3� activity [1515].

2.28. Drugs interacting with peptidyl-prolylcis-trans isomerase D

Peptidyl-prolyl cis-trans isomerase D or CyclophilinD (Cyp D; EC 5.2.1.8. Isomerase) is implicated in celldeath pathways. Blockade of Cyp D could be a potenttherapeutic strategy for degenerative disorders such asAD, ischemia, and multiple sclerosis [1516]. SolubleA� is also found in mitochondria, where it interactswith Cyp D, a component of the mitochondrial per-meability transition pore. Interference with the normalfunctions of this protein resulted in disruption of cellhomeostasis and ultimately cell death [1517].

The Hsp90-associated cis-trans peptidyl-prolylisomerase-FK506 binding protein 51 (FKBP51) wasrecently found to co-localize with the microtubule-associated protein tau in neurons and physically

interact with tau in brain tissues from humans, whodied from AD [1518].

PIN1 is a peptidyl-prolyl isomerase, which catalyzescis-trans isomerization of peptide bonds N-terminalto specific phospho-serine/threonine-proline motifs.PIN1 isomerizes phosphorylated tau and thus restoresthe ability of phosphorylated tau to bind microtubules,and eventually promote dephosphorylation of tau byPP2A phosphatase [1519].

Scynexis is investigating a series of Cyp D inhibitorsfor the potential treatment of muscle injury, ischemia,reperfusion injury, trauma, and neurodegenerative dis-ease (Thomson Reuters Pharma, update of June 28,2011).

2.29. Drugs interacting with phosphodiesterases

Several excellent reviews on PDE inhibition andcognition enhancement were published [1520–1524].Based on the expression of PDE mRNA in thehuman brain, it was suggested that PDE1 and PDE10inhibitors are strong candidates for the developmentof cognition enhancers. Chronic PDE type 2 inhi-bition with BAY60-7550 improved memory in theA�PPswe/PS1dE9 mouse model of AD [1525]. The


medicinal chemistry of PDE4D allosteric modulators[1526], of PDE4 inhibitors [1527], of PDE5 inhibitors[1528, 1529], and of PDE10A inhibitors was reviewed[1530, 1531].

Etazolate (EHT-202; SQ-20009; Exonhit; seeFig. 10) is an orally active PDE4 inhibitor and anxi-olytic GABAA receptor modulator, which shifts A�PPprocessing toward the �-secretase pathway [503, 504,1532–1536]. The results of the first Phase II 3-month,randomized, placebo-controlled, double-blind study inAD patients was reported [505] (Thomson ReutersPharma, update of September 13, 2011). See also sec-tion 2.2. Drugs interacting with �-secretase.

PF-02545920 (MP-10; Pfizer; Fig. 21) is a PDE10Ainhibitor in a randomized, double-blind, placebo-controlled Phase II clinical trial in patients withacute schizophrenia (n = 260) since October 2010.PF-02545920 is also evaluated for the treatment ofHuntington’s disease [1531, 1537–1540]. (ThomsonReuters Pharma, update of July 19, 2012).

Lu-AF11167 (Lundbeck) is an inhibitor of a brain-expressed PDE enzyme for the potential treatment ofAD, Huntington’s chorea, and schizophrenia in a PhaseI clinical trial since March 2011 (Thomson ReutersPharma, update of August 8, 2012). The structure wasnot communicated.

There are several PDE inhibitors in preclinical eval-uation (in alphabetical order):

AMG-7980 (Amgen, Fig. 21) is a novel PDE10Ainhibitor with a Ki of 0.94 nM useful as tritiatedligand to measure PDE10A target occupancy in ratbrain [1541, 1542].

AVE-8112 (Aventis, now sanofi and Michael J.Fox Foundation) is a PDE4 inhibitor for the poten-tial treatment of Parkinson’s disease. In April 2012,a US Phase Ib study was planned (Thomson ReutersPharma, update of May 30, 2012). The structure wasnot communicated.

BCA-909 (BCR-909; Boehringer Ingelheim underlicense from biocrea GmbH) is a PDE2 inhibitor forthe potential treatment of mild cognitive impairmentin schizophrenia and AD (Thomson Reuters Pharma,update of May 30, 2012). The structure was notcommunicated.

Cilostazol (Otsuka), a selective PDE3 inhibitor, pro-tected against A�1-40-induced suppression of viabilityand neurite elongation [1543].

Dual PDE10/PDE 2 inhibitors (biocrea GmbH)are investigated for the potential treatment ofschizophrenia and AD (Thomson Reuters Pharma,update of January 18, 2012). Structures were notcommunicated.

GEBR-7b (University of Genoa; Fig. 21) is a novelPDE4D selective inhibitor that improves memory inrodents at non-emetic doses [1544] (Thomson ReutersPharma, update of December 21, 2011).

ITI-002A, IC-200214, and ITI-214 (Takedaunder license of Intra-Cellular Therapies) are PDE1inhibitors for the potential oral treatment of cogni-tive disorders associated with schizophrenia (ThomsonReuters Pharma, update of July 30, 2012). The struc-tures were not communicated.

OMS-182410 (Omeros) is a PDE10 inhibitor forthe potential treatment of schizophrenia (ThomsonReuters Pharma, update of July 19, 2012). The struc-ture was not communicated.

PDE2A inhibitor (Pfizer, Fig. 21) is evaluated forthe potential treatment of cognitive impairment asso-ciated with schizophrenia. In March 2012, a PDE2Ainhibitor with an IC50 of 4 nM was presented at the243rd ACS Meeting in San Diego (Thomson ReutersPharma, update of August 24, 2012).

Allosteric PDE4 inhibitors (Tetra Discovery Part-ners; West Virginia University) are evaluated forthe potential treatment of mild cognitive impairment(Thomson Reuters Pharma, update of July 5, 2012).Structures were not communicated.

PDE7 inhibitors (Omeros) are a potential newtreatment of Parkinson’s disease (Thomson ReutersPharma, update of May 23, 2012). The structures werenot communicated.

A PDE9 inhibitor (Pfizer; Fig. 21) for the potentialtreatment of AD was found to penetrate mouse brainand had a half-life of 6.8 hour in dog (Thomson ReutersPharma, update of April 14, 2011).

A PDE10 inhibitor (biocrea, a spin-out from BioTieTherapeutics following its acquisition of elbion,Fig. 21) is investigated for the potential treatmentof Huntington’s disease. (Thomson Reuters Pharma,update of May 29, 2012).

18F-PF-0430 (Pfizer, Fig. 21) is a PDE2-selectiveCNS PET ligand for the potential diagnosis ofAlzheimer’s disease. (Thomson Reuters Pharma,update of October 03, 2012).

PF-999 (Pfizer, Fig. 21) is a PDE2A inhibitor for thepotential treatment of cognitive impairment associatedwith schizophrenia. (Thomson Reuters Pharma, updateof September 6, 2012).

Sildenafil (Pfizer, launched as Viagra in 1998) andTadalafil (Lilly launched as Cialis in 2003), potentPDE5 inhibitors, restored cognitive function withoutaffecting A� burden in a mouse model of AD. Tadalafilreversed cognitive dysfunction in a mouse model of AD[1545, 1546].


Fig. 21. Ten phosphodiesterase inhibitors and a phospholipase A2 inhibitor.

THPP-1 (Merck, Fig. 21) is a potent, orally bioavail-able PDE10A inhibitor, which improved episodic-likememory in rats and executive function in Rhesus mon-keys [1547].

VP1.15 (CSIC Madrid and University of Toronto,Fig. 18) is a dual GSK-3 and PDE7 inhibitor acting as

an antipsychotic and cognitive enhancer in C57BL/6Jmice [1276, 1277].

The development of many PDE inhibitors wasterminated, of D-159687 and DG-071 (deCODEgenetics, now DGI Resolution), denbufylline (BRL-30892; SmithKline Beecham, now GSK [1548]),


HT-0712 (IPL-455903; Helicon under license fromOrexo; a PDE4 inhibitor, Fig. 21 [1549, 1550]), IC-041(Intra-Cellular Therapies), KS-505a (Kyowa HakkoKirin), of MEM-1018, MEM-1091, MEM-1414(R-1533) and MEM-1917 (Memory Pharmaceu-ticals, now Roche), MK-0952 (Merck, a selectivePDE4 inhibitor [1551]), NVP-ABE171 (Novartis[1552–1554]), PF-4181366 and PF-04447943 (Pfizer;a PDE9A inhibitor [1555, 1556]), PQ-10 (Pfizer),propentofylline (HWA 285; Hoechst Werke Albert,now sanofi [1327–1329, 1331, 1332, 1557, 1558]),R-1627 (Roche), rolipram (Meiji Seika under licensefrom Bayer Schering Pharma [1521, 1559–1566]),V-11294A (Napp Pharmaceutical Group) andYF-012403 (Columbia University, a PDE5 inhibitor).

2.30. Drugs interacting with Phospholipase A2and D2

Phospholipase A2 reduction ameliorated cognitivedeficits in a mouse model of AD [1567–1569]. Thesefindings were confirmed by genetic phospholipase A2and D2 ablation studies [1570–1572].

Rilapladib (SB-659032; GSK using a technol-ogy licensed from Human Genome Science; Fig. 21)is a lipoprotein-associated phospholipase A2 (LP-PLA2) inhibitor for the potential oral treatment ofatherosclerosis and AD. In October 2011 a random-ized, double-blind, placebo-controlled Phase II studywas initiated in 120 AD patients with evidence ofcardiovascular disease in Europe. The study was sched-uled to complete in November 2012 (Thomson ReutersPharma, update of June 26, 2012).

Icosapent ethyl (AMR-101, SC-111, LAX-101;MND-21; Epadel; ethyl-eicosapentaenoic acid;Mochida Pharmaceutical and Amarin under licensefrom Scotia Holdings), a phospholipase A2 inhibitor,was launched in Japan for the treatment of arte-riosclerosis obliterans. The drug was in Phase IIaclinical trials for the treatment of AD by Mochida,which were completed in May 2007 and in Phase IIaclinical trials for the treatment of memory disordersin age-associated memory impairment in the UK byAmarin, which started in May 2008. By 2011 thedevelopment for age-associated memory impairmentwas discontinued (Thomson Reuters Pharma, updateof August 29, 2012).

2.31. Drugs interacting with plasminogenactivator inhibitor (PAI)

PAI-1 (serpin E1) is a serine protease inhibitorthat functions as the principal inhibitor of tissue

plasminogen activator (tPA) and urokinase, the acti-vators of plasminogen and hence fibrinolysis [1573].Elevated serum PA1-1 was associated with a highrisk for cognitive dysfunction [1574]. PAI-1 promotedsynaptogenesis and protected against A�1-42-inducedneurotoxicity [7]. PAI-1 was also related to lowerspeed and visuomotor coordination in elderly subjects[1575]. PAI-1 may be a useful marker for vasculardementia [1576]. The plasmin system of AD patientswas discussed [1577].

IMD-4482 (Institute of Medicinal MolecularDesign, IMMD) is an inhibitor of PAI-1 for the poten-tial treatment of fibrotic diseases. The indication ADis no longer followed up (Thomson Reuters Pharma,update of January 19, 2012).

The development of the PAI aleplasinin (PAZ-417;Wyeth, now Pfizer) was terminated.

2.32. Drugs interacting with poly ADP-ribosepolymerase (PARP)

Cognitive impairment can be prevented by PARP-1 inhibitors administered after hypoglycemia [1578,1579]. Cognitive and motor deficits were reduced inmice deficient in PARP-1 [1580].

E-7016 (Eisai following the acquisition of MGIPharma, formerly Guilford; presumed to be GPI-21016under license from Johns Hopkins University, Fig. 22)is an orally active, brain-penetrable, PARP PAR syn-thase inhibitor currently in Phase II clinical trialsfor the treatment of stage III/IV melanoma patients[1581]. The indications AD and stroke were abandoned(Thomson Reuters Pharma, update of June 15,2012).

MP-124 (Mitsubishi Tanabe Pharma) in a PARPinhibitor for the potential treatment of acute ischemicstroke in Phase I clinical trials since December 2008(Thomson Reuters Pharma, update of February 04,2011). The structure was not communicated.

AL-309 (Allon Therapeutics), a peptide, is a neu-roprotective agent and PARP stimulator in preclinicalstudies (Thomson Reuters Pharma, update of May 9,2012).

2.33. Drugs interacting with prolyl endo peptidase

Several reviews on prolyl endo peptidase, alsoknown as prolyl oligopeptidase, as a potential targetfor the treatment of cognitive disorders were published[1582–1584]. Sustained efforts over many years havegone into the discovery and characterization of potentprolyl endopeptidase inhibitors for the treatment of


memory disorders [1585]. Potent prolyl endopeptidaseinhibitors, such as KYP-2047 and JTP-4819, did notincrease striatal dopamine, acetylcholine, neurotensinand substance P levels [1586–1588].

Subchronic administration of rosmarinic acid, anatural prolyl oligopeptidase inhibitor, enhanced cog-nitive performances [1589].

The development of many prolyl endopeptidaseinhibitors was terminated, of eurystatin A (Bristol-Myers Squibb [1590–1593]), JTP-4819 (JapanTobacco [1594–1597]), KYP-2047 (Univ. of Kuopioand Finncovery [1598]), ONO-1603 (Ono Pharmaceu-ticals [1599, 1600]), S-17092 (Servier [1601–1605])and S-19825 (Servier [1606]), SUAM-1221 (Chinoinand sanofi [1598, 1607–1610]), Y-29794 (Yoshit-omi, now Mitsubishi Pharma Corp. [1611, 1612]),Z-321 (Zeria Pharmaceutical [1613–1615]) and ZTTA[1616].

2.34. Drugs interacting with prostaglandin D & Esynthases

Reviews on the biochemical, structural, genetic,physiological, and patho-physiological features oflipocalin-type prostaglandin D synthase were dis-closed [1617, 1618]. The three prostaglandin Esynthases were described [1619] as was prostaglandinE2 synthase inhibition as a therapeutic target [1620]and the COX-1 mediated prostaglandin E2 elevationand contextual memory impairment [1621]. Deletionof microsomal prostaglandin E synthase-1 protectedneuronal cells from the cytotoxic effects of A�[1622].

HF-0220 (7-beta-hydroxy-epiandrosterone; New-ron Pharmaceuticals; Fig. 22) is a cytoprotectivesteroid, which stimulated prostaglandin D synthasefor the potential treatment of AD. A Phase IIa mul-ticenter, double-blind, placebo-controlled, biomarkertrial (NCT00357357) in AD patients was initiated inApril 2007. The randomized, double-blind, placebo-controlled pilot study enrolled 42 patients in the UK,Sweden, and India. Subjects received 1 to 220 mg/dayof the drug and were allowed to continue with theircurrent AD treatment. Results were reported in Octo-ber 2008. HF-0220 was well tolerated at all doses(Thomson Reuters Pharma, update of August 21,2012).

AAD-2004 (GNT Pharma, formerly Neurotech andUS subsidiary AmKor, Fig. 22) is a prostaglandin Esynthase-1 inhibitor for the treatment of AD, Parkin-son’s disease, and amyotrophic lateral sclerosis. APhase I study was initiated in April 2010. By December

2011, the Phase Ia single ascending dose trial had beensuccessfully completed. In April 2012, it was reportedthat a Phase Ib multiple ascending-dose trial to eval-uate safety and biomarker profiles was planned forthat year (Thomson Reuters Pharma, update of May 4,2012).

The development of an analogue of AAD-2004, i.e.,NG-2006 (GNT Pharma) was terminated.

2.35. Drugs interacting with protein kinase C

Activation of PKC� prevents synaptic loss, A� ele-vation, and cognitive deficits in AD transgenic mice[1623, 1624]. The pharmacology of PKC activatorswas extensively reviewed [1625–1629].

APH-0703 (Aphios Corp.), a potent PKC activa-tor, enhanced the generation of non-amyloidogenic,soluble A�PP in fibroblasts from AD patients. Itreduced brain amyloid plaques (A�40 and A�42) indouble-transgenic mice. The drug, formulated usingAphios’s hydrophobic-based and SFS-PNS polymernanospheres technologies, is in Phase II clinical trialssince May 2010 (Thomson Reuters Pharma, update ofJuly 5, 2012). The structure was not communicated.Potent activators of PKC are indirect activators of �-secretase [1630–1632].

Bryostatin-1 (Blanchette Rockefeller Neuro-sciences Institute) is a naturally occurring PKCactivator isolated from the Californian marinebryozoan Bugula neritina. In February 2012, theInstitute was preparing to initiate clinical trials inneurological disorders. Dual effects of bryostatin-1on spatial memory and depression were described[1633–1635]. Postischemic PKC activation to rescuelong-term memory was investigated [1636, 1637]. Thechemistry and biology of bryostatins was reviewed[504] (Thomson Reuters Pharma, update of February24, 2012). See also Section 2.2. Drugs interactingwith �-secretase.

DCP-LA (Hyogo College of Medicine; Fig. 22)is an activator of PKC� for the potential treatmentof stroke and cognitive disorder (Thomson ReutersPharma, update of May 25, 2012).

PKC epsilon activators (Blanchette RockefellerNeurosciences Institute) are evaluated for the poten-tial treatment of cognitive disorder (Thomson ReutersPharma, update of February 17, 2012). The structureswere not communicated.

The development of FR-236924 (Fujisawa, nowAstellas; an activator of PKC� [1638–1641]) and ofK-252c (Kyowa Hakko Kogyo; a PKC inhibitor) wasterminated.


Fig. 22. A poly ADP-ribose polymerase inhibitor, prostaglandin D and E modulators, a protein kinase C � activator, a Rac1 GTPase inhibitorand a ras farnesyl transferase inhibitor.

2.36. Drugs interacting with protein tyrosinephosphatase

The role of striatal-enriched protein tyrosine phos-phatase in cognition was described [1642] as was theinvolvement of PTPN5, the gene encoding the striatal-enriched protein tyrosine phosphatase in schizophreniaand cognition [1643]. A genome-wide associationstudy in 700 schizophrenic patients found that threeintronic SNPs in the protein tyrosine phosphatasereceptor type O were associated with learning andmemory [1644]. Knockout mice revealed a role forprotein tyrosine phosphatase in cognition [1645].

LDN-33960 (Yale University) is a striatal-enrichedprotein tyrosine phosphatase inhibitor, whichincreased the phosphorylation of NMDA receptorsand of ERK in a dose dependent manner. The drugrestored memory in a novel object recognition test intriple transgenic mice. It appears that the developmentof LDN-33960 was terminated (Thomson ReutersPharma, update of June 19, 2012).

2.37. Drugs interacting with Rac1 GTPase

The role of Rac1 GTPase in cognitive impairmentfollowing cerebral ischemia in the rat was described[1646]. The modulation of synaptic function by Rac1may be a possible link to fragile X syndrome pathology[1647, 1648].

Cytotoxic Necrotizing Factor 1, a modulatorof Rho GTPases including Rac, Rho, and Cdc42subfamilies improved object recognition in mice[1649].

Sanquinarinium chloride (ExonHit; Fig. 22) is anselective Rac1/1b GTPase nucleotide binding inhibitorwith IC50’s of 58 �M and 4.6 �M for Rac1 and Rac1b,respectively in nucleotide binding inhibition assays inpreclinical development (Thomson Reuters Pharma,update of July 20, 2011).

The development of EHT-1864 (EHT-206, EHT-101; ExonHit), an orally active small molecule Rac1GTPase inhibitor capable of crossing the blood brainbarrier was discontinued [1650–1652].


Fig. 23. A S-adenosylhomocysteine hydrolase and a sirtuin inhibitor, a sirtuin activator, a steroid sulfatase and a transglutaminase 2 inhibitor.

2.38. Drugs interacting with Ras FarnesylTransferase

Inhibiting farnesylation, but not geranylgeranyla-tion, replicated the enhancement of LTP caused bysimvastatin via the activation of Akt [1653].

LNK-754 (OSI-754, CP-609754; AstraZenecafollowing the acquisition of Link Medicine’s neuro-science assets under license from OSI Pharmaceu-ticals, a subsidiary of Astellas Pharma, and Pfizer;Fig. 22) is an orally active inhibitor of ras farnesyltransferase. Two Phase I clinical trials were initiatedin the US, one in May 2009 in 40 healthy elderlysubjects and one in November 2009 in 110 healthyelderly subjects and in patients with mild AD. Treat-ment of transgenic mice at 6 months of age for 3 monthsshowed a clear reduction of plaques caused by either�-synuclein or A� [1654] (Thomson Reuters Pharma,update of July 13, 2012).

2.39. Drugs interacting withS-adenosylhomocysteine hydrolase

Homocysteine potentiated A� neurotoxicity [1655].The S-adenosyl homocysteine hydrolase inhibitor

3-deaza-adenosine prevented cognitive impairmentfollowing folate and vitamin E deprivation in mice[1656].

L-002259713 (Merck, Fig. 23) is a potent inhibitorof S-adenosylhomocysteine hydrolase for the potentialtreatment of AD. The development was discontinued(Thomson Reuters Pharma, update of June 19,2012).

2.40. Drugs interacting with sirtuin

The neuronal protection by sirtuins in AD wasdescribed [1657] as were details on the sirtuin pathwayin aging and AD [1658].

Resveratrol (Fig. 23) is a natural phyto compound,which activates Sirtuin-1 [1659–1664]. It reducedA� accumulation [1665–1668]. It remodeled solu-ble oligomers and fibrils of A� into off-pathwayconformers [1669]. Resveratrol is not a direct acti-vator of SIRT1 enzyme activity [1670]. Resveratrolimproved memory deficits in mice fed a high-fat diet[1671]. Subchronic oral toxicity and cardiovascularsafety pharmacology studies were carried out [1672].The biosynthesis of resveratrol in yeast and in mam-malian cells was worked out [1673]. The Georgetown


University Medical Center started at Phase II, ran-domized, double-blind, placebo-controlled study inpatients with mild to moderate AD (expected n = 120)in the US in May 2012 (NCT015048549). A novelapplication in Huntington’s disease was discussedrecently [1674] (Thomson Reuters Pharma, update ofJune 22, 2012).

Selisistat (SEN-196, EX-527, SEN-0014196; SienaBiotech under license from Elixir Pharmaceuticals;Fig. 23) is a sirtuin-1 inhibitor for the potentialtreatment of Huntington’s disease in Phase II tri-als (PADDINGTON, NCT01485965) in Europe sinceApril 2011 (Thomson Reuters Pharma, update of May29, 2012).

INDUS-815C (Indus Biotech) is a natural NAD-dependent deacetylase sirtuin-2 (SIRT-2) inhibitorfor the potential treatment of Huntington’s disease.In addition, the drug is evaluated for the potentialtreatment of age-related macular degeneration andretinopathy (Thomson Reuters Pharma, updates ofAugust 19, 2011 and August 16, 2011, respectively).The structure was not communicated.

2.41. Drugs interacting with steroid sulfatase

Steroid sulfatase is a potential modifier of cog-nition in attention deficit hyperactivity disorder[1675].

DU-14 (Dusquesne University, Fig. 23) is asteroid sulfatase inhibitor for the potential enhance-ment of cognitive function via enhanced levels ofplasma dehydro-epiandrosterone and brain acetyl-choline [1676–1679]. Its development was terminated.

2.42. Drugs interacting with transglutaminase(TG2)

Tissue transglutaminase catalyzes protein cross-linking, an important molecular process in AD.Accumulation of insoluble proteins with isopeptidebonds, products of tissue transaminase activity, cor-related with cognitive impairment [1680].

CHDI-00339864 (Fig. 23) and CHDI-00316226(Evotec in collaboration with the CHDI Founda-tion) are selective TG2 inhibitors (IC50 = 7 nM forTG2 for CHDI-00316226) for the potential treat-ment of Huntington’s disease. It displayed an 85fold greater selectivity for TG2 over Factor XIIIA(Thomson Reuters Pharma, update of February 10,2012).

2.43. Drugs interacting with ubiquitincarboxyl-terminal hydroxylase (Usp14)

Inhibitors of this enzyme could accelerate the degra-dation of neurodegenerative disease-related proteins,such as tau, TDP-43, and ataxin-3. Changes in hip-pocampal synaptic transmission were observed inUsp14-deficient mice [1681].

Usp14 inhibitors (Proteostasis Therapeutics underlicense from Harvard University) are investigated forthe potential treatment of neurodegenerative diseases(Thomson Reuters Pharma, update of August 15,2012). Structures were not communicated.

3. CONCLUSION

With the launch of donepezil (Aricept) in 1996,rivastigmine (Exelon) in 2000, and galantamine(Reminyl) in 2001 (all inhibitors of AChE andBChE), three valuable medications are available forthe treatment of patients with mild to moderate AD.Huperzine A was launched in China in 1995, but thefour times a day administration makes it less attractive,a problem which will be solved by a transdermal patchcurrently in Phase I evaluation as XEL-001HP by XelPharmaceuticals.

The development of ten Phase III compounds testedfor the indication AD was terminated, of the AChEinhibitors amiridin (Nikken), eptastigmine (Medi-olanum), metrifonate (Bayer), phenserine (Anonyx),and velnacrine (HMR, now sanofi), of the �-secretaseinhibitors begacestat (Pfizer) and semagacestat (Lilly),the �-secretase modulator tarenflurbil (Myriad Genet-ics), and of the MAO inhibitors rasagiline (Teva) andsafinamide (Merck Serono).

Currently there is one compound interacting withenzymes in the pre-registration phase (WIN-026,WhanIN, an AChE inhibitor), one compound inPhase III trials (masitinib, AB Science, a kinaseinhibitor), and 15 drugs in Phase II evaluation(posiphen and Shen Er Yang, two AChE inhibitors),ladostigil (a dual AChE and MAO inhibitor), etazolate(an �-secretase activator), avagacestat and NIC5-15 (�-secretase inhibitors), CHF-5074 (�-secretasemodulator), tideglusib (GSK-3� inhibitor), EVP-0334 (HDAC inhibitor), RG-1577 (MAO-B inhibitor),PF-02545920 (PDE10A inhibitor), rilapladib (PLA2inhibitor), HF-0220 (prostaglandin D synthase stim-ulator), APH-0703 (PKC activator), and selisistat(sirtuin-1 inhibitor).

It may be that positive results will be obtained fromthe masitinib Phase III trials within the next two to


three years, whereas results from the Phase II trialswill be available only within the next five to six years.

DISCLOSURE STATEMENT

Authors’ disclosures available online (http://www.j-alz.com/disclosures/view.php?id=1508).

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Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with … · tal activities, including pre-attentional sensory gating, attention,learningandmemory,problemsolving,plan-ning,reasoningandjudgment,understanding,knowing