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Journal of Alzheimer’s Disease 33 (2013) 547–658
DOI 10.3233/JAD-2012-121537
IOS Press
Review
Cognitive Enhancers (Nootropics). Part 2:
Drugs Interacting with Enzymes
Wolfgang Froestl∗ , Andreas Muhs and Andrea Pfeifer
AC 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, and
psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed
in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To
classify the compounds, a concept is proposed assigning drugs to 19 categories according to their mechanism(s) of action, in
particular 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 with
amyloid-␤ 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 in
PubMed under the term cognitive enhancers, 26,680
entries under the term nootropic and 242 entries under
the term cognition enhancers. Scifinder lists 5,105
references under the research topic nootropic, 535
references under the term cognitive enhancer, and
9,780 references for cognition enhancers. The Thomson Reuters Pharma database lists 1,106 drugs as
nootropic agents or cognition enhancers and gives zero
results under the term cognitive enhancer. The term
nootropics was coined by the father of piracetam Corneliu Giurgea in 1972/1973 [1, 2], NOOS = mind and
TROPEIN = 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 suffering
from Alzheimer’s disease (AD), schizophrenia, stroke,
attention deficit hyperactivity disorder, or aging. Mark
J. Millan and 24 eminent researchers [3] presented an
excellent overview on cognitive dysfunction in psychiatric disorders in the February 2012 issue of Nature
Reviews Drug Discovery and defined cognition as “a
suite of interrelated conscious (and unconscious) mental activities, including pre-attentional sensory gating,
attention, learning and memory, problem solving, planning, reasoning and judgment, understanding, knowing
and representing, creativity, intuition and insight, spontaneous thought, introspection, as well as mental time
travel, self awareness and meta cognition (thinking and
knowledge about cognition)”.
Since a first review in 1989 on “Families of Cognition Enhancers” by Froestl and Maı̂tre [4], substantial
progress has been made in the understanding of
ISSN 1387-2877/13/$27.50 © 2013 – IOS Press and the authors. All rights reserved
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 cognition
enhancing drugs to 19 categories:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Drugs interacting with Receptors (Part 1)
Drugs interacting with Enzymes (Part 2)
Drugs interacting with Cytokines (Part 3)
Drugs interacting with Gene Expression
(Part 3)
Drugs interacting with Heat Shock Proteins
(Part 3)
Drugs interacting with Hormones (Part 3)
Drugs interacting with Ion Channels (nonReceptors) (Part 3)
Drugs interacting with Nerve Growth Factors
(Part 3)
Drugs interacting with Re-uptake Transporters
(Part 3)
Drugs interacting with Transcription Factors
(Part 3)
Antioxidants (Part 3)
Metal Chelators (Part 3)
Natural Products (Part 3)
Nootropics (“Drugs without mechanism”)
(Part 3)
Peptides (Part 3)
Drugs preventing amyloid-␤ aggregation (Part 3)
16.1. Ligands interacting with amyloid-␤
(Part 3)
16.2. Inhibitors of serum amyloid P component
binding (Part 3)
16.3. Vaccines against amyloid-␤ (Part 3)
16.4. Antibodies against amyloid-␤ (Part 3)
Drugs interacting with tau (Part 3)
17.1. Small molecules preventing tau aggregation (Part 3)
17.2. Ligands interacting with tau (Part 3)
17.3. Vaccines against tau (Part 3)
17.4. Antibodies against tau (Part 3)
Stem Cells (Part 3)
Miscellaneous (Part 3)
In Part 1, drugs interacting with receptors were
described [5]. In Part 2, we describe drugs interacting with enzymes and in Part 3, drugs interacting with
targets 3 to 10 and compounds and preparations of
categories 11 to 19.
2. DRUGS INTERACTING WITH ENZYMES
Researchers have been investigating drugs interacting with a wide variety of enzymes in order to
identify valuable cognition enhancers. These enzymes
are:
2.1 Drugs interacting with Acetyl- & Butyrylcholinesterase (AChE & BChE)
2.1.1. Drugs inhibiting AChE and other biological targets
2.1.1.1. Dual AChE inhibitors and
AChE receptor ligands
2.1.1.2. Dual AChE and amyloid-␤
inhibitors
antioxidants
2.1.1.4. Dual AChE and ␤-secretase-1
or ␥-secretase inhibitors
2.1.1.5. Dual AChE inhibitors and calcium channel blockers
cannabinoid receptor antagonists
2.1.1.7. Dual AChE and fatty acid
amide hydrolase inhibitors
2.1.1.8. Dual AChE inhibitors and histamine H3 receptor antagonists
2.1.1.9. Dual AChE and monoamine
oxidase inhibitors
metal chelators
2.1.1.11. Dual AChE inhibitors and Nmethyl-D-aspartic acid receptor channel blockers
platelet activating factor antagonists
2.1.1.13. Dual AChE and serotonin transporter inhibitors
2.1.1.14. Dual AChE and sigma receptor
inhibitors
2.2 Drugs interacting with ␣-Secretase
2.3 Drugs interacting with ␤-Secretase
2.4 Drugs interacting with ␥-Secretase
2.4.1. ␥-Secretase Inhibitors
2.4.2. ␥-Secretase Modulators
2.4.3. Inhibitors of ␥-Secretase Activating
Protein
2.4.4. Notch Pathway Inhibitors
2.5. Drugs interacting with ␤-Hexosaminidase
2.6. Drugs interacting with 11␤-Hydroxysteroid
Dehydrogenase
2.7. Drugs interacting with Calpain
2.8. Drugs interacting with Carbonic Anhydrase
2.9. Drugs interacting with Caspases
2.10. Drugs interacting with Catechol-O-methyltransferase
2.11. Drugs interacting with Cathepsin
2.12. Drugs interacting with Cholesterol 24Shydroxylase (CYP46A1)
2.13. Drugs interacting with Cyclooxygenase
2.14. Drugs interacting with D-Amino Acid
Oxidase
2.15. Drugs interacting with Glutaminyl Cyclase
2.16. Drugs interacting with Glyceraldehyde-3Phosphate Dehydrogenase
2.17. Drugs interacting with Glycogen Synthase
Kinase-3␤
2.18. Drugs interacting with Guanylyl Cyclase
2.19. Drugs interacting with Heme Oxygenase
2.20. Drugs interacting with Histone Deacetylase
2.21. Drugs interacting with HMG-CoA Reductase
2.22. Drugs interacting with Insulin-degrading
Enzyme
2.23. Drugs interacting with Kinases ( =GSK-3␤
/
and
=
/ PKC)
2.24. Drugs interacting with Kynurenine MonoOxygenase and Kynurenine Transaminase II
2.25. Drugs interacting with 5-Lipoxygenase
2.26. Drugs interacting with Monoamine Oxidase
2.27. Drugs modulating O-linked N-Acetylglucosaminidase
2.28. Drugs interacting with Peptidyl-prolyl cis-trans
Isomerase D
2.29. Drugs interacting with Phosphodiesterases
2.30. Drugs interacting with Phospholipases A2 and
D2
2.31. Drugs interacting with Plasminogen Activator
Inhibitor
2.32. Drugs interacting with Poly ADP-Ribose Polymerase
2.33. Drugs interacting with Prolyl Endo Peptidase
2.34. Drugs interacting with Prostaglandin D & E
Synthases
2.35. Drugs interacting with Protein Kinase C
2.36. Drugs interacting with Protein Tyrosine Phosphatase
2.37. Drugs interacting with Rac1 GTPase
2.38. Drugs interacting with Ras Farnesyl Transferase
2.39. Drugs interacting with S-Adenosylhomocysteine Hydrolase
2.40. Drugs interacting with Sirtuin
2.41. Drugs interacting with Steroid sulfatase
2.42. Drugs interacting with Transglutaminase
2.43. Drugs interacting with Ubiquitin Carboxylterminal Hydroxylase (Usp14).
549
2.1. Drugs interacting with Acetyl- and
Butyrylcholinesterase
Since the publication of the cholinergic hypothesis of AD by Bartus et al. in 1982 [6], tremendous
efforts have been undertaken to find either selective
acetylcholine receptor agonists (described in Part 1)
or acetylcholinesterase (AChE) inhibitors [7–15]. The
history of the cholinergic hypothesis was traced back
[16]. In retrospect, the latter approach (i.e., AChE
inhibitors) turned out to be more successful than the big
efforts to find selective acetylcholine receptor agonists.
Tacrine
(tetrahydroaminoacridine,
Cognex;
Warner-Lambert, Pfizer) was approved by the Food
and Drug Administration (FDA) in 1993 and was
launched in 1995 for the treatment of AD. It potently
blocks butyrylcholinesterase (BChE) (IC50 = 47 nM)
and AChE (IC50 = 190 nM) [17]. Tacrine has a short
half-life (2–3 hours) and must be administered 4
times a day. The major problem is its severe, though
reversible, hepatotoxicity [17, 18].
Donepezil (Aricept; E2020; co-developed by Eisai
and Pfizer, Fig. 1) was approved by the FDA in November 1996 and was launched in the US in January
1997 for the treatment of mild-to moderate AD. In
October 2006, FDA approval for the treatment of
severe AD was granted. It potently blocked AChE
(IC50 = 23 nM), whereas blockade of BChE was 320
times weaker (IC50 = 7,420 nM) [17]. The Japanese
inventors disclosed values of IC50 = 5.7 nM for AChE
and IC50 = 7,140 nM for BChE (factor 1250) [19].
Donepezil interacts with the active site of AChE and the
peripheral anionic site of the enzyme [20]. Its long terminal disposition half-life of 70 hours supports oncedaily administration [18]. Interestingly, the two enantiomers of donepezil racemize rapidly in vivo [21, 22].
The sales for donepezil reported by Eisai for 2011
totaled USD 1.853 billion (Thomson Reuters Pharma,
update of August 24, 2012).
2,301 publications on donepezil are listed in
PubMed (as of August 29, 2012).
For the synthesis and medicinal chemistry of
donepezil, see [19, 23], for an efficient process for
large-scale synthesis of donepezil [24, 25], and for
molecular modeling of donepezil [26, 27].
Many preclinical and mechanistic reviews have been
published [28–37]. Interestingly, donepezil eliminated
the suppressive effects of amyloid-␤ (A␤)42 on longterm potentiation (LTP) in rat hippocampal slices [38,
39]. Synergistic effects of donepezil and the 5-HT4
receptor agonist RS-67333 on the object recognition were observed in mice [40]. Pharmacokinetic
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Fig. 1. Launched acetylcholinesterase inhibitors.
considerations for donepezil dosing strategies were
presented [41].
There is extensive literature available on clinical trial
results; see (in chronological order) [42–66]. Broader
considerations of higher doses of donepezil in the
treatment of mild, moderate, and severe AD were communicated recently [67], in particular on the question
of the case of the 23 mg dose [68]. For the effects
of donepezil on levels of cholinesterases in the cerebrospinal 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 daily
lives of young adults with Down syndrome [82] and
in female Down syndrome patients [83], whereas in
children with Down syndrome of age 10–17 years,
donepezil did not show any benefit versus placebo [84].
Donepezil was used for the treatment of patients
with Parkinson’s disease [85–87] and for the treatment
of memory impairment in multiple sclerosis patients
[88].
Many galenical forms have been developed.
Donepezil hydrochloride fine granule formulation was
launched in Japan in September 2001. Donepezil rapid
oral disintegration tablet was launched in Japan in July
2004 and in the US in June 2005. Donepezil oral jelly
formulation was launched in Japan in December 2009.
Donepezil oral sustained release high-dose (23 mg)
tablet formulation was launched in the US in August
2010. The US NDA donepezil once weekly transdermal formulation in collaboration with Teikoku Seiyaku
was submitted in June 2010. A dry syrup formulation
administered by suspending the dry syrup in water
is in pre-registration in Japan. A fast dissolving oral
film strip formulation in collaboration with Applied
Pharma Research and Labtec is in clinical evaluation,
as is donepezil oral rapid disintegration film in collaboration with Kyukyu Pharmaceuticals. Donepezil
transdermal patch with Labtec, donepezil hydrochloride transdermal patch with Nitto Denk and Kowa, and
NAL-8812, a 3-day patch formulation co-developed
with NAL Pharmaceuticals are in preclinical evaluations, as is the Immediate Suspension encapsulation by
ALRISE Biosystems. NAL-8817 is an orally dissolving film formulation of donepezil using the BIO-FX
fast-onset oral cavity drug delivery system technology
in preclinical evaluation (Thomson Reuters Pharma,
update of May 31, 2012).
Deuterated donepezil is investigated by the company Deuteria Pharmaceuticals for the potential
treatment of AD (Thomson Reuters Pharma, update
of August 10, 2012).
Donepezil + memantine (ADS-8704, Arimenda;
Adamas Pharmaceuticals), a once-daily fixed dose
combination extended release formulation, is currently
tested in Phase II clinical trials. In May 2012, the FDA
approved Phase III studies in an end-of-Phase II meeting. First clinical results were presented [89] (Thomson
Reuters Pharma, update of July 5, 2012).
Rivastigmine (Exelon, SDZ-ENA-713; SDZ-212713; ENA-713; Novartis, Fig. 1) is a potent BChE
inhibitor (IC50 = 37 nM). It blocks AChE with an
IC50 = 4,150 nM, a factor of 112 times less than BChE
[17]. It forms a carbamoylated complex with the activesite serine inactivating it for about 10 hours producing
a “pseudo-irreversible” inhibition. For an excellent
review on the neurobiology of BChE, see [90, 91].
Rivastigmine was launched for the treatment of mild
to moderate AD in 2000 in the EU and the US and in
2010 in Japan. It was approved for the treatment of
mild to moderately severe dementia associated with
idiopathic Parkinson’s disease. Rivastigmine transdermal patch was launched in the EU in 2007 and in Japan
in 2011 in collaboration with the Japanese licensee Ono
Pharmaceuticals.
Sales for rivastigmine for 2011 were USD 1.067
billion representing a 6% increase on 2010 (Thomson
Reuters Pharma, update of August 24, 2012).
There are currently 1,181 publications on rivastigmine listed in PubMed (as of August 29, 2012).
Several syntheses of rivastigmine were published
[92–96].
Excellent papers on the preclinical characterization
of rivastigmine were communicated [97–102].
Extensive literature exists on the clinical trial
results of rivastigmine in AD (in chronological order)
[103–112]. Rivastigmine at doses of up to 12 mg/day
had useful efficacy in patients with mild-moderate
dementia of the Alzheimer type. Reports from larger
Phase III studies confirmed these findings. The b.i.d.
administration is the more efficacious regimen and had
comparable tolerability to the t.i.d. regimen.
Rivastigmine was evaluated for the treatment of
dementia in Parkinson’s disease [113–120]. Oral
rivastigmine 3–12 mg/day for 24 weeks was significantly more effective than placebo in ameliorating
cognitive and functional decline, including attentional
deficits, in patients with Parkinson’s disease dementia. Rivastigmine was also effective in patients with
dementia with Lewy bodies. Benefits were seen on tests
551
of attention, working memory, and episodic secondary
memory [121]. Rivastigmine was successfully applied
for the treatment of vascular dementia [122–125],
for treatment of hallucinations in Creutzfeldt-Jakob
disease [126], and memory deficits induced by electroconvulsive 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 trials
using the rivastigmine transdermal patch [130–154]
describing enhanced tolerability and significantly less
side effects.
NAL-8822 (NAL Pharmaceuticals) is a one-day
patch formulation of rivastigmine using its Bio-D3
transdermal drug delivery system technology in preclinical evaluation (Thomson Reuters Pharma, update
of 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 the
Amaryllidaceae family that include daffodils and the
common snowdrop (Galanthea woronowii [155]). It
blocks AChE (E.C. 3.1.1.7) with an IC50 of 800 nM
and BChE (E.C. 3.1.1.8) with an IC50 of 7,320 nM
[17]. Galantamine was launched in 2001 for the
treatment of mild to moderate AD in Europe and the
US and in March 2011 in Japan. In 2005, Johnson
& Johnson launched an extended release capsule
formulation.
The sales of galantamine in 2011 for Johnson &
Johnson were USD 470 million, for Shire USD 40 million, and for Takeda USD 34 million (Thomson Reuters
Pharma, update of August 27, 2012).
There are currently 1,602 publications on galantamine (and galanthamine) listed in PubMed (as of
August 29, 2012).
To a small extent, galantamine is still produced from
snowdrops [156, 157]. However, chemical syntheses
have taken over. A technical process for an efficient
nine-step procedure, which affords (−)-galanthamine
in 12% overall yield, was presented by Sanochemia
[158]. The synthetic schemes from academic laboratories were not scaled up [159–163].
The pharmacological characterization of galantamine was described in depth [164–175]. Galantamine weakly inhibited hERG channels [176].
Interestingly, galantamine not only blocks AChE
and BChE, but also acts as a positive allosteric modulator of nicotinic acetylcholine receptors enhancing
the concentrations of acetylcholine in the brain by a
second mechanism [177–182].
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The pharmacokinetics of galantamine were
reported [183–187].
Many publications described the clinical trial results
of galanthamine in AD (in chronological order)
[188–201 [1]]. Galantamine improved and stabilized
cognitive performance, activities of daily living, and
behavioral symptoms over the course of 6 months,
and its efficacy and tolerability are comparable with
those of other AChE inhibitors (rivastigmine and
donepezil). Galantamine proved to be one of the standard 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 pharmacoeconomics [78, 80, 204]. The historical development
of galantamine as a clinically used drug was traced
back [205].
Johnson & Johnson developed and launched Razadyne ER (Reminyl XL), an extended release capsule
formulation, in April 2005 in the US. Patients
treated with the extended release formulation had
better overall Alzheimer’s Disease Assessment Scale
(ADAS-cog/11) scores than the placebo group after six
months (Thomson Reuters Pharma, update of March
21, 2012).
NAL-8801 (NAL Pharmaceuticals) is a one day
patch formulation of galantamine using the Bio-D3
transdermal drug delivery system technology in preclinical evaluation (Thomson Reuters Pharma, update
of May 31, 2012).
Memogain (GLN-1062; Galantos Pharma) is a prodrug, the benzoyl ester, of galantamine administered as
an intranasal formulation. Memogain has a more than
15 times higher bioavailability in the brain than the
same dose of galantamine. It is cleaved enzymatically
to galantamine [206]. It is in Phase I since November
2011 (Thomson Reuters Pharma, update of December
28, 2011).
Huperzine A (Cerebra; Shanghai Institute of Materia Medica; Fig. 1) is a natural Lycopodium alkaloid
found in extracts from Huperzia serrate [207]. It was
launched in China for the treatment of AD in 1995. The
drug is administered in low oral doses of 0.1 mg four
times a day. Huperzine A blocked AChE with an IC50
of 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 and
300 nM [211]. Molecular modeling studies revealed
that huperzine A binds to the bottom of the binding
cavity of AChE with its ammonium group interacting
with Trp-84, Phe-330, Glu-199, and Asp-72 (catalytic
site) and to the opening of the gorge with its ammonium group interacting with Trp-279 (peripheral site)
[212]. Tyr-337 is essential for inhibition of recombinant human AChE by huperzine A [213]. The X-ray
structures of Torpedo californica AChE complexed
with (+)-huperzine A and (−)-huperzine B was presented [214].
Currently huperzine A is produced in large scale
from natural sources, in particular from Phlegmariurus squarrosus, a member of the Huperziaceae [215],
although several chemical synthesis schemes were
worked out [208, 216–222]. A large-scale synthetic
route resulted from a joint venture by process chemists
of Shasun Pharma (UK and India), Rhodia Pharma
(USA), and Debiopharm (Switzerland) [223].
There are currently 358 publications on huperzine
A listed in PubMed (as of August 29, 2012).
Excellent reviews on the pharmacology of
huperzine A have been published (in chronological
order) [224–230]. In particular, the neuroprotective effects of huperzine A have been investigated
in great detail, e.g., protective effects against A␤associated neurotoxicity [231–235]. Huperzine A dose
dependently increased secretory amyloid-␤ protein
precursor (A␤PP) release suggesting a modulatory
effect of huperzine A on ␣-secretase activity [236,
237]. These findings were confirmed independently
[238, 239]. This mechanism seems to play via
Wnt/␤-catenin signaling. Chronic administration of
huperzine A to double transgenic mice led to an
increase in ADAM10 and a decrease in ␤-secretase-1
and A␤PP695 protein levels [240]. Recently huperzine
A was also evaluated in triple transgenic mice confirming the improvement of cognitive performance
and the non-amyloid pathway activation [241].
Reviews on results of clinical trials of huperzine A
were published [242–244]. A Phase II clinical study
in 210 AD patients treated with either placebo, 200 ␮g
bid, or 400 ␮g bid of huperzine A (70 patients per arm)
showed no effect in the 200 ␮g group, but huperzine
A 400 ␮g bid showed a 2.27 point improvement in
ADAS-cog at 11 weeks versus a 0.29 decline in the
placebo group (p = 0.001) [245] (Thomson Reuters
Pharma, update of February 20, 2012).
The company Xel Pharmaceuticals (Draper, Utah) is
developing the once-weekly sustained release transdermal patch formulation XEL-001HP. This formulation
is currently tested in a Phase I clinical trial in
China since September 2008. Xel Pharmaceuticals
is also investigating the sustained release topical gel
formulation XEL-001HG in preclinical evaluation
(both Thomson Reuters Pharma, update of March 14,
2012).
Novartis chemists synthesized novel analogues of
huperzine A. The program was terminated [246].
WIN-026 (INM-176, KR-WAP-026; WhanIn under
license from Scigenic & Scigen Harvest) is an AChE
inhibitor with antioxidant and anti-A␤ properties containing a 95% extract of Angelica gigas Nakai in the
pre-registration phase [247]. In June 2008, a Phase
III clinical trial for the treatment of AD was initiated, which was completed by May 2011. The results
were submitted to the Korean FDA. Launch is expected
for the second half of 2012. The memory ameliorating effects of INM-176 in mice were described [248]
(Thomson Reuters Pharma, update of May 30, 2012).
Posiphen (the (+)-enantiomer of phenserine, QR
Pharma under license from TorreyPines Therapeutics,
Fig. 2) is in Phase II clinical trials for the oral treatment of AD since June 2009. It was effective to lower
A␤ levels in cell cultures and in mice [249]. Interestingly, posiphen also blocked the expression of brain
␣-synuclein [250, 251]. Posiphen is a candidate drug to
lower CSF A␤PP, A␤ peptide, and tau levels in humans
[252] (Thomson Reuters Pharma, update of July 25,
2012).
Shen Er Yang (Changchun Huayang High
Technology Co Ltd., Shanghai, Fig. 2) is a
tablet formulation of 1,2,3,4,5,6,7,8-octohydro9-phenylacetamidoacridine, a dual cholinesterase
inhibitor in Phase II clinical trials since March 2011
(Thomson Reuters Pharma, update of April 18, 2012).
Methanesulfonyl fluoride (SeneXta under license
from the University of Texas at El Paso, Fig. 2) is an
AChE inhibitor in Phase I clinical trials for AD and
post-stroke cognitive impairment. A Phase II clinical
trial for AD was planned for 2011. For the inhibition
of BChE by methanesulfonyl fluoride, see [253]; for
the inhibition of AChE [254]. Learning and memory
enhancing effects were described [255–258]. A report
on a double-blind, placebo-controlled study of safety
and efficacy in 5 men and 10 women (60–82 years) with
Mini-Mental State Examination (MMSE) scores of
9–24, who had senile dementia of the Alzheimer type,
was published. Methanesulfonyl fluoride improved
cognitive performance as measured by the MMSE,
ADAS-cog, Global Deterioration Scale, and the Clinical Interview Based Impression of Change [259]
(Thomson Reuters Pharma, update of June 28, 2012).
There are currently many cholinesterase inhibitors
in preclinical evaluation (in alphabetical order):
Bisnorcymserine (QR Pharma, under license from
TorreyPines Therapeutics; Fig. 2) is a dual BChE and
553
A␤PP inhibitor. An IND was cleared by the FDA in
December 2010. The inhibition of serum BChE by
bisnorcymserine was reported [260]. For the crystal
structure of the complex, see [261] (Thomson Reuters
Pharma, update of July 25, 2012).
Bis-(7)-tacrine (Mayo Foundation; Fig. 2) was
one of the first homodimers reported in the literature 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 calcium
channel blockers.
FS-0311 (Shanghai Institute for Materia Medica;
Fig. 2) is a bis-huperzine B derivative with similar
potency for the inhibition of AChE as donepezil but
higher potency than huperzines A and B. It antagonized cognitive deficits induced by scopolamine or by
transient brain ischemia [263].
Huprines (tacrine-huperzine A hybrids, Fig. 2)
were presented by scientists of the University of
Autonoma de Barcelona [264–269] and independently
from the University of Hong Kong [270]. French scientists also significantly contributed to novel huprine
derivatives [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). They
are very potent AChE inhibitors with Ki values of
0.026 nM for huprine-X and 0.033 nM for huprine
Y versus 31 nM for tacrine, 1.1 nM for donepezil,
and 4.6 nM for huperzine A [267]. Other scientists
measured IC50 values of 0.78 nM for (±)-huprineY and 4.58 nM for (±)-huprine-Z in human AChE
preparations [274]. (±)-Huprine-X is an agonist at
M1 muscarinic acetylcholine receptors (Ki = 338 nM)
and at M2 mAChRs (Ki = 4.66 ␮M) [275]. The binding of huprine-X to Torpedo californica AChE was
resolved in an X-ray structure at 2.1 Å resolution
[276]. Huprine-X facilitated learning and memory in
the Morris water maze [277]. Chronic treatment of
Tg2576 (A␤PPswe ) mice and of 3xTgAD mice with
0.12 ␮mol/kg huprine-X i.p. for 21 days caused a significant reduction of insoluble A␤40 by 40% (p < 0.05)
in the hippocampus of 3xTgAD mice while showing
no effect in A␤PPswe mice [278]. Additional data on
huprine X in triple transgenic mice were disclosed
recently [241].
Another way to create huperzine A-tacrine hybrids
is to link the primary amino group of huperzine A to the
primary amino group of tacrine with methylene groups
[279]. The best compounds showed Ki values against
554
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 described
huprine-tacrine heterodimers [280, 281].
Dimerization of an inactive fragment of huperzine
A led to bis-(12)-hupyridone (Hong Kong University, Fig. 3) displaying an IC50 = 52 nM versus 115 nM
for huperzine A [282]. The tether length of 12-13
methylene groups is consistent with simultaneous
binding to both the catalytic and the peripheral site
of AChE (see Fig. 5). Bis-(12)-hupyridone may also
act via ␣7 nicotinic acetylcholine receptors [283].
NP-0336 (Noscira) is a BChE inhibitor in preclinical
evaluation (Thomson Reuters Pharma, update of July
19, 2011). The structure was not communicated.
555
Fig. 3. Acetylcholinesterase inhibitors in preclinical evaluation II.
Fig. 4. Dual acetylcholinesterase and muscarinic M2 ACh receptor blocker.
SPH-1285 (Sanochemia Pharmazeutika, formerly
Waldheim Pharmazeutika; Fig. 3 shows SPH-1286)
is a neuroprotective derivative of galantamine for the
potential treatment of glaucoma (Thomson Reuters
Pharma, update of January 3, 2012).
The most potent AChE inhibitor is the molecule
syn-1 (Fig. 3) with Kd of 77 fM synthesized at the
Scripps Research Institute linking a tacrine part via
click chemistry to a phenanthridium unit. The tacrine
part is binding to the catalytic site (see Fig. 5), the
556
Fig. 5. Indole-tacrine heterodimers binding simultaneously to the
catalytic 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 were
discovered recently, such as benzoxazolinones [285],
indolizinoquinoline [286], isoindoline-1,3-diones
[287], pyrrolo isoxazol benzoic acid derivatives [288],
pyrrolo thiazoles [289], quinazolines [290], and
quinoline derivatives [291] acting as AChE inhibitors.
Also tacrin-ferulic acid-nitric oxide (NO) donor
trihybrides were presented [292].
Excellent reviews describe quantitative structure
activity relationships (QSAR) [293, 294], virtual
screening techniques [295], and the use of support vector machines for a classification of AChE inhibitors
[296]. High throughput screening and molecular
modeling for novel AChE inhibitors was discussed
[297].
The development of many AChE inhibitors was
terminated (in alphabetical order) of amiridin (ipidacrine hydrochloride; Nikken Chemicals [298–300]),
AP-2238 (University of Bologna [301–303]), BZYX
(Zhejiang University), CI-1002 (Parke-Davis, now
Pfizer), CHF-2822 and CHF-2957 (Chiesi), EN-101
(an orally active 20-base antisense oligonucleotide
directed against an AChE sequence; Amarin under
license from Yissum [304]), eptastigmine (MF-201;
Mediolanum [305–309], ER-127528 (Eisai), F-3796
(Pierre Fabre), FR-152558 (Fujisawa), galantamine
liposomal (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 (dehydroevodiamine hydrochloride, DHED; Jeil Pharmaceuticals
in collaboration with Seoul Univ.), LB-1003 (Lifelike
Biomatic), 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 from
the Shanghai Institute of Materia Medica; a once–daily
prodrug, a Schiff base of huperzine A with 2-hydroxy3-methoxy-5-chloro-benzaldehyde [319], NP-7557
(Nastech [325]), NXX-066 (Astra), P26 (Phytopharm), P-10358, P-11012, P-11149, and P-11467
(Hoechst Marion Roussel, now sanofi), phenserine
and (-)-phenserine (Axonyx under license from NIH,
Daewoong Pharmaceuticals [326–329], of controlled
release and transdermal formulations of physostigmine (Forest Laboratories, Lohmann Therapie Systeme [330–332], protexia (PEG-rBChE; PEGylated
recombinant human butyryl-cholinesterase; PharmAthene under license from Nexia Biotechnologies; a
protein produced in the milk of goats in a pegylated
formulation; the development as post-exposure therapy
for chemical nerve agent, currently in Phase I trials, is
ongoing [333, 334]), Ro-46-5934 (Roche; a dual AChE
inhibitor and M2 muscarinic acetylcholine receptor
antagonist), RS-1439 (Sankyo; a dual AChE and serotonin re-uptake inhibitor), S-9977 (Servier; a dual
AChE and serotonin re-uptake inhibitor), SDZ-ENX792 (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 Pharmaceutical, a subsidiary of Boehringer Ingelheim and Arena
[344, 345]), tolserine (Axonyx under license from
NIH [346–349], UCB-11056 (UCB), velnacrine (HP029; 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 other
biological targets
Tremendous efforts have been undertaken to combine AChE inhibition and interaction with multiple
targets thought to be responsible for AD pathogenesis
to create “multi-target-directed ligands” [357–370].
2.1.1.1. Dual AChE inhibitors and AChE receptor
ligands. Caproctamine (University of Bologna;
Fig. 4) is a potent AChE inhibitor (Ki = 104 nM) and
a competitive M2 muscarinic acetylcholine receptor
antagonist (Kb = 410 nM) [371].
MHP-133 (Medical College of Georgia; Fig. 4) is an
AChE inhibitor interacting with M1 muscarinic acetylcholine, 5-HT4 and I2 imidazoline receptors [372,
373].
Ro-46-5934 (Hoffmann-La Roche, Fig. 4) is a dual
AChE inhibitor and M2 AChR antagonist for the
potential treatment of AD. The development was discontinued [374].
An attempt to combine tacrine and xanomeline led
to hybride compounds displaying potent acetyl and
BChE inhibition (pIC50 ’s of 8.2 and selectivity ratio
of 1.0). The hybrids did not bind as agonists to the
orthosteric muscarinic acetylcholine M1 receptor but
as antagonists to an allosteric site of the M1 AChR
thereby reducing the amount of acetylcholine [375].
2.1.1.2. Dual AChE and amyloid-β inhibitors. AChE
colocalizes with A␤ peptide deposits in the brains
of AD patients and promoted A␤ fibrillogenesis by
forming stable AChE-A␤ complexes. AChE bound
through its peripheral site to the A␤ nonamyloidogenic
form and acted as a pathological chaperone inducing
a conformational transition to the amyloidogenic form
[376–380].
One approach is to design ligands binding to both
the catalytic as well as to the peripheral anionic site of
AChE inhibitors (Fig. 5) [381].
After first attempts [301, 302, 371, 382–384] an
important breakthrough was achieved with NP-61.
NP-61 (NP-0361; Noscira, previously Neuropharma) is a once-daily dual binding site AChE and
A␤ secretion inhibitor currently in Phase I clinical
trials for the treatment of AD. The structure was
not disclosed, but is probably a combination of
6-chloro-tacrine (binding to the catalytic binding site)
linked via a methylene bridge from the primary amine
to the amide nitrogen of indole propionamide binding
at the peripheral binding site [381]. Key biological
data 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 in
the thioflavin T test: IC50 = 2 ␮M, inhibition of A␤40
aggregation without AChE in the thioflavin T test:
49% at 100 ␮M [385, 386]. NP-61 was able to reverse
cognitive impairment tested in the Morris water maze
and to reduce plaque load in cortex and hippocampus
of 6 month-old human A␤PP (Swedish mutation)
557
transgenic mice treated once daily by oral gavage
for three months (the doses were not communicated)
IDN-5706, a hyperforin derivative, decreased the
content of AChE associated with different types of A␤
plaques in 7-month-old double A␤PPSWE /PS1 transgenic 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␤ deposits
after treatment of A␤PP/PS1 mice for four weeks. It
promoted the degradation of intracellular A␤ in astrocytes and protected against A␤ toxicity in cultured
astrocytes and neurons (chemistry: [388]; biology:
[389]).
This is an area of research with numerous novel
contributions presenting new piperidinium-type compounds [390], new piperidine derivatives [391],
donepezil-type inhibitors [392], novel pyrano[3,2c]quinoline-6-chlorotacrine hybrids [393], pyridinylidene hydrazones [394], novel bis(7)-tacrine derivatives
[395], hybrid compounds combining donepezil and
AP2238 [303], heterodimers of enantiopure huprine
X 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], isaindigotone derivatives [402], and oxoisoaporphine-based
inhibitors [403]. Berberine derivatives act as multifunctional agents of antioxidant, inhibitors of AChE,
BChE, and A␤ aggregation [404].
Bisnorcymserine (QR Pharma, under license from
TorreyPines Therapeutics; see Fig. 2) is a dual BChE
and A␤PP inhibitor.
2.1.1.3. Dual AChE inhibitors and antioxidants.
Lipocrine (University of Bologna; Fig. 6) is a combination of 6-chlorotacrine with ␣-lipoic acid [405].
It has been shown that ␣-lipoic acid is an universal
antioxidant [406–408], which protected rat cortical
neurons against cell death induced by A␤. Lipocrine
inhibited AChE with an IC50 of 0.25 nM and BChE
with 10.8 nM within 1 minute. It inhibited the aggregation of A␤ with an IC50 of 45 ␮M and showed
significant antioxidant activity against formation of
reactive oxygen species in SH-SY5Y cells after treatment 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 a
combination of the polyamine amide caproctamine
[371] showing AChE and M2 muscarinic ACh receptor blocking properties with a 1,4-benzoquinone
558
Fig. 6. Dual acetylcholinesterase inhibitors with amyloid-␤ inhibitor, antioxidant, BACE-1 inhibitor, and calcium channel blocker activities.
functionality derived from coenzyme Q or idebenone
as a radical scavenger [366, 410, 411]. It inhibited
AChE with an IC50 of 1.55 nM, human AChE-induced
aggregation of A␤40 with an IC50 of 28.3 ␮M and
A␤42 self-aggregation with an IC50 of 5.93 ␮M.
NAD(P)H:quinone oxidoreductase 1 (NQO1) is the
enzyme responsible for the regeneration and maintenance of the CoQ-reduced state. Memoquin is a good
substrate for NQO1 with a Km of 12.7 ␮M. In addition,
memoquin also effectively blocked ␤-secretase-1 with
an IC50 of 108 nM. The compound reduced the number of A␤ plaques in transgenic AD11 mice after oral
administration and rescued behavioral deficits in an
object recognition test in transgenic AD11 mice [412].
Introduction of methyl groups in the ␣-position of
the terminal benzylamine moieties (Fig. 6; Memoquin,
R = Me, both in (R)-configuration) led to an improved
derivative (inhibition of AChE with IC50 of 0.5 nM;
inhibition of human AChE-induced aggregation of
A␤40 with IC50 of 9.34 ␮M [413, 414].
Combination of the 2,5-diamino-benzoquinone
scaffold with curcumin derived substituents is another
way to multitarget-directed ligands [415].
Dual-acting drugs with extremely potent AChE
inhibiting activity and antioxidant properties were presented [416]. Hybrides between 6,8-dichlorotacrine
and melatonin showed an IC50 of 8 pM against
human AChE and potent peroxyl radical absorbance
capacities of 2.5-fold the value of Trolox in the oxygen
radical absorbance capacity assay using fluorescein
(ORAC-FL). Full experimental details were provided [417]. N-acylamino-phenothiazines are selective
BChE inhibitors and protected neurons against exogenous and mitochondrial free radicals [418, 419]. A
combination of tacrine and ferulic acid was described
[420] as were novel piperazine derivatives [421].
Berberine derivatives act as multi-functional agents of
antioxidant, inhibitors of AChE, BChE, and A␤ aggregation [422].
2.1.1.4. Dual AChE and β-secretase-1 or γ-secretase
inhibitors. Memoquin (University of Bologna, Fig. 6)
is a potent inhibitor of AChE with an IC50 of 1.55 nM
and of ␤-secretase-1 with an IC50 of 108 nM (see previous section 2.1.1.3.).
Coumarin derivatives are also dual human AChE
and ␤-secretase-1 inhibitors [423]. Inhibitions of
AChE with IC50 of 180 nM and of ␤-secretase-1 with
IC50 of 150 nM were measured.
Researchers from the Shanghai Institute of Materia 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 inhibiting
properties showed the following values: AChE:
IC50 = 75 nM, BChE: IC50 = 1 nM, ␤-secretase-1:
IC50 = 2.8 ␮M [425]. Quinoxaline-based hybrid compounds 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 been
presented recently [427].
2.1.1.5. Dual AChE inhibitors and calcium channel blockers. Bis(7)-tacrine (Mayo Foundation, see
Fig. 2), first synthesized in 1996 [262], is a very
potent AChE inhibitor (IC50 = 0.4 nM) with significantly less affinity to BChE (IC50 = 390 nM, selectivity
for AChE by a factor of 980). Bis(7)-tacrine was
extensively characterized. It reversed AF64A-induced
deficits in navigational memory in rats [428]. It protected against ischemic injury in primary cultured
mouse astrocytes [429]. It reduced hydrogen peroxideinduced injury in rat pheochromocytoma cells [430]. It
showed inhibitory action on N-methyl-D-aspartic acid
(NMDA) receptors with an IC50 of 0.763 ␮M [431].
Bis(7)-tacrine significantly reduced the augmentation
of (L-type) high-voltage activated inward calcium
559
currents induced by A␤ [432]. For an excellent review,
see [433].
ITH-4012 (TK-19; CSIC Madrid; Fig. 6) is an
AChE inhibitor with an IC50 of 0.8 ␮M [434]. It caused
an elevation of the cytosolic concentration of Ca2+
in fura 2-loaded bovine chromaffine cells from concentrations of 10 to 250 nM, which was related to the
induction of protein synthesis relevant for cell survival.
This cytoprotective action of ITH-4012 was reversed
by the protein synthesis inhibitor cycloheximide.
ITH-12118 (CSIC Madrid; Fig. 6), a tacripyrine,
combines tacrine and a L-type voltage-dependent calcium channel blocker of the nimodipine type. The
synthetic work was described in [435, 436] and the
extensive biological characterization in [437] showing that ITH12118 could be a paradigmatic multitarget
compound having selective brain effects with smaller
peripheral side effects. Additional chemical and pharmacological studies were published [438].
The development of NP-34 (or NP-04634; Noscira,
formerly Neuropharma), a natural product derived
from the marine sponge Aplysina cavericola with calcium channel blocking and AChE inhibiting properties
was terminated [439].
2.1.1.6. Dual AChE inhibitors and cannabinoid receptor antagonists. CB1 receptor antagonists increased
ACh release in certain brain areas including cortical regions and the hippocampus [440]. The CB1
antagonist scaffolds of diaryl-pyrazolines and diarylimidazoles [441, 442] were combined with tacrine.
Compound 20 (Solvay, now Abbott, Fig. 7) displayed
an IC50 of 316 nM for acetylcholinesterase and a Ki
of 48 nM for CB1 receptors. The Ki for CB2 receptors
was >1 ␮M [443].
2.1.1.7. Dual AChE & fatty acid amide hydrolase inhibitors. In regions of A␤-enriched neuritic
plaques an increased activity of the enzyme fatty
acid amide hydrolase (FAAH) was selectively demonstrated [444]. Inhibitors of FAAH may regulate
endocannabinoid signaling and may counteract neuroinflammation. First dual cholinesterase and FAAH
inhibitors were synthesized at the University of
Bologna [445]. One carbamate derivative (shown in
Fig. 7) displayed IC50 ’s of 50 nM for FAAH, 74.9 nM
for human AChE, and 1.57 nM for human BChE.
MIQ-001 (Meta-IQ Aps) is a fatty acid metabolism
inhibitor for the potential treatment of AD. A Phase
I healthy volunteer study was performed with doses
from 6 to 100 mg/day starting in February 2010. No
side-effects were observed. Meta-IQ generated excel-
560
Fig. 7. Dual acetylcholinesterase & fatty acid amide hydrolase inhibitor, dual acetylcholinesterase inhibitor & cannabinoid, and histamine H3
receptor antagonists.
lent preclinical data showing efficacy in restoration of
short and long term memory in an AD mouse model
The structure was not communicated.
The development of AMR-109 (Amarin Corp.,
ultra-pure eicosapentanoic acid), a modulator of
omega-3 fatty acids, was terminated. For the neuroprotective effects of eicosapentenoic acid against
A␤ induced impairment of LTP and memory, see
[446–448]. For a review on polyunsaturated farry acids
as cognitive enhancers see [449].
2.1.1.8. Dual AChE inhibitors and histamine H3 receptor 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 antagonist (Ki = 0.33 nM) inhibiting also histamine Nmethyltransferase (HMT with IC50 = 48 nM) [450].
University of Parma medicinal chemists described
potent dual non imidazole histamine H3 receptor antagonists 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 oxidase
inhibitors. Increased monoamine oxidase (MAO) B
activity was found in AD brains [453]. A combination
of AChE and of MAO B inhibitors in one molecule
was attempted already in 1996 [454, 455]. The
breakthrough was achieved with Ladostigil.
Ladostigil (TV-3326; Avraham Pharmaceuticals
under license from Yissum Research Development,
a wholly owned company of the Hebrew University
of Jerusalem; Fig. 8) combines the carbamate moiety
of the BChE inhibitor rivastigmine with the propargylamine pharmacophore of the MAO-B inhibitors
selegiline and rasagiline. Ladostigil is more potent
against 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 with
little inhibition of liver and small intestine MAO.
561
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 in
a cumulative effect. 50 ␮mol/kg given daily for 7 and
14 days inhibited both MAO-A and MAO-B by >60%.
80% inhibition of the brain enzymes was achieved with
a 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 trials
in 190 patients in Europe since December 2010 for
the oral treatment of AD. In February 2012 a Phase
II trial was initiated in Israel and Europe in patients
suffering from mild cognitive impairment (Thomson Reuters Pharma, update of May 18, 2012). See
also section 2.26. Drugs interacting with Monoamine
Oxidase.
Spanish medicinal chemists described potent dual
cholinesterase and MAO inhibitors [473–475].
2.1.1.10. Dual AChE inhibitors and metal chelators.
HLA20A (Technion Haifa; Fig. 8) is a combination
of an 8-hydroxy-quinoline metal chelator, which was
carbamoylated at the 8-hydroxy function to interact
with AChE as does rivastigmine [476, 477]. Inhibition
of AChE was measured with IC50 ’s of 0.5 ␮M and for
BChE with 42.58 ␮M. Interaction with AChE readily
cleaved the carbamoyl moity to release the chelator
readily forming complexes with FeSO4 and CuSO4 .
The prochelator is nontoxic to human SH-SY5Y cells
at 25 or 50 ␮M. A recent review described the field in
great detail [478].
Novel indanone derivatives were designed as AChE
inhibitors and metal-chelating agents [479].
2.1.1.11. Dual AChE inhibitors and N-methyl-Daspartic acid receptor channel blockers. Carbacrine
(University of Bologna, Fig. 9), a potent AChE
inhibitor (IC50 = 2.15 nM), and weak inhibitor of
BChE (IC50 = 296 nM), blocked AChE-induced A␤
aggregation to 58% at 100 ␮M and A␤ selfaggregation to 36% at 50 ␮M and inhibited NMDA
receptors with an IC50 of 0.74 ␮M. It is a noncompetitive open-channel blocker. In the ORAC test carbacrine
was a good antioxidant (IC50 = 0.07 ␮M), more potent
than trolox [480].
University of Jena researchers presented bivalent
␤-carbolines as dual AChE inhibitors and NMDA
receptor blockers such as compound 22b (Fig. 9):
IC50 = 0.5 nM for AChE, 5.7 nM for BChE, and 1.4 ␮M
for the NMDA receptor, respectively [481].
Bis(7)-tacrine (Mayo Foundation, Fig. 2, see section 2.1.1.5. Dual AChE inhibitors and calcium
channel blockers) inhibited NMDA receptors with an
IC50 of 763 nM [431].
2.1.1.12. Dual AChE inhibitors & platelet activating factor antagonists. PMS-777 (University of
Paris 7-Denis Diderot and Shanghai Jiao Tong
University; Fig. 10), synthesized in 1996 [482,
483], is a tetrahydrofuran derivative, which inhibited
AChE (IC50 = 2.48 ␮M), BChE (IC50 = 4.47 ␮M), and
acted as platelet factor antagonist (IC50 = 12.5 ␮M)
[484–490]. It inhibited A␤-induced human neuroblastoma SH-SY5Y cell apoptosis in a concentration
dependent manner. It decreased reactive oxygen
species up to 32%, NO production up to 5 times,
and TNF␣ release by 33% (Thomson Reuters Pharma,
update of June 20, 2012).
562
Fig. 9. Dual acetylcholinesterase inhibitors and NMDA receptor blocker.
PMS-1339 (University of Paris 7-Denis Diderot
and Shanghai Jiao Tong University; Fig. 10) is a
novel 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 antagonist (IC50 = 332 nM) [491] (Thomson Reuters Pharma,
update of June 20, 2012).
2.1.1.13. Dual AChE and serotonin transporter
inhibitors. RS-1259 (BGC-20-1259; BRG under
license from Daiichi Sankyo; Fig. 10) is a dual inhibitor
of AChE (IC50 = 101 nM) and of the serotonin transporter (IC50 = 42 nM). It significantly ameliorated the
age-related short-term memory impairment at a dose of
1 mg/kg in rats 24-25 months of age [492]. At 2 mg/kg
RS-1259 was also effective in recovering from memory
deficits. For the design, synthesis and structure-activity
relationships see [493–495]. Its development was terminated.
2.1.1.14. Dual AChE and sigma receptor inhibitors.
SP-04 (Samaritan Pharmaceuticals; Fig. 10) is an
inhibitor of AChE and of sigma-1 receptors. For synthesis and biological evaluation, see [496] (Thomson
Reuters 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-Leu17
bond within the A␤ sequence to generate the soluble N-terminal A␤PP fragment (sA␤PP␣) and the
membrane bound CTF83 (carboxy-terminal fragment
of 83 residues in length) thus precluding the formation and subsequent deposition of A␤. The activation
of the ␣-secretase processing of A␤PP as a therapeutic approach in AD was reviewed [497–501]. The
activation of ␣-secretase is controlled by the protein phosphorylation signal transduction pathway of
protein 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 inhibitor
and anxiolytic GABAA receptor modulator. Etazolate
dose-dependently increased the secreted levels of nonamyloidogenic sA␤PP␣ in cortical neurons of rats
thus shifting A␤PP processing toward the ␣-secretase
pathway [503]. Etazolate improved the memory performance in aged rats [504]. The results of the first Phase
II 3-month, randomized, placebo-controlled, double-
563
Fig. 10. Two dual acetylcholinesterase & platelet-activating factor, one acetylcholinesterase & serotonin transporter, one acetylcholinesterase
and sigma-1 receptor inhibitor(s) and an ␣-secretase activator.
blind study in AD patients were reported [505]. The
drug was shown to be safe and well tolerated (Thomson
Reuters Pharma, update of September 13, 2011).
Bryostatin-1 (Blanchette Rockefeller Neurosciences Institute) is a naturally occurring PKC
activator isolated from the Californian marine bryozoan Bugula neritina. Bryostatin-1 increased brain
levels of sA␤PP␣ and reduced brain A␤40 levels,
which may be explained by activation of ␣-secretase
[499, 506]. In February 2012, the Institute was
preparing to initiate clinical trials in neurological
disorders. Chemistry and biology of bryostatins was
reviewed [507] (Thomson Reuters Pharma, update
of February 24, 2012). See also section 2.35. Drugs
interacting with Protein Kinase C.
NP-17, NP-21, NPM-01, NPM-05B1, and NPM05B2 (Noscira) are orally available ␣-secretase
activators of marine origin for the potential treatment
of AD (Thomson Reuters Pharma, updates of July 27,
2011). The structures were not communicated.
Many compounds shifted A␤PP processing toward
the ␣-secretase pathway in in vitro experiments, such
as muscarinic acetylcholine receptor agonists, MAOB inhibitors, statins, non-steroidal anti-inflammatory
drugs (NSAIDs), neuropeptides such as PACAP,
estrogen, and others [499]. However, the benefit for
AD patients in clinical trials was (so far) disappointing.
2.3. Drugs interacting with beta secretase
In the amyloidogenic pathway, A␤PP is first
cleaved by ␤-secretase (BACE1, EC 3.4.23.46 [508,
509]) between residue methionine 671 and aspartic
acid 672 to release a 100 kDa N-terminal fragment
sA␤PP and a 12 kDa membrane bound CFT99,
which is subsequently cleaved by ␥-secretase within
the transmembrane region to form C-terminal A␤
peptides ranging from 38 to 43 residues. ␤-secretase
was cloned simultaneously by five groups in 1999 and
early 2000: at Amgen [510, 511]; at Elan [512], at
Pharmacia & 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
564
site motifs at amino acids 93-96 and 289-292. It
is structurally related to renin, cathepsins D and E,
pepsinogens A and C, and the retroviral aspartic
proteases [516, 517]. The ␤-secretase-1 gene was
described [518] as was the cell biology, regulation,
and inhibition of ␤-secretase [519]. For the enzymatic
activities of ␤-secretase-1 and ␤-secretase-2 (BACE2;
EC 3.4.23.45) in AD, see [520]. ␤-secretase-1 is
also required for myelination and correct bundling of
axons by Schwann cells [521, 522].
An X-ray crystal structure of ␤-secretase-1 bound
to the octapeptidic inhibitor OM99-2 was published
[523, 524]. Apo and inhibitor complex structures of
␤-secretase-1 at the resolution of 1.75 Å were determined [525]. X-ray crystal structures of ␤-secretase-1
bound to a macrocyclic peptidomimetic [526] and to
a spiropiperidine iminohydantoin were communicated
[527], as was the crystal structure of an active form of
␤-secretase-1 [528].
␤-secretase-1 knockout mice are healthy despite
lacking the primary ␤-secretase activity in the brain
[529, 530]. ␤-secretase-1 null mice are rescued from
A␤-dependent hippocampal memory deficits [531].
A rare gene mutation in the A␤PP was identified
in an Icelandic population by scientists of deCode
genetics, which protects against AD and age-related
cognitive decline. This A673T mutation is directly
adjacent to the cleavage site of ␤-secretase (methionine
671 and aspartic acid 672) [532]. For a commentary,
see [533].
In view of the importance of the amyloid hypothesis
for AD, it is not surprising that many pharmaceutical companies embarked on medicinal chemistry
programs to discover ␤-secretase inhibitors (in alphabetical order): Actelion, Allosterix, ALSP, Amgen,
Archer Pharmaceuticals, Astellas, Astex Therapeutics,
AstraZeneca, BACE Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, CoMentis (company of
Prof. Jordan Tang), Critical Outcome Technologies, De
Novo Pharmaceuticals, DuPont Pharma, Elan, Envoy
Therapeutics, Evotec, Genetics Company, GlaxoSmithKline, IntelliHep, JADO Technologies, Johnson
& Johnson, Kyoto University, LG Life Sciences,
Ligand Pharmaceuticals, Lilly, Locus Pharmaceuticals, Medivir, Merck, NasVax, Noscira, Novartis,
Pfizer, ProMediTech, Roche, Samada Research, sanofi,
Schering-Plough, Senex Biotechnology, Shionogi,
Sibia, Sunesis Pharmaceuticals, Takeda, Trans-Tech
Pharma, Vertex Pharma, Vitae Pharmaceuticals, and
Wyeth. In addition, there are numerous excellent
papers by competent synthetic organic chemists and
molecular modelers working at universities. The prob-
lems of ␤-secretase inhibitors are mostly due to their
peptidomimetic structures displaying high molecular
weight, high polar surface area, low oral bioavailability, metabolic instability, low blood brain barrier
penetration, and susceptibility to P-glycoprotein transport out of the brain.
There are many interesting reviews on the pharmacology and medicinal chemistry of ␤-secretase
inhibitors (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 clinical trials since June 2010 (n = 50) and December 2010
(n = 60) in the US. The studies were completed in
October 2010 and in April 2011, respectively. In April
2012 a randomized, double-blind, placebo-controlled,
Phase I/II study (NCT01561430) was initiated in
patients with mild cognitive impairment due to AD
(expected n = 129) in the US and is scheduled to complete in December 2013. For medicinal chemistry, see
[582–586] (Thomson Reuters Pharma, update of July
CTS-21166 (ASP-1702, ATG-Z1; Astellas Pharma
and CoMentis) is a ␤-secretase-1 inhibitor in Phase I
clinical trials since June 2007. In 48 volunteers, the
drug was safe and well tolerated (Thomson Reuters
Pharma, update of July 10, 2012). The structure was
not communicated.
E-2609 (Eisai) is a ␤-secretase inhibitor in Phase
I clinical trials since December 2010 in the US in
healthy young and elderly volunteers (n = 48). The
trial was completed in May 2012. Multiple-ascending
oral doses of E-2609 (25 to 400 mg for 14 days)
were studied at a single site in the US in this ongoing
trial in healthy human volunteers of 50 to 85 years
of age (both genders). The drug was safe and well
tolerated with minor adverse effects. Reductions of
A␤ in CSF and plasma were demonstrated following
both single and repeated administrations (Thomson
Reuters Pharma, update of August 07, 2012). The
structure was not communicated.
HPP-854 (TTP-854; High Point Pharmaceuticals,
a spin-out from TransTech Pharma) is a ␤-secretase
inhibitor in Phase I clinical trials since November 2009
MK-8931 (SCH-900931; Schering-Plough, now
Merck; Fig. 11) is an inhibitor of ␤-secretase in
Phase I clinical trials since October 2009 (n = 40).
In April 2012 data were presented from a two-part,
Fig. 11. Beta-secretase inhibitors.
565
566
randomized, double-blind, placebo-controlled single
rising-dose study (n = 40). Single doses of MK-8931
from 2.5 to 550 mg were well-tolerated [587]. For
medicinal chemistry, see [548, 588–593] (Thomson
For further documentation on the impressive
␤-secretase-1 inhibitor research program ongoing at
Merck see (in chronological order): [594–621 [2]].
At the occasion of the 244th ACS meeting in
Philadelphia Merck presented a bicyclic iminoheterocycle compound (Fig. 11) with an optimized
thiadiazine subunit with high affinity for ␤-secretase.
RG-7129 (Roche from a research collaboration with
Siena Biotech) is a small molecule ␤-secretase (BACE)
inhibitor in Phase I development since September
2011 (Thomson Reuters Pharma, update of August 8,
2012). The structure was not communicated. See also
the interesting papers [621, 622].
Several ␤-secretase inhibitors of known structure are
Amgen (presumably AC-3; AMG-0683; Fig. 11)
investigated series of 2-aminoquinolines and 2aminopyridines as ␤-secretase-1 inhibitors [623].
Hydroxy-ethylamine containing ␤-secretase inhibitors
were described very recently [624, 625] (Thomson
AZ-13 (Astex Pharmaceuticals and AstraZeneca;
Fig. 11) at 50, 75, 100, or 300 mmol/kg achieved a
concentration-dependent decrease in A␤40 , A␤42 , and
sA␤PP levels in brain and plasma of C57BL/6 mice.
For medicinal chemistry, see [626–629] (Thomson
Bristol-Myers Squibb (Fig. 11) is investigating a
series of 7-aza-indole compounds with IC50 values of
10 nM against BACE-1 and 800 nM against BACE2. For medicinal chemistry, see [630–635] (Thomson
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 nM
in a HEK-293 cellular assay. For medicinal chemistry,
see [636–643] (Thomson Reuters Pharma, update of
August 13, 2012).
Johnson & Johnson (presumably JNJ-715754,
Fig. 11) is evaluating compounds from a series
of 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 chemistry papers were communicated [644–649] (Thomson
Reuters 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 BACE1
inhibitors [650–665]. KMI-429 (Fig. 12) is a
␤-secretase 1 inhibitor with enhanced cell membrane
permeability (IC50 = 3.9 nM). KMI-574 (Fig. 12)
is a ␤-secretase inhibitor produced by substituting
the side chain of KMI-429 with a bioequivalent
material to enhance blood-brain barrier permeability
(IC50 = 5.6 nM). KMI-1027 (Fig. 12) is a low molecular weight ␤-secretase inhibitor with enhanced in vivo
enzyme stability and blood-brain barrier permeability
(IC50 = 50 nM). KMI-1303 (Fig. 12) is a ␤-secretase
1 inhibitor with higher affinity for active site pockets
(IC50 = 9 nM). The structures were obtained from
the Wako Online Catalog, Research for Alzheimer’s
Disease, edition November 2011.
L-655240 (Merck, Fig. 12) is a thromboxane A2
antagonist, which was re-discovered as a BACE1
inhibitor with IC50 of 4.47 ␮M by Chinese authors
[666].
Novartis (Fig. 11) investigated a series of cyclic
sulfoxide hydroxyethylamine ␤-secretase-1 inhibitors.
The compound reduced CSF and brain A␤40 levels in
a dose-dependent manner and showed good efficacy
at a 10 fold lower dose, when co-administered with
the CYP3A4 inhibitor ritonavir in various animal models. For medicinal chemistry, see [667–671]. (Thomson
TAK-070 (University of Tokyo under license from
Takeda) is a ␤-secretase and A␤ aggregation inhibitor
WAY-258131 (Wyeth, now Pfizer; Fig. 11) inhibited
␤-secretase-1 with an IC50 value of 10 nM and reduced
A␤40 with an IC50 value of 20 nM. For medicinal
chemistry, see [672–689] (Thomson Reuters Pharma,
Several companies have ␤-secretase-1 inhibitors
in preclinical development, whose structures were
not communicated (in alphabetical order): Allosterix,
BACE Therapeutics, Boehringer Ingelheim, Envoy
Therapeutics [690], Evotec [691, 692], Il Dong
Pharma (Seoul), IntelliHep (heparinoid ␤-secretase
inhibitors), LG Life Sciences [693], ProMediTech,
Samada Research, Vitae Pharmaceuticals in collaboration with Boehringer Ingelheim and the Technical
University of Munich [694, 695].
A dual ␤-secretase-1 inhibitor and metal chelator
was described [696].
Dual ␣7 nicotinic acetylcholine receptor activators and ␤-secretase-1 inhibitors are investigated in
a program at the University of Maryland (Thomson
Reuters Pharma, update of February 24, 2012).
Fig. 12. Beta-secretase inhibitors II.
567
568
JADO Technologies synthesized a membraneanchored version of a ␤-secretase transition-state
inhibitor by linking it to a sterol moiety. This inhibitor
reduced enzyme activity much more efficiently than
did the free inhibitor in cultures cells and in vivo [697].
BBS-1 BACE inhibitor mAb vaccine (NasVax
under license from Ramot at Tel Aviv University) is
investigating a vaccine based on its lead mAb candidate
BBS-1 (blocking ␤-site-1), which inhibits the ability
of ␤-secretase-1 to cleave A␤PP (Thomson Reuters
Antibodies directed against the ␤-secretase cleavage 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 allow
transcytosis across the blood-brain barrier [700, 701]
This technique was pioneered by W. M. Pardridge of
UCLA [702–708].
Excellent papers on ␤-secretase-1 inhibitors from
universities were presented (in alphabetical order of
their location): Mahidol University Bangkok [709,
710], University of Darmstadt [711], TU Dresden
[712], University of Duisburg-Essen [713], Gwangju
Institute of Science and Technology Korea [714],
Linköping University [715]; University of Liverpool
[716, 717], University of Marseille [718], Max-PlanckInstitut für Biochemie Martinsried [719], University
of Montréal [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 Institute of Materia Medica [730, 731], Shujitsu University
[732], Stockholm University [733–735], University
of 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 chronological 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 abandoned the search for novel ␤-secretase-1 inhibitors,
such as Actelion, De Novo, the Genetics Co (CallistoGen), Ligand, Locus Pharmaceuticals, Medivir [779],
Noscira, and Plexxikon.
The development of allosteric peptide BACE-1
inhibitors (Allosterix), of ARC-050 (Archer Pharmaceuticals), AZD-3839 (AstraZeneca [780, 781]),
BACE inhibitors (BACE Therapeutics, Evotec,
Samada Research, and ProMediTech/LG Life Sciences), GRL-8234 (Oklahoma Medical Research
Foundation [782]), GSK-188909 (GSK [783–791]),
LY-2811376 (Lilly [792]), SIB-1281 (Sibia), of TAK070 (Takeda [793, 794]), and of TC-1 (Merck under
license from Sunesis [795, 796]) was terminated.
2.4. Drugs interacting with gamma-secretase
␥-secretase is an aspartyl protease that cleaves
its substrates within the transmembrane region in a
process termed regulated-intramembrane-proteolysis
(RIP). The enzyme consists of four protein components: presenilin 1 or 2, which contains the catalytic
domain, nicastrin, Aph-1 (anterior pharynx-1), and
Pen-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 of
nicastrin (a 709 amino acid type 1 membrane glycoprotein), which may facilitate its interaction with the
docking site on presenilin followed by relocation to the
active site on presenilin, where it is cleaved [798–812].
␥-secretase cleaves A␤PP transmembrane domain in a
progressive stepwise manner at the ␧, ζ, and ␥-sites,
resulting in A␤ species of varying length. This stepwise cleavage may occur via two different routes. They
initiate with the formation of A␤49 and A␤48 and
then proceed via the cleavage at approximately every
three residues, i.e., every helical turn of the substrate.
The two product lines are ␧49-ζ46-␥43-␥40 and ␧48ζ45-␥42. Further cleavage will subsequently generate
the other isoforms A␤39 , A␤38 , and A␤37 , of which
A␤38 results from the product line containing A␤42
[813–816]. The mechanism of ␥-secretase dysfunction
in 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 the
smaller cytosolic fragment NICD (Notch intracellular
domain) important in signal transduction pathways. ␥secretase inhibitors that are not Notch-sparing may
cause severe gastrointestinal toxicity and interfere
with the maturation of B- and T-lymphocytes in mice
[822–827]). Note that A␤PP interacts with Notch
receptors [828].
The first proof that ␥-secretase inhibitors reduced
A␤ peptide levels in the brain was published already
in 2001 by Elan scientists [829].
In view of the importance of the amyloid hypothesis
for AD, it is not surprising that many pharmaceutical companies embarked on medicinal chemistry
programs to discover ␥-secretase inhibitors and
modulators (in alphabetical order): Archer Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Cellzome,
Eisai, Elan, EnVivo Pharmaceuticals, Harvard Medical School, Intra-Cellular Therapies, Janssen, Lilly,
Merck, Myriad Genetics, NeuroGenetic Pharmaceuticals, Ortho-McNeill, Pfizer, Roche, TorreyPinesTherapeutics and Wyeth (now Pfizer). There are many highly
interesting publications on medicinal chemistry and
pharmacology of ␥-secretase inhibitors and modulators 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 design
of ␥-secretase inhibitors was presented [607].
Many excellent reviews on the therapeutic potential of ␥-secretase inhibitors and modulators were
published [850, 853–863].
2.4.1. Gamma-secretase inhibitors
Avagacestat (BMS-708163; Bristol-Myers Squibb;
Fig. 13) is an orally active ␥-secretase inhibitor that
selectively inhibited A␤ production. A Phase II trial
in 200 AD patients was initiated in February 2009;
a second Phase II trial in 270 prodromal AD (mild
cognitive impairment) patients over a period of 104
weeks was initiated in May 2009. First reports on the
tolerability profile, pharmacokinetic parameter, and
pharmacodynamics markers were published [864–866
[3]]. A sensitive and selective LC-MS/MS method for
determination of avagacestat in plasma and CSF was
presented [866]. For medicinal chemistry and pharmacology, see [867, 878] (Thomson Reuters Pharma,
NIC5-15 (Humanetics under license from the
Mount Sinai School of Medicine, Fig. 13) is the natural
product D-pinitol, which inhibits the formation of A␤
plaques and inhibits ␥-secretase. In July 2009 encouraging Phase IIa data of the study NCT00470418 were
reported (Thomson Reuters Pharma, update of January
19, 2012).
E-2212 (Eisai), a ␥-secretase inhibitor, is in Phase
I clinical evaluation since January 2010 (n = 91). The
structure of E-2212 was not communicated. E-2212
replaces 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 model
and displayed excellent oral pharmacokinetics. GSI-1
lowered A␤40 plasma concentration. By August 2011,
569
Phase I trials had begun. For the extensive medicinal
chemistry see [879–902] (Thomson Reuters Pharma,
Several ␥-secretase inhibitors are currently in preclinical evaluation (in alphabetical order):
Harvard Medical School scientists are investigating a series of Notch-sparing ␥-secretase inhibitors for
the potential treatment of AD (one structure shown
in Fig. 13). One of the compounds (AD-1068) has an
IC50 value of 9 nM against A␤42 and an IC50 value of
1.8 ␮M for Notch. For medicinal chemistry (early work
was performed in part at the University of Tennessee),
see [903–911]. An excellent review was published in
2010 [848]. It appears that the development was terminated recently (Thomson Reuters Pharma, update of
June 25, 2012).
MRK-560 (SCH-1375975; Schering-Plough, now
Merck; Fig. 13) reduced A␤ plaque deposition without evidence of notch-related pathology in the Tg2576
mouse [912–915]. For medicinal chemistry, see [885,
916–919, 895, 896, 920–927] (Thomson Reuters
Pharma, update of November 24, 2011).
NGP-555 (NeuroGenetic Pharmaceuticals, Fig. 14)
has an IC50 for A␤ of 8.3 nM. It reduced levels of
A␤42 in brain and plasma at doses up to 100 mg/kg p.o.
Chronic treatment with 50 mg/kg for 7 months significantly reduced the percentage area of plaques in mouse
brains. There was no evidence of Notch-mediated GI
toxicity [928]. A potential follow-up compound may be
NGP-328, whose structure was not disclosed (Thomson Reuters Pharma, update of June 4, 2012).
Pepscan Therapeutics is investigating a series of
peptide-based ␥-secretase inhibitors for the potential
treatment of AD (Thomson Reuters Pharma, update of
April 1, 2011). The structures were not communicated.
Pfizer (Fig. 14) presented a novel ␥-secretase
inhibitor containing a bicyclo-[1.1.1]-pentanyl moiety
with an IC50 of 0.178 nM being equipotent to avagacestat (IC50 = 0.196 nM) [929]. For additional medicinal
chemistry papers from Pfizer, see [930–935] (Thomson
RO-02 (Roche; Fig. 14) inhibited enzyme activity with an A␤42 inhibition IC50 value of 500 nM.
For medicinal chemistry, see [936] (Thomson Reuters
Large ␥-secretase inhibitor research programs were
also ongoing at Amgen [937] and at Elan, see
[938–947].
Excellent papers on ␥-secretase inhibitors from universities were presented (in chronological order) 2001:
[948, 949]; 2004: [950, 951]; 2005: [952]; 2006: [953,
954]; 2009: [955, 956]; 2010: [957]; 2012: [958, 959].
570
Fig. 13. ␥-secretase inhibitors.
␥-secretase inhibitors have been presented (in chronological order) [960–967].
Critical Outcome Technologies is investigating
orally available, dual ␤- and ␥- secretase inhibitors
(Thomson Reuters Pharma, update of June 24,
2011).
The development of several ␥-secretase inhibitors
was terminated, of ARC-069 (Archer Pharmaceuticals, 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 ELND007 (both Elan [944–946, 980, 981]; GSI-136 (Wyeth,
now Pfizer [982]), MK-0752 (Merck; in Phase II for the
treatment of cancer, but terminated for the indication
of AD [983]); PF-03084014 (Pfizer; in Phase I for the
treatment of cancer, but terminated for the indication
of AD [984–987]), RO-4929097 (RG-4733; Roche,
for the indication breast cancer [988–993]), semagacestat (LY-450,139; Eli Lilly [931, 932, 994–1010])
and of SR-973 (DuPont/Scios, now Bristol-Myers
Squibb).
2.4.2. Gamma-secretase modulators
A ␥-secretase modulator interacts with allosteric
binding sites at the protease complex shifting the proteolytic processing of A␤PP toward higher production
of shorter A␤ species such as A␤38 at the expense of
the highly toxic A␤42 isoform. Impairment of Notch
processing and signaling was not observed [1011].
Reviews on ␥-secretase modulators were presented (in
chronological 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, Flurizan, Myriad Genetics, Loma Linda University;
Fig. 14) is a COX inhibitor and ␥-secretase modulator that selectively reduced the levels of A␤42 in
vivo [1025, 1026]). The IC50 values for the inhibition of COX-1 are 44 ␮M, of COX-2 : 123 ␮M, and of
A␤42 : 280 ␮M [1027]. Chronic administration of Rflurbiprofen attenuated learning impairments in transgenic A␤PPswe mice [1028]. Tarenflurbil upregulated
nerve growth factor and brain-derived neurotrophic
factor protecting both human neuroblastoma cell lines
and primary neurons from cytotoxicity associated with
exposure to A␤42 or hydrogen peroxide [1029].
571
Fig. 14. ␥-secretase inhibitors and modulators.
Tarenflurbil was tested in a Phase II study in 210
patients with doses of 400 mg and 800 mg twice per
day or placebo for 12 months. Patients with mild AD in
the 800 mg tarenflurbil group had lower rates of decline
than those in the placebo group concerning activities
of daily living. In patients with moderate AD 800 mg
tarenflurbil twice a day had no significant effects on
ADCS-ADL and ADAS-cog [1030].
Tarenflurbil was tested in a Phase III study in 1,684
patients, of which 1,046 completed the trial. Tarenflurbil had no beneficial effect on the co-primary
outcomes for ADCS-ADL and for ADAS-cog [1031];
for commentaries see [1032–1034] (Thomson Reuters
With the termination of the development of
tarenflurbil, the NO-releasing flurbiprofen derivative
HCT-1026 (NicOx) was also stopped.
CHF-5074 (Chiesi Farmaceutici; Fig. 14) showed a
concentration dependent inhibitory activity on A␤42
secretion (IC50 = 40 ␮M). At 300 ␮M, an inhibitory
effect was detected on COX-1 (–40%), but not on
COX-2 [1035]. It is devoid of Notch-interfering activities in vitro [1036]. Treatment of 6 months old hA␤PP
transgenic 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 15
months of age resulted in a significant attenuation of
the neurogenesis impairment in hippocampus [859,
1038]. For the reduction of the accumulation of hyperphosphorylated tau, see [1039], for the restoration
of 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, placebocontrolled Phase I ascending oral dose study in 48
healthy males with 200, 400, and 600 mg/day for 14
days (n = 12 each per dose level and 12 receiving
placebo). 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 since
June 2011 in healthy volunteers. By June 2012, the
Phase I trial was completed (Thomson Reuters Pharma,
update of August 14, 2012). Its structure was not communicated.
572
Several ␥-secretase modulators are currently in preclinical evaluation (in alphabetical order):
Amgen (Fig. 15) presented preclinical data on a
novel ␥-secretase modulator at the occasion of the
41st SFN Meeting in Washington in November 2011
(Thomson Reuters Pharma, update of December 6,
2011).
AZ-4800 (AstraZeneca; Fig. 15) at 75, 150, and
300 ␮mol/kg caused a dose dependent decrease of
brain A␤42 1.5 hours after administration to C57
mice (Thomson Reuters Pharma, update of April 1,
2011). For medicinal chemistry, see [1042, 1043].
AstraZeneca scientists described the detailed pharmacological evaluation of the ␥-secretase modulators
AZ3303 and AZ1136 (both Fig. 16) [1044, 1045]. The
second-generation ␥-secretase modulators have different modes of action regarding Notch processing [1046]
BIIB-042 (Biogen Idec; Fig. 15) is a ␥-secretase
modulator, which significantly reduced brain A␤42 levels in CF-1 mice and in Fisher rats and plasma A␤42
levels in cynomolgus monkeys. For medicinal chemistry, see [1047, 1048] (Thomson Reuters Pharma,
update of March 27, 2012).
GSM-2 (Merck UK [1049], Fig. 15), as was investigated by scientists of Astellas [1050], significantly
ameliorated memory deficits in Tg2576 mice and did
not affect normal cognition in wild-type mice. In contrast ␥-secretase inhibitors avagacestat (BMS-708163)
and semagacestat (LY-450139) on subchronic dosing
impaired normal cognition in 3 month old Tg2576
mice.
GSM-10h (GSK, Fig. 15) is an orally
active piperidine-derived ␥-secretase modulator
[1051–1054]. GSK is also investigating ␥-secretase
modulators derived from pyridazines (Fig. 15 [1055])
and from pyridines (Fig. 15) [1056] (Thomson
Janssen described a novel series of bicyclic heterocycles as potent ␥-secretase modulators [1057].
Merck (Fig. 16) is investigating ␥-secretase modulators with fused 5,6-bicyclic heterocycles. The best
compound had an IC50 of 122 nM for the inhibition
of 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 chemistry
was described [1058–1063]. Important mechanistic
insights were contributed [1064] (Thomson Reuters
Merck (Fig. 16) presented a new series of triazole
analogues, which inhibited A␤42 and A␤40 with IC50
values of 0.2 and 2.06 ␮M, respectively, and showed
a hERG interaction of IC50 > 10 ␮M [1065, 1066].
In a third series, Merck scientists presented pyridone
and pyridazone heterocycles as ␥-secretase modulators
[1067].
Pfizer medicinal chemists presented novel dihydrobenzofuran amides as orally bioavailable, centrally
active ␥-secretase modulators [1068] (Thomson
Roche presented novel ␥-secretase modulators at the
occasion of the Alzheimer’s Association International
Conference in Paris, France, July 16–21, 2011. One
compound (Fig. 16) had an A␤42 EC50 value of 0.1 ␮M
and demonstrated dose-dependent efficacy in transgenic A␤PPswe mice. CSF A␤42 levels were reduced
in non-transgenic rats for longer than 8 hours. A good
pharmacokinetic profile was seen (Thomson Reuters
SPI-014, SPI-1802, SPI-1810, and SPI-1865
(Satori Pharmaceuticals, Figure 16) are ␥-secretase
modulators reducing the levels of A␤42 without altering total A␤ levels in cell lines and in animal models
of AD (Thomson Reuters Pharma, update of July 31,
TorreyPines Therapeutics presented a novel class of
aminothiazoles as ␥-secretase modulators. Compound
3 (Fig. 16) displayed an IC50 for A␤42 of 5 nM [1069].
Excellent papers on ␥-secretase modulators from
universities 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].
␥-secretase modulators were presented from the University of Duesseldorf [1084], the Massachusetts
General Hospital [1085–1087], and Vanderbilt University [1088].
Dual modulators of ␥-secretase and peroxisome
proliferator-activated receptor ␥ (PPAR␥) were
presented to produce compounds with IC50 (A␤42 ) of
5.1 ␮M and EC50 (PPAR␥) of 6.6 ␮M [1089, 1090].
The development of JNJ-4018677 and JNJ42601572 (Janssen, formerly Ortho-McNeil Pharmaceuticals under license from Cellzome) [1091] was
discontinued.
2.4.3. Inhibitors of gamma-secretase activating
protein
␥-secretase activating protein (GSAP) interacts
both with ␥-secretase and its substrate, the A␤PP
Fig. 15. ␥-secretase modulators.
573
574
Fig. 16. ␥-secretase modulators and a Notch pathway inhibitor.
carboxy-terminal fragment (A␤PP-CTF). Reducing
GSAP concentrations in cell lines decreased A␤
concentrations, hence GSAP may be a new therapeutic target for AD [1092]. For a commentary, see
[1093]. The immunohistochemical characterization of
␥-secretase activation protein expression in AD brains
was described [1094]; the purification and characterization of human GSAP [1095].
IC-200155 (Intra-Cellular Therapies) is a compound that decreases A␤ levels in the brain by
575
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 not
communicated.
2.4.4. Notch pathway inhibitors
AGT-0031 (AxoGlia Therapeutics; Fig. 16) is an
inhibitor of the Notch pathway, which is involved in
astrocyte differentiation and inflammatory activation
for the potential treatment of multiple sclerosis and
AD (Thomson Reuters Pharma, update of February
29, 2012).
2.5. Drugs interacting with beta hexosaminidase
The first report of short-term memory deficits in a
murine model of lysosomal storage diseases including
Sandhoff disease was described [1096].
Amicus Therapeutics is investigating small
molecule pharmacological chaperones that bind to and
activate the lysosomal enzyme beta-hexosaminidase
for the potential oral treatment of AD. These
compounds lowered the levels of GM2 and GM3
gangliosides associated with A␤ aggregation (Thom-
son Reuters Pharma, update of March 28, 2012). No
structures were communicated.
2.6. Drugs interacting with 11 beta
hydroxysteroid dehydrogenase
The topic 11␤-hydroxysteroid dehydrogenase type
1 (11␤-HSD-1), brain atrophy, and cognitive decline
was reviewed [1097, 1098]. 11␤-HSD1 expression was
enhanced in the aged mouse hippocampus and caused
memory impairment [1099]. Enhanced hippocampal
LTP and spatial learning was found in 11␤-HSD1
knockout mice [1100, 1101]. Partial deficiency or
short term inhibition of 11␤-HSD1 improved cognitive
function in aged mice [1102, 1103]). Inhibition of 11␤hydroxysteroid dehydrogenase by carbenoxolone (100
mg three times per day) improved cognitive function
in elderly men [1104].
ABT-384 (Abbott Laboratories) is in a doubleblind safety/efficacy Phase II trial since May 2010 in
patients (n = 260) with mild to moderate AD in the UK.
Despite being safe, well tolerated and tested at doses
associated with full inhibition of brain 11␤-HSD-1
activity, it did not induce symptomatic improvement in
576
mild to moderate AD during the 12-week trial period.
Therefore the trial was terminated (Thomson Reuters
Pharma, update of July 18, 2012). The structure of
ABT-384 was not communicated.
KR-1-2 (Korea Research Institute of Chemical
Technology) suppressed cortisol by inhibiting 11␤hydroxysteroid dehydrogenase type 1. The drug is
intended for the treatment of glaucoma and dementia (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 dehydrogenase
1 (11␤-HSD1) for the potential treatment of agerelated cognitive disorders, such as memory loss
[1102]. UE-2343 showed cognition enhancement in
aged transgenic Tg2576 mice after one month of treatment in a passive avoidance test and a significant
reduction of their A␤ plaque load (Thomson Reuters
Pharma, update of March 15, 2012). Another class
of 11␤-HSD1 inhibitors, i.e., 1,5-substituted 1H tetrazoles, was described [1105].
2.7. Drugs interacting with calpain
The mechanistic involvement of the calpaincalpastatin system in AD neuropathology was
reviewed [1106]. Calpain inhibitors for the treatment
of AD were discussed [1107, 1108]. Over-activated
calpain caused a down-regulation of cAMP-dependent
protein kinase in AD brain [1109]. Neuronal overexpression of the endogenous inhibitor of calpains,
calpastatin, in a mouse model of AD reduced A␤
pathology [1110].
A-705253 (Abbott, formerly Knoll; Fig. 17) is
an orally active calpain inhibitor for the potential
treatment of AD. A-705253 significantly reduced
cholinergic neurodegeneration caused by A␤ in a
dose-dependent manner in rats [1111–1117]. It also
prevented stress-induced tau hyperphosphorylation in
vitro and in vivo [1118, 1119] (Thomson Reuters
Pharma, update of May 16, 2011).
ABT-957 (Abbott) is a calpain inhibitor for the
potential treatment of neurological disorders including AD (Thomson Reuters Pharma, update of March
AK-295 (CX-295, Vasolex; AxoTect under license
from Cortex Pharmaceuticals using technology
licensed from Alkermes, Fig. 17) attenuated motor and
cognitive deficits following experimental brain injury
in the rat [1120] (Thomson Reuters Pharma, update of
February 9, 2012).
SNJ-1945 (Senju Pharmaceutical; Fig. 17) is a
potent calpain inhibitor for the potential oral treatment of age-related macular degeneration, retinopathy,
and optic neuritis. Preclinical data were reported
[1121–1124]. Medicinal chemistry papers were contributed [1125–1128] (Thomson Reuters Pharma,
update of April 18, 2012).
The development of calpain inhibitors BDA410 (Mitsubishi-Tokyo Pharmaceuticals), CEP-3122
(Cephalon, now Teva), EP-475 (University of Tennessee), MDL-28170 (Hoechst Marion Roussel, now
sanofi [1129–1131]), and of TH-3501 (University of
Virginia) was terminated.
2.8. Drugs interacting with carbonic anhydrase
Carbonic anhydrase dysfunction impaired cognition
and was associated with mental retardation, AD, and
aging [1132].
The Blanchette Rockefeller Neurosciences Institute is investigating phenylalanine compounds acting
as carbonic anhydrase activators for the potential
treatment of attention deficit disorders and memory
problems in AD (Thomson Reuters Pharma, update of
February 16, 2012).
2.9. Drugs interacting with caspases
Caspases, or cysteine-aspartic proteases or cysteinedependent aspartate-directed proteases, are a family of
cysteine 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 irreversible inhibitor of active caspase-6 for the
potential treatment of AD (Thomson Reuters Pharma,
update of July 18, 2012). The structure was not
communicated.
2.10. Drugs interacting with
Catechol-O-methyltransferase (COMT)
The topic COMT, cognition, and psychosis was
reviewed [1139–1141]. The potential role of COMT
inhibitors for the treatment of cognitive deficits associated with schizophrenia was described [1142, 1143].
Tolcapone (Tasmar; Roche, launched in 1997)
improved cognition and cortical information processing in normal human subjects [1144]. Tolcapone and
Entacapone (Comtan; Orion in collaboration with
Novartis launched in 1999) blocked fibril formation of
␣-synuclein and A␤ and protected against A␤-induced
toxicity [1145].
The company Cerecor is investigating COMT
inhibitors for the potential treatment of schizophrenia
including cognition (Thomson Reuters Pharma, update
of April 12, 2012). Structures were not communicated.
2.11. Drugs interacting with cathepsin
Reduction of cathepsin B in transgenic mice
expressing human wild-type A␤PP resulted in significantly decreased brain A␤ [1146, 1147]. Higher
cathepsin B levels were found in plasma of AD patients
compared to healthy controls [1148].
Aloxistatin (E-64d; AB-007; ALP-496; ALSP;
Fig. 17) is an inhibitor of cathepsin B for the potential treatment of AD and traumatic brain injury
[1149–1152]. Aloxistatin was previously evaluated for
the treatment of Duchenne muscular dystrophy by
Taisho Pharmaceuticals, but the development was terminated (Thomson Reuters Pharma, update of June 29,
2012).
Acetyl-L-leucyl-L-valyl-L-lysinal (ALSP) is a cysteine protease inhibitor, which caused a significant
reduction in brain A␤ and ␤-secretase activity by
approximately 50% after i.c.v. administration of
0.06 mg/g brain weight/day for 28 days [1153] (Thomson Reuters Pharma, update of June 28, 2012).
The development of CEL-5A (University of California at Irvine; a cathepsin D inhibitor) and cystatin
C (New York University/Nathan Kline Institute, a cysteine protease inhibitor) was terminated.
2.12. Drugs interacting with cholesterol
24S-hydroxylase (CYP46A1)
Abnormal induction of the cholesterol-catabolic
enzyme CYP46 in glial cells of AD patients was
already recognized in 2001 by researchers at the
Karolinska Institute [1154], followed by [1155–1157].
It was shown that polymorphism in the cholesterol
24S-hydroxylase gene (CYP46A1) associated with
the ApoE␧3 allele increased the risk of AD and
of mild cognitive impairment [1158, 1159]. Similar results were obtained in elderly Chinese subjects
[1160, 1161]. CYP46A1 functional promotor haplotypes decipher genetic susceptibility to AD [1162].
Reviews were published [1163, 1164]. The crystal
structure of the enzyme was elucidated [1165]. The
cDNA cloning was described by scientists from the
577
University of Texas [1166], who generated also KO
mice [1167].
AAV-CYP46A1 (INSERM in collaboration with
sanofi) is an adeno-associated virus gene therapy encoding cholesterol 24-hydroxylase (CYP46A1
gene) for the potential injectable treatment of AD.
Reduced A␤ peptides, amyloid deposits, and trimeric
oligomers were observed in A␤PP23 mice. Significant improvements in cognitive function assessed by
the 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 interacting
with Gene Expression.
2.13. Drugs interacting with cyclooxygenase
(COX)
COX (EC 1.14.99.1) is an enzyme that is responsible for the formation of prostaglandins, prostacyclin,
and thromboxane. NSAIDs exert their effects through
inhibition of COX. Oligomers of A␤1-42 induced the
activation of COX-2 in astrocytes [1169].
Epidemiological studies have documented a reduced
prevalence of AD among users of NSAIDs [1170,
1171, 1026, 1172–1178]).
In the Rotterdam study, 6,989 subjects 55 years
of age or older were analyzed for the association of NSAIDs use and AD. The relative risk
of AD was 0.95 in subjects with short-term use
(1 month) of NSAIDs, 0.62 in subjects with
intermediate-term use (1 to 24 months), and 0.20
in those with long-term use (more than 24 months)
[1179]. Several clinical trials using indomethacin,
diclofenac/misoprostol, naproxen, nimesulide, celecoxib, and rofecoxib showed no benefit for AD
patients, reviewed by [1177]. The ADAPT research
group could not show a prevention of AD dementia
in a clinical trial using naproxen and celecoxib [1180,
1181].
The NSAIDs ibuprofen, indomethacin, and sulindac
sulfide preferentially decreased the highly amyloidogenic A␤42 peptide [1172]. This effect was not
mediated by inhibition of COX, but by an allosteric
modulation of ␥-secretase [1064] and by a change in
presenilin 1 conformation [1182]. A list of compounds
decreasing the formation of A␤42 peptide comprising
diclofenac, (R)-flurbiprofen, fenoprofen, ibuprofen,
indomethacin, meclofenamic acid. and sulindac was
presented [1183]. NSAIDs dose-dependently destabilized preformed A␤ fibrils in vitro [1184, 1185]. These
effects were also shown in transgenic mice in vivo
[1025, 1177].
578
A␤42 -lowering NSAIDs constitute the founding
members of the new class of ␥-secretase modulators
[1186], vide supra section 2.4.2.
2.14. Drugs interacting with D-amino acid
oxidase
The therapeutic potential of D-amino acid oxidase
(DAAO) inhibitors was described [1187]. Several susceptibility genes for psychiatric disorders have been
identified, among others G72, which is the D-amino
acid oxidase activator [1188–1191].
AS-2651816-00 (Astellas Pharma) is a novel DAAO
inhibitor for the potential treatment of schizophrenia
with an IC50 of 1.5 nM against human DAAO (Thomson Reuters Pharma, update of August 24, 2012). It
is a 3-hydroxy-pyridazin-4(1H)-one, but the precise
structure was not communicated.
Eisai following the acquisition of MGI Pharma
was investigating DAAO inhibitors to enhance the
activity of D-serine. The compound 6-chlorobenzo[d]
isoxazol-3-ol (CBIO) showed an IC50 of 200 nM. Its
development was terminated. Also the development of
DAAO inhibitors of Merck and Pfizer and of SEP227900 (Sunovion) was terminated.
ized in healthy volunteers (n = 100). First results
showed that oral administration of PQ-912 was safe
and well tolerated with relevant therapeutic levels in
blood and CSF (Thomson Reuters Pharma, update of
January 4, 2012). The structure of PQ-912 was not
communicated.
glyceraldehyde-3-phosphate dehydrogenase
A proteomics analysis of the AD hippocampal
proteome showed an increase of the levels of glyceraldehyde 3-phosphate dehydrogenase [1205]. A
decrease of the activity of cerebral glyceraldehyde-3phosphate dehydrogenase in different animal models
of AD was observed [1206].
Omigapil (SNT-317, TCH-346, CGP-3466; Santhera under license from Novartis; Fig. 18) is an orally
bioavailable glyceraldehyde 3-phosphate dehydrogenase modulator with anti-apoptotic properties for the
treatment of Parkinson’s disease and amyotrophic lateral sclerosis in Phase I clinical trials [1207–1221]
(Thomson Reuters Pharma, update of April 11,
2012).
2.15. Drugs interacting with Glutaminyl Cyclase
2.17. Drugs interacting with glycogen synthase
kinase-3β (GSK-3β)
Glutaminyl cyclase (QC) is an enzyme that catalyzes
the formation of pyroglutamic peptides or proteins
from a N-terminal glutamine residue. Human QC can
perform in parallel the conversion of a N-terminal glutamate of a peptide to a pyroglutamated peptide. When
A␤ is cleaved between amino acids 2 and 3, a peptide with a N-terminal glutamate is formed, which is
cyclized by QC to the N-terminal pyroglutamate. This
transformation renders the molecule more hydrophobic and increases its aggregation velocity [1192–1197].
Hence a QC inhibitor could prevent the formation
of this species [1198–1204]. Secondary glutaminylcyclase inhibitor interactions were presented [4].
PBD-150 (Probiodrug; Fig. 18) is a potent inhibitor
of human glutaminyl cyclase (IC50 = 17 nM) and
totally inhibits formation of A␤3,11 -(pE)40,42 in cell
culture at 1 ␮M (Thomson Reuters Pharma, update of
February 24, 2012).
A second generation of compounds was evaluated,
in which the 1-propyl imidazole residue was replaced
by the more rigid benzimidazole.
PQ-912 (Probiodrug) is a potent QC inhibitor in
Phase I clinical studies with single- and multiple
ascending dose, blinded, placebo-controlled, random-
GSK-3␤ (EC 2.7.11.26, 47 kDa) is a serine/threonine protein kinase ubiquitously expressed
and involved in many cellular signaling pathways
playing a key role in the pathogenesis of AD. It
is probably the link between A␤ and tau pathologies. A␤ activates GSK-3␤ through impairment of
phosphatidyl-inositol-3/Akt signaling. A␤-activated
GSK-3␤ induced hyperphosphorylation of tau, neurofibrillary tangle formation, neuronal death, and
synaptic loss (all found in AD brains). GSK-3␤
induced memory deficits in vivo. Crucial is the
phosphorylation at serine 9. The cited papers are
listed 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 structure
was resolved [1261, 1262]. 3D-QSAR studies were
reported [1263, 1264]. Ligand-based virtual screening
was elucidated [1265]. Scoring functions were applied
[1266].
Tideglusib (NP-12, NP-031112; Nypta; Noscira,
previously known as Neuropharma; Fig. 18) is the
579
Fig. 18. A glyceraldehyde 3-phosphate dehydrogenase modulator, a glutaminyl cyclase inhibitor, 10 glycogen synthase-3␤ and one HDAC
inhibitor.
580
lead compound of a series of orally active thiadiazolidinediones, potent inhibitors of GSK-3 [1267]. A
Phase IIb clinical trial in AD patients was initiated in
Spain, Germany, Finland, and the UK in April 2011.
In January 2012, randomization of patients (n = 308)
was completed in the double-blind trial. Preliminary
results are expected by the end of 2012. In December 2009, a Phase II trial for progressive supranuclear
palsy was initiated in the US and in Europe. Enrollment
was completed in October 2010 (n = 125). The drug
was granted orphan status for progressive supranuclear
palsy in November 2009. First positive results of a
clinical pilot study were reported [1268]. (Thomson
There are currently many GSK-3␤ inhibitors in preclinical evaluation (in alphabetical order):
AX-9839 (ActivX Biosciences, Kyorin Pharmaceuticals, Fig. 18) is an inhibitor of GSK-3␤ for the
potential treatment of diabetes, AD, and various CNS
disorders [1269] (Thomson Reuters Pharma, update of
April 18, 2012).
CG-9, CG-701338, CG-701446, and CG-701448
(Crystal Genomics) are lead compounds from a series
of GSK-3 inhibitors for the potential treatment of cancer, AD, and schizophrenia (Thomson Reuters Pharma,
update of May 02, 2012). The structures were not communicated.
CP-70949 (Pfizer; Fig. 18) is a selective inhibitor
of GSK-3␤ in preclinical evaluation [1270] (Thomson
Dual GSK-3␤/casein kinase 2 modulators (University of Illinois at Chicago) are investigated for the
potential treatment of Alzheimer’s disease. (Thomson
Reuters Pharma, update of September 20, 2012). Structures were not communicated.
GSK-3␤ inhibitors (Pfizer, Fig. 18) investigated a
series of oxazole derivatives. The shown compound
had an IC50 of 5 nM and a more than 100-fold selectivity against all other kinases and met safety criteria
(Thomson Reuters Pharma, update of Aug. 28, 2012).
JI-7263 (Jeil Pharmaceuticals) is the lead compound
from a series of GSK-3␤ inhibitors for the potential treatment of AD and amyotrophic lateral sclerosis
Mitsubishi-Tanabe (Fig. 18) presented a potent
GSK-3␤ inhibitor at the AIMECS 11 meeting in Tokyo
with an IC50 of 12 nM (Thomson Reuters Pharma,
update of January 24, 2012).
NNI-362 (NNI-AD; NeuroNascent) is a multikinase
and GSK-3␤ modulator inhibiting several tau phosphorylation sites. Other orally active compounds that
stimulate neuron formation are NNI-X01, NNI-C, and
NNI-251 (Thomson Reuters Pharma, update of July
19, 2012). The structures were not communicated.
NP-101020 (Noscira) is a GSK-3␤ inhibitor for the
potential treatment of AD (Thomson Reuters Pharma,
update of January 12, 2012). The structure was not
communicated.
SN-2127 (AstraZeneca, Fig. 18) is one of several
GSK-3␤ inhibitors in evaluation by AstraZeneca as
are SN-2568, SN-3728, and others (Thomson Reuters
Pharma, update of April 4, 2012).
Takeda (Fig. 18) presented a very potent GSK-3␤
inhibitor with IC50 of 2 nM. After oral administration a significant reduction of tau phosphorylation was
observed in aged JNPL3 mice [1271–1273]; Thomson Reuters Pharma, update of January 04, 2012). The
compound MMBO (Fig. 18) decreased tau phosphorylation and ameliorated cognitive deficits in a transgenic
model of AD [1274]).
TWS-119 (Scripps Research Institute; Fig. 18) is
a compound that can induce neurogenesis in murine
embryonic stem cells. The target of TWS-119 was
shown to be GSK-3␤ by affinity-based and biochemical methods [1275].
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/6J
mice [1276, 1277].
Extensive programs to identify GSK-3␤ inhibitors
have been ongoing at AstraZeneca [1226, 1278–1280],
at ChemDiv [1281], at GSK (e.g., SB-415286 and
others [1282–1287]), at GVK Biosciences [1288], at
Johnson & Johnson [1289–1292], at Kemia [1293], at
Lilly [1294–1296], at Roche [1297], at Vertex [1298]),
and at Yuyu in collaboration with CrystalGenomics
[1299].
Potent GSK-3␤ inhibitors were described by
researchers at universities (in alphabetical order of
their location): University of Athens [1300], University
Autonoma de Barcelona [1301], Technical University
of 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 of
La Rochelle [1314], University of Leuven [1231,
1239–1241], CSIC Madrid [1315–1318], University
of Louisiana at Monroe [1319], CNRS/Institut Curie
Orsay [1320], Peking University [1321], Indian Institute of Technology Roorkee [1322], Korea Institute of
Science and Technology Seoul [1323], Fudan University Shanghai [1324], and the University of Talca, Chile
[1325].
SAR studies on GSK-3␣ inhibitors were published
by researchers at the Technical University Darmstadt,
University of Naples, University of Leuven, and Tel
Aviv University [1326].
The Broad Institute is investigating ATP noncompetitive and allosteric inhibitors of GSK-3␤ (Thomson
Reuters Pharma update of June 3, 2011).
DM-204 (DiaMedica following its acquisition of
Sanomune) is a monoclonal antibody that inhibits
GSK-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; Mitsubishi
Pharma and sanofi). Also the development of
Propentofylline (HWA 285; Hoechst Werke Albert,
now sanofi) for AD and for vascular dementia has been
terminated after results of the 72 week propentofylline
long-term use (PLUS) clinical trial showed no treatment differences between the propentofylline-treated
group and the placebo-treated group [1327–1331].
Propentofylline attenuated tau hyperphosphorylation
by reducing the activated form of GSK-3␤ and by
increasing 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 XD4000 series (Xcellsyz, Lonza group) was terminated.
2.18. Drugs interacting with guanylyl cyclase
Soluble guanyl cyclase may be required for
emotional learning and for both reference and
working memory [1334]. A selective irreversible
inhibitor 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 avoidance task in rats. Activation of soluble guanyl cyclase
and cGMP formation in the brain represents one element of effective neuroprotective pathways mediated
by NO [1335]. The design and synthesis of nomethiazoles as NO-chimeras for neurodegenerative therapy
was described [1336].
sGC-1016 (sGC Pharma) is a sustained-release NO
mimetic for the potential treatment of AD in Phase I
clinical trial, which was completed in July 2012 showing high bioavailability (Thomson Reuters Pharma,
update of July 17, 2012). The structure was not communicated.
GT-715 and GT-1061 (Cita NeuroPharmaceuticals,
Vernalis) were prototypes of engineered NO mimetics,
581
which activated soluble guanylyl cyclase and increased
cGMP formation. They improved task acquisition in
cognitively impaired animals and in the 6-OHDA
model of Parkinson’s disease [1337–1341]. The development of both compounds was terminated.
2.19. Drugs interacting with heme oxygenase
Glial heme oxygenase-1 expression in AD and mild
cognitive impairment was reviewed [1342–1346].
OB-28 (Osta Biotechnologies) is a heme
oxygenase-1 inhibitor for the potential injectable
treatment of AD showing statistically significant
improvement in behavioral deficits in double transgenic (A␤PPSWE/PS1dE9) mice (n = 103) after
treatment 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 correct” HDAC(s) to treat cognitive disorders [1347]. The
roles of HDAC inhibition in neurodegenerative conditions were discussed [1348]. The role of HDAC6 in
Alzheimer’s disease was discussed [1349]. The loss of
HDAC5 impaired memory function [1350].
EVP-0334 (EnVivo under license from MethylGene) is developing the orally active HDAC inhibitor
as a cognition enhancer for the potential treatment
of AD. A Phase I clinical trial was started in May
2009 and finished in May 2010. Phase II trial are
underway since November 2011. Medicinal chemistry
papers were published [1351, 1352] (Thomson Reuters
4-Phenylbutyrate (Digna Biotech SL) ameliorated
cognitive deficits and reduced tau pathology in an
AD 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 for
the potential treatment of AD since April 2010 (Thomson Reuters Pharma update of May 30, 2012).
Other HDAC inhibitors are currently in preclinical
evaluation (in alphabetical order):
CHDI-390576 and CHDI-00381817 (HDAC4
inhibitors) are investigated by the CHDI Foundation in
collaboration with BioFocus DPI (Thomson Reuters
Pharma update of August 10, 2012). The structures
were not disclosed.
Crebinostat (Harvard Medical School, Fig. 18)
is a novel HDAC inhibitor and enhancer of CREB-
582
regulated transcription and modulator of chromatinmediated neuroplasticity [1358].
KAR-3010, KAR-3084, and KAR-3166 (Karus
Therapeutics) are HDAC6 inhibitors for the potential oral treatment of immune and inflammatory
disease including AD (Thomson Reuters Pharma
update of July 05, 2012). The structures were not
disclosed.
LB-201 and LB-205 (Lixte Biotechnology) are
drugs that target HDAC and prevent the degradation
and restore the activity of glucocerebrosidase for the
potential treatment of neurological disorders such as
Gaucher’s disease [1359] (Thomson Reuters Pharma
update of April 05, 2012). The structures were not
disclosed.
Dual PKC activators and HDAC inhibitors were
described [1360].
The development of EHT-0205 (ExonHit) was
terminated.
2.21. Drugs interacting with HMG-CoA reductase
The enzyme 3-hydroxy-3-methyl-glutaryl-CoA
reductase (EC 1.1.1.88) is the rate-controlling enzyme
of the mevalonate pathway, which produces cholesterol and other isoprenoids. It is the target of the
statins (or HMG-CoA reductase inhibitors). In a
large study comprising 9,844 participants at ages
from 40 to 45 years the risk of AD was evaluated in
relation to cholesterol levels. The analyses revealed
that cholesterol levels >220 mg/dL were a significant
risk factor for AD [1361]. See also the review [1362].
A lower prevalence of probable AD in a cohort of
patients taking lovastatin or pravastatin between 60
and 73% (p < 0.001) lower than the total patient population or compared with patients taking other medications typically used for the treatment of hypertension or
cardiovascular disease was found [1363–1367]. Excellent reviews were provided [1368–1375]. The link
between altered cholesterol metabolism and AD was
described [1376]. Statins, risk of dementia, and cognitive function were discussed [1377].
Statins can shift A␤PP processing to the nonamyloidogenic ␣-secretase pathway, e.g., simvastatin,
which in addition prevented neuroinflammation and
oxidative stress [1378, 1379], atorvastatin, which in
addition prevented neuroinflammation [1380, 1381]
and lovastatin, which in addition stimulated the upregulation of ␣7 nicotinic acetylcholine receptors [1382,
1383]. A␤40 blocked cerebral perivascular sympathetic ␣7-nAChRs, which was prevented by statins
such as mevastatin and lovastatin [1384, 1385].
Pitavastatin attenuated celecoxib- and streptozotocininduced experimental dementia [1386]. Atovastatin
and pitavastatin reduced senile plaque and phosphorylated tau in aged A␤PP mice [1387, 1388].
These promising biological results in experimental
animals were not confirmed in extensive clinical trials.
Only a slight reduction of cognitive decline in a large
study including 3,334 participants was found [1389].
A post hoc analysis from three double-blind, placebocontrolled, clinical trials of galantamine in patients
with AD was done [1390]. Patients were divided into
four treatment groups, statin plus galantamine (n = 42),
statin alone (n = 50), galantamine alone (n = 614),
and placebo (n = 619). Galantamine was associated
with a significant beneficial effect on cognitive status (p < 0.001). The use of statins did not produce a
significant beneficial effect (p = 0.083).
A proof-of-concept randomized controlled trial of
Atorvastatin (Lipitor, Pfizer, launched in 1996) indicated a trend for symptomatic benefit in mild to
moderate AD patients [1391–1393]. But the large
LEAD (Lipitor’s effect in Alzheimer’s Dementia)
study in 640 patients, who were randomized to atorvastatin 80 mg/day or placebo for 72 weeks followed by
a double-blind, 8-week atorvastatin withdrawal phase
did not show a significant benefit for cognition as
measured by ADAS-cog (p = 0.26) or for global function as measured by ADCS-Clinical Global Impression
of Change (p = 0.73) compared with placebo [1394,
1395]).
Pravastatin (Pravachol, Mevalotin; Daiichi
Sankyo, launched in 1989) was evaluated in PROSPER (Prospective Study of Pravastatin in the Elderly
at Risk) in 5,804 participants at six different time
points. No difference in cognitive decline was found
in patients treated with pravastatin compared to
placebo (p > 0.05). During a three year follow-up
period no effect on cognitive decline was observed
[1396].
Simvastatin (Zocor, MK-0733; Merck launched
in 1989) was evaluated in a 406 patient Phase III
study conducted by the National Institute of Aging.
Patients were treated with 20 mg simvastatin per day
for six weeks and with 40 mg/day simvastatin for
an additional 18 months. Simvastatin lowered lipid
levels, but had no effect on change of ADAS-cog
score or on secondary outcome measures [1397–1403].
Chronic simvastatin treatment rescued cognitive function in a transgenic mouse model of AD and enhanced
LTP in the CA1 region of the hippocampus in slices
from C57BL/56 mice via inhibition of farnesylation
[1404–1406].
583
Fig. 19. One HMG-CoA-reductase, 7 kinase and one kynurenine aminotransferase II inhibitor(s).
NST-0037 (Neuron BioPharma; Fig. 19) is a natural small molecule HMG-CoA-reductase inhibitor,
which also has neuroprotective, antioxidant, and
anti-convulsive activity. The synthesis was described
[1407]. Potential follow-up compounds are NST-0005
and NST-0060, whereas the development of NST-0021
was terminated (Thomson Reuters Pharma, update of
June 13, 2012).
584
2.22. Drugs interacting with insulin-degrading
enzyme
The role of insulin-degrading enzyme in AD was
discussed [1408, 1409]. The expression and functional
profiling of insulin-degrading enzyme in elderly and
AD patients was reported [1410] as was the characterization in human serum [1411].
The company Inventram is investigating insulindegrading enzyme activators for the potential treatment
of type 2 diabetes and AD (Thomson Reuters Pharma,
update of April 20, 2012). No structures were communicated.
2.23. Drugs interacting with Kinases ( =
/ GSK-3β
and =
/ PKC)
Advances in the development of kinase inhibitor
therapeutics for AD were presented [1412]. Noteworthy is that acetyl-L-carnitine (ST-200, Nicetile,
Zibren; launched by Sigma-Tau in Italy in 1985 and
in South Korea in 1995 as a memory enhancer) ameliorated spatial memory deficits induced by inhibition
of phosphoinositol-3-kinase and PKC [1413]. Also
clioquinol seems to operate in a similar way [1414].
Masitinib (AB-1010, AB Science; Fig. 19) is an
inhibitor of c-kit, Lyn and PDGF-R kinases. It was
evaluated in a Phase II clinical trial as an adjunct
therapy to cholinesterase inhibitor and/or memantine
in 26 patients with mild-to-moderate AD versus
placebo (n = 8). The masitinib treated patients showed
improvements in MMSE scores, the ADAS-Cog and
the Alzheimer’s Disease Cooperative Study Activities
of Daily Living Inventory with statistical significance
between treatment arms at week 12 and/or week
24 (p = 0.016 and 0.030, respectively) [1415]. In
September 2010, EMA approved a pivotal Phase III
trial in 300 AD patients to assess safety and efficacy of
6 mg/kg/day masitinib over 24 weeks. The biological
characterization was described [1416] (Thomson
Reuters Pharma, update of August 10, 2012). Numerous other kinase inhibitor therapeutics are currently
AIK-2, AIK-2a, AIK-2c, and AIK-21 (Allinky
Biopharma) are non-ATP-competitive MAP kinase
inhibitors for the potential treatment of cerebrovascular stroke and AD (Thomson Reuters Pharma, update
of October 28, 2011). The structures were not communicated.
Beta carboline alkaloids (Translational Genomics
Research Institute) including harmol (Fig. 19) inhibit
dual specificity tyrosine phosphorylation regulated
kinase 1A (DYRK1A) and tau phosphorylation
(IC50 = 90 nM). (Thomson Reuters Pharma, update of
June 8, 2012).
Cadeprin (group S8A serine protease) antagonists
are investigated by researchers from the Universities
of Strathclyde and Glasgow [1417] (Thomson Reuters
Casein kinase 1δ inhibitors (Proteome Sciences),
such as PS-110 and PS-278, are investigated for the
potential treatment of AD. (Thomson Reuters Pharma,
update of July 2, 2012). Structures were not communicated.
CDK5/p25 inhibitors (Pfizer) are investigated for
the potential treatment of AD. A novel pyrrolo[3,2b]pyridine derivative (Fig. 19) displayed low nM
potency. (Thomson Reuters Pharma, update of April
14, 2011).
CZC-25146 (GSK, following its acquisition of
Cellzome) is leucine-rich repeat kinase 2 (LRRK2)
inhibitor for the potential treatment of Parkinson’s disease. [1418] (Thomson Reuters Pharma, update of June
1, 2012).
Dasatinib (Bristol-Myers Squibb, launched 2006), a
Src tyrosine kinase inhibitor, attenuated A␤ associated
microgliosis in a murine model of AD [1419].
DYRK-1 alpha protein kinase inhibitors (Arrien
Pharmaceuticals) are evaluated for the potential
treatment of Alzheimer’s disease and Down syndrome.
Structures were not communicated.
DYRK-1 alpha protein kinase inhibitors (Carna
Biosciences) is a program in the stage of lead optimization. (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 p21activated kinase. The drugs have a potential for the
treatment of fragile X syndrome, autism, schizophrenia, and AD (Thomson Reuters Pharma, update of
August 14, 2012). Structures were not communicated.
G-2019S (Zenobia Pharmaceuticals in collaboration with Johns Hopkins University) is a LRRK2
inhibitor for the potential treatment of Parkinson’s disease (Thomson Reuters Pharma, update of March 13,
2012). The structure was not communicated.
Hydroxy-fasudil (Fig. 19, Asahi Kasei Pharma
Corp.), a rho kinase (ROCK) inhibitor, improved
spatial learning and working memory in rats in
a water radial-arm maze [1420]. ROCK inhibition
led to an increase of Rac1 activity and to an
activation of PKCζ which in turn phosphorylated
KIBRA involved in the formation of memory [1421].
ROCK inhibition prevented tau hyperphosphorylation
[1422].
KIBRA pathway modulators (Amnestix Inc., a
wholly owned subsidiary of SYGNIS Pharma) offer a
new genetic link to cognition that may benefit patients
suffering from AD. For the association of KIBRA and
late onset AD, see [1423], for enhancement of cognition in anxiety disorders [1424] (Thomson Reuters
LDN-22684 (Sirtris Pharmaceuticals) is a LRRK2
inhibitor for the potential treatment of Parkinson’s disease [1425] (Thomson Reuters Pharma, update of June
LRRK2 inhibitors (Arrien Pharmaceuticals) are
investigated for the potential oral treatment of
Parkinson’s disease (Thomson Reuters Pharma,
update of May 18, 2012). The structures were not
communicated.
LRRK2 inhibitors (Genentech, Fig. 19) are investigated for the potential treatment of Parkinson’s
disease. The medicinal chemistry was described
[1426]. (Thomson Reuters Pharma, update of June 26,
2012). The lead structure was communicated.
LRRK2 inhibitors (Genosco, Oscotec Inc.) are
investigated for the potential treatment of Parkinson’s
disease (Thomson Reuters Pharma, update of April 20,
LRRK2 inhibitors (Oncodesign Biotechnology)
are investigated for the potential treatment of cancer
and CNS diseases including Parkinson’s disease
The structures were not communicated.
LRRK2 inhibitors (Origenis GmbH) are investigated for the potential treatment of Parkinson’s disease
The structures were not communicated.
LRRK2 inhibitors (Pfizer) are investigated for the
potential treatment of Parkinson’s disease (Thomson
Reuters Pharma, update of June 20, 2012). The structures were not communicated.
LRRK2 inhibitors (Vernalis/Lundbeck) are investigated for the potential treatment of Parkinson’s
disease (Thomson Reuters Pharma, update of May 02,
MARK inhibitors (microtubule affinity regulating kinase; Medical Research Council Technology,
MRCT) are investigated for the inhibition of tau phosphorylation (Thomson Reuters Pharma, update of June
1, 2012).
MARK3 inhibitors (microtubule affinity regulating kinase 3, CDC25-associated kinase-1; Merck) are
in preclinical evaluation for the potential treatment of
585
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 Reuters
Minokine (MW01-2-069A-SRM; Northwestern
University; Fig. 19) is a p38 MAP kinase inhibitor for
the potential oral treatment of neurodegenerative diseases including AD (Thomson Reuters Pharma, update
of April 27, 2011).
NNI-351 (NNI-depression, NNI-DS, NeuroNascent; Fig. 19) is an orally active compound
preventing stress-induced neurogenesis reduction
via inhibition of dual specificity tyrosinephosphorylation-regulated kinase 1 alpha (DYRK-1␣)
protein (Thomson Reuters Pharma, update of March
22, 2012).
P-005 (NB Health Laboratory) is a small molecule
highly selective kinase inhibitor for the potential treatment of AD (Thomson Reuters Pharma, update of
December 23, 2011). The structure was not communicated.
Protein kinase inhibitors (ManRos Therapeutics)
are evaluated as AD medication (Thomson Reuters
Pharma, update of February 24, 2011). The structures
were not communicated.
SEL-103 (Selvita Life Sciences Solutions) is a program in collaboration with Orion Corporation, Espoo
Finland, to investigate novel, orally bioavailable and
highly selective small molecules for the potential
treatment of multiple cognitive disorders including
AD (Thomson Reuters Pharma, update of July 4,
2012).
SEL-141 (Selvita Life Sciences Solutions) is a program targeting kinases involved in tau phosphorylation
for the potential treatment of AD, Down syndrome, and
cognitive disorders. Focus is on DYRK1A (Thomson
Reuters Pharma, update of July 4, 2012). Structures
Sorafenib, a small molecular inhibitor of tyrosine protein kinases (VEGFR and PDGFR) and of
raf restored working memory in A␤PPSWE transgenic
mice [1427].
TTT-3002 (TauTaTis) is a multi-targeted kinase
inhibitor that can inhibit the LRRK2 gene and tumor
growth for the potential treatment of Parkinson’s disease, AD, and cancer. (Thomson Reuters Pharma,
update of January 25, 2012). The structure was not
communicated.
URMC-099-C (Califia, the University of Nebraska
Medical Center and the University of Rochester) is an
inhibitor of mixed lineage kinase-3 for the treatment
of HIV-associated neurocognitive disorder (Thomson
586
Reuters Pharma, update of June 5, 2012). The structure
was not communicated.
Inhibitors of the protein kinase c-raf1, such as GW5074 and ZM-336372, protected cortical cells against
A␤ toxicity [1428].
The development of AIKb2 (Allinky Biopharma;
a MAP kinase inhibitor), BA-1001 (BioAxone; a
rho kinase inhibitor [1429]), GW-5074 (GSK, a craf1 inhibitor), ORS-1006 (Arrien Pharmaceuticals, a
LRRK2 inhibitor), Pan-MLK inhibitors (Cephalon,
now Teva), PLX-3397 (Plexxikon, a subsidiary of Daiichi Sankyo; an oral small-molecule dual Fms/kit and
Flt3-ITD inhibitor; a Phase II trial for the treatment
of acute myelogenous leukemia continues), RS-4073
(Daiichi Sankyo; a potentiator of TrkA and Map
kinase activation), SB-203580 (SmithKline Beecham,
now GSK; a protein kinase and cytokine suppression
binding protein (CSBP)/p38 inhibitor [1430], SCIO323 (Scios, a p38 kinase inhibitor), SRN-003-556
(SIRENADE Pharmaceuticals; an ERK2 inhibitor),
and of ZK-808762 (University of Göttingen; a
serine protease and Factor Xa inhibitor) was
terminated.
2.24. Drugs interacting with kynurenine
mono-oxygenase and kynurenine
transaminase II
The kynurenine metabolism in AD was described
[1431]. Reduction of kynurenic acid formation
enhanced hippocampal plasticity and cognitive
behavior [1432]. Crystal structure-based selective targeting of kynurenine aminotransferase II for cognitive
enhancement was discussed [1433].
CHDI-003940246 and CHDI-00340246 (Evotec in
collaboration with the CHDI Foundation) are kynurenine mono-oxygenase inhibitors for the potential
treatment of Huntington’s disease (Thomson Reuters
Pharma, update of January 10, 2012). The structures
PF-04859989 (Pfizer, Fig. 19) is an inhibitor of
kynurenine (oxoglutarate) aminotransferase II for the
potential treatment of schizophrenia [1434] (Thomson
Reuters Pharma, update of March 21, 2012).
2.25. Drugs interacting with 5-lipoxygenase
The enzyme 5-lipoxygenase (5-LO) catalyzes the
conversion of arachidonic acid to 5-hydroxy-peroxyeicosatetraenoic acid (5-HPETE) and subsequently
to 5-hydroxy-eicosatetraenoic acid (5-HETE), which
are metabolized to different leukotrienes [1435]. The
group of Domenico Pratico found that A␤ deposition
in brains of Tg2576 mice lacking 5-LO was reduced
by 64 to 80%, suggesting that pharmacological inhibition of 5-LO could provide a novel therapy for AD
[1436]. Additional investigations showed that 5-LO
regulated the formation of A␤ by activating the cAMPresponse element binding protein (CREB), which in
turn increased transcription of the ␥-secretase complex
[1437, 1438].
In a Letter to the Editor of Annals of Neurology,
Kenji Hashimoto [1439] suggested to test minocycline, which protected PC12 cells against NMDAinduced injury via inhibiting 5-lipoxygenase activation
[1440].
Minocycline (Wyeth, now Pfizer and Takeda
launched in 1999) is a second generation tetracycline that effectively crosses the blood brain barrier.
It improved cognitive impairment in AD models
[1441]. It provided protection against A␤25-35 induced
alterations of the somatostatin signaling pathway
[1442, 1443]. It reduced microglial activation [1444,
1445] and A␤-derived neuroinflammation [1446].
It recovered MTT-formazan exocytosis impaired by
A␤ [1447]. Minocycline inhibited ␤-secretase-1 in
a transgenic model of AD-like amyloid pathology
[1448]. It reduced the development of abnormal tau
species in models of AD [1449–1451]. Minocycline
improved negative symptoms in patients with early
schizophrenia [1452].
A new class of 5-lipoxygenase inhibitors was communicated recently [1453].
2.26. Drugs interacting with monoamine oxidase
Recent efforts of medicinal chemists to explore
ligands targeting MOAs were reviewed [1454]. A
patent-related survey on new MOA inhibitors was published [1455]. The changes of MAO A and B in AD
were elucidated [1456] as was the platelet MAO B
activity in dementia [1457].
Ladostigil (TV-3326; Avraham Pharmaceuticals
under license from Yissum Research Development, a
wholly owned company of the Hebrew University of
Jerusalem; see Fig. 8) is a dual acetylcholine esterase
and MAO inhibitor currently in Phase II clinical trials in 190 patients in Europe since December 2010
See section 2.1.1.9. Dual AChE and MAO inhibitors.
RG-1577 (RO-4602522; EVT-302; Roche under
license from Evotec) is an orally active, selective,
and reversible MAO-B inhibitor. The company was
planning 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 not
communicated.
OG-45 (Oryzon Genomics) is a dual MAO-B
inhibitor and lysine specific demethylase-1 inhibitor.
Its structure was not communicated.
VAR-10200 (HLA-20; Varinel; Fig. 20) is a dual
iron-chelating agent and MAO-B inhibitor for the
potential treatment of age-related macular degeneration [1458] (Thomson Reuters Pharma, update of
February 24, 2012).
VAR-10300 (M-30; Varinel, Technion and the
Weizmann Institute of Science; Fig. 20) combines
the iron-chelating properties of 8-hydroxy-quinoline
with the MAO inhibitor moiety of rasaglinine [470,
1459–1465] (Thomson Reuters Pharma, update of May
15, 2012).
Rasagiline (TVP-1012; (R)-enantiomer; Azilect;
marketed by Teva and Lundbeck; Fig. 20) proved to be
a very valuable drug for the treatment of Parkinson’s
disease with sales in 2011 of USD 290 million reported
by Teva and USD 221 million reported by Lundbeck.
Rasagiline was extensively characterized (in chronological order) [1466–1478]. The effects of rasagiline on
cognitive deficits in cognitively-impaired Parkinson’s
disease patients were evaluated [1479]. A␤PP processing properties of rasagiline were described [1480].
Rasagiline improved learning and memory in young
healthy rats [1481]. In July 2004 Eisai initiated Phase
II clinical trials in the US for the treatment of AD, later
also in combination with donepezil. In March 2008
development for the indication AD was discontinued
(Thomson Reuters Pharma, update August 29, 2012).
Safinamide (FCE-26743; NM-1015, PNU151774E; Zambon under license from Newron, who
acquired the rights from Pharmacia and Upjohn,
now Pfizer; Fig. 20) is a potent MAO B inhibitor
(IC50 = 98 nM; MAO A: IC50 = 580 ␮M, selectivity
index: 5,918 for the potential treatment of Parkinson’s
disease and AD [1482]. The first synthesis was
described in 1998 [1483] followed by the solid-phase
synthesis [1482]. The enantiomeric separation of
safinamide was disclosed [1484]. The biological
characterization was described in detail [1485–1487].
Several reviews were published [1488–1490]. Phase
III trials in early Parkinson’s disease patients began
in June 2004. An expert opinion on safinamide in
Parkinson’s disease was published [1491]. A Phase
III trial in AD patients was abandoned in late 2007
(Thomson Reuters Pharma, update of August 21,
2012).
587
The development of many other MAO inhibitors
for the indication AD was terminated, of bifemelane
(MCI-2016; SON-216; Sosei under license from Mitsubishi [1492, 1493]), EVT-301 (Evotec under license
from Roche), EXP-631 (Bristol-Myers Squibb),
4-fluoroselegiline (Chinoin, now sanofi), HT-1067
(Helicon Therapeutics), indantadol (Vernalis under
license 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-linked
N-acetylglucosaminidase (O-GlcNAcase;
OGA)
O-GlcNAcase is the enzyme that plays a role in
the removal of N-acetylglucosamine groups from serine and threonine residues in both the nucleus and
the cytoplasm of cells [1500, 1501]. O-GlcNAcase
may compete with phosphorylation of the same serine or threonine residues. Studies to elucidate the
binding mode were carried out by [1502, 1503].
O-GlcNAcylation directly regulates core components
of the pluripotency network [1504].
Alectos Therapeutics/Merck are investigating
O-GlcNAcase modulators (Thomson Reuters Pharma
updates of July 5, 2012).
GlcNAcstatin (University of Dundee in collaboration with Aquapharm Biodiscovery; Fig. 20) is a
marine natural product for the potential treatment of
AD [1505, 1506]. For an efficient and versatile synthesis of GlcNAcstatin derivatives, see [1507] (Thomson
NButGT (Seoul National University; Fig. 20),
a specific inhibitor of O-GlcNAcase, reduced A␤
production by lowering ␥-secretase activity both in
vitro and in vivo. O-GlcNAcylation takes place at the
S708 residue of nicastrin, a component of ␥-secretase
[1508] = [5]. The synthesis was described by chemists
of the Simon Fraser University [6].
SEG-4 (Summit Corporation) inhibited OGA with
IC50 and Ki values of 10 and 72 nM, respectively. The
compound significantly reduced tau phosphorylation
(Thomson Reuters Pharma, update of August 2, 2012).
Thiamet-G (Simon Fraser University) is a
potent inhibitor of human O-GlcNAcase (Ki = 21 nM;
Fig. 20) and efficiently reduced phosphorylation of
tau at Thr231, Ser396, and Ser422 in both rat cor-
588
Fig. 20. Four monoamine oxidase and three O-linked N-acetylglucosaminidase inhibitors.
tex and hippocampus [1509–1512]. For commentaries
see [1513, 1514]. Acute thiamet G treatment led to
a decrease in tau phosphorylation at Thr181, Thr212,
Ser214, Ser262/Ser356, Ser404, and Ser409 and an
increase in tau phosphorylation at Ser199, Ser202,
Ser396, and Ser422 in mouse brain, probably via stimulation of GSK-3␤ activity [1515].
2.28. Drugs interacting with peptidyl-prolyl
cis-trans isomerase D
Peptidyl-prolyl cis-trans isomerase D or Cyclophilin
D (Cyp D; EC 5.2.1.8. Isomerase) is implicated in cell
death pathways. Blockade of Cyp D could be a potent
therapeutic strategy for degenerative disorders such as
AD, ischemia, and multiple sclerosis [1516]. Soluble
A␤ is also found in mitochondria, where it interacts
with Cyp D, a component of the mitochondrial permeability transition pore. Interference with the normal
functions of this protein resulted in disruption of cell
homeostasis and ultimately cell death [1517].
The Hsp90-associated cis-trans peptidyl-prolyl
isomerase-FK506 binding protein 51 (FKBP51) was
recently found to co-localize with the microtubuleassociated protein tau in neurons and physically
interact with tau in brain tissues from humans, who
died from AD [1518].
PIN1 is a peptidyl-prolyl isomerase, which catalyzes
cis-trans isomerization of peptide bonds N-terminal
to specific phospho-serine/threonine-proline motifs.
PIN1 isomerizes phosphorylated tau and thus restores
the ability of phosphorylated tau to bind microtubules,
and eventually promote dephosphorylation of tau by
PP2A phosphatase [1519].
Scynexis is investigating a series of Cyp D inhibitors
for the potential treatment of muscle injury, ischemia,
reperfusion injury, trauma, and neurodegenerative disease (Thomson Reuters Pharma, update of June 28,
2011).
2.29. Drugs interacting with phosphodiesterases
Several excellent reviews on PDE inhibition and
cognition enhancement were published [1520–1524].
Based on the expression of PDE mRNA in the
human brain, it was suggested that PDE1 and PDE10
inhibitors are strong candidates for the development
of cognition enhancers. Chronic PDE type 2 inhibition with BAY60-7550 improved memory in the
A␤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; see
Fig. 10) is an orally active PDE4 inhibitor and anxiolytic GABAA receptor modulator, which shifts A␤PP
processing toward the ␣-secretase pathway [503, 504,
1532–1536]. The results of the first Phase II 3-month,
randomized, placebo-controlled, double-blind study in
AD patients was reported [505] (Thomson Reuters
Pharma, update of September 13, 2011). See also section 2.2. Drugs interacting with ␣-secretase.
PF-02545920 (MP-10; Pfizer; Fig. 21) is a PDE10A
inhibitor in a randomized, double-blind, placebocontrolled Phase II clinical trial in patients with
acute schizophrenia (n = 260) since October 2010.
PF-02545920 is also evaluated for the treatment of
Huntington’s disease [1531, 1537–1540]. (Thomson
Lu-AF11167 (Lundbeck) is an inhibitor of a brainexpressed PDE enzyme for the potential treatment of
AD, Huntington’s chorea, and schizophrenia in a Phase
I clinical trial since March 2011 (Thomson Reuters
Pharma, update of August 8, 2012). The structure was
not communicated.
There are several PDE inhibitors in preclinical evaluation (in alphabetical order):
AMG-7980 (Amgen, Fig. 21) is a novel PDE10A
inhibitor with a Ki of 0.94 nM useful as tritiated
ligand to measure PDE10A target occupancy in rat
brain [1541, 1542].
AVE-8112 (Aventis, now sanofi and Michael J.
Fox Foundation) is a PDE4 inhibitor for the potential treatment of Parkinson’s disease. In April 2012,
a US Phase Ib study was planned (Thomson Reuters
Pharma, update of May 30, 2012). The structure was
not communicated.
BCA-909 (BCR-909; Boehringer Ingelheim under
license from biocrea GmbH) is a PDE2 inhibitor for
the potential treatment of mild cognitive impairment
in schizophrenia and AD (Thomson Reuters Pharma,
update of May 30, 2012). The structure was not
communicated.
Cilostazol (Otsuka), a selective PDE3 inhibitor, protected against A␤1-40 -induced suppression of viability
and neurite elongation [1543].
Dual PDE10/PDE 2 inhibitors (biocrea GmbH)
are investigated for the potential treatment of
schizophrenia and AD (Thomson Reuters Pharma,
update of January 18, 2012). Structures were not
communicated.
589
GEBR-7b (University of Genoa; Fig. 21) is a novel
PDE4D selective inhibitor that improves memory in
rodents at non-emetic doses [1544] (Thomson Reuters
Pharma, update of December 21, 2011).
ITI-002A, IC-200214, and ITI-214 (Takeda
under license of Intra-Cellular Therapies) are PDE1
inhibitors for the potential oral treatment of cognitive disorders associated with schizophrenia (Thomson
Reuters Pharma, update of July 30, 2012). The structures were not communicated.
OMS-182410 (Omeros) is a PDE10 inhibitor for
the potential treatment of schizophrenia (Thomson
Reuters Pharma, update of July 19, 2012). The structure was not communicated.
PDE2A inhibitor (Pfizer, Fig. 21) is evaluated for
the potential treatment of cognitive impairment associated with schizophrenia. In March 2012, a PDE2A
inhibitor with an IC50 of 4 nM was presented at the
243rd ACS Meeting in San Diego (Thomson Reuters
Allosteric PDE4 inhibitors (Tetra Discovery Partners; West Virginia University) are evaluated for
the potential treatment of mild cognitive impairment
Structures were not communicated.
PDE7 inhibitors (Omeros) are a potential new
treatment of Parkinson’s disease (Thomson Reuters
Pharma, update of May 23, 2012). The structures were
not communicated.
A PDE9 inhibitor (Pfizer; Fig. 21) for the potential
treatment of AD was found to penetrate mouse brain
and had a half-life of 6.8 hour in dog (Thomson Reuters
A PDE10 inhibitor (biocrea, a spin-out from BioTie
Therapeutics following its acquisition of elbion,
Fig. 21) is investigated for the potential treatment
of Huntington’s disease. (Thomson Reuters Pharma,
1 8F-PF-0430 (Pfizer, Fig. 21) is a PDE2-selective
CNS PET ligand for the potential diagnosis of
Alzheimer’s disease. (Thomson Reuters Pharma,
update of October 03, 2012).
PF-999 (Pfizer, Fig. 21) is a PDE2A inhibitor for the
potential treatment of cognitive impairment associated
with schizophrenia. (Thomson Reuters Pharma, update
of September 6, 2012).
Sildenafil (Pfizer, launched as Viagra in 1998) and
Tadalafil (Lilly launched as Cialis in 2003), potent
PDE5 inhibitors, restored cognitive function without
affecting A␤ burden in a mouse model of AD. Tadalafil
reversed cognitive dysfunction in a mouse model of AD
[1545, 1546].
590
Fig. 21. Ten phosphodiesterase inhibitors and a phospholipase A2 inhibitor.
THPP-1 (Merck, Fig. 21) is a potent, orally bioavailable PDE10A inhibitor, which improved episodic-like
memory in rats and executive function in Rhesus monkeys [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/6J
mice [1276, 1277].
The development of many PDE inhibitors was
terminated, of D-159687 and DG-071 (deCODE
genetics, now DGI Resolution), denbufylline (BRL30892; SmithKline Beecham, now GSK [1548]),
HT-0712 (IPL-455903; Helicon under license from
Orexo; a PDE4 inhibitor, Fig. 21 [1549, 1550]), IC-041
(Intra-Cellular Therapies), KS-505a (Kyowa Hakko
Kirin), of MEM-1018, MEM-1091, MEM-1414
(R-1533) and MEM-1917 (Memory Pharmaceuticals, now Roche), MK-0952 (Merck, a selective
PDE4 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 license
from Bayer Schering Pharma [1521, 1559–1566]),
V-11294A (Napp Pharmaceutical Group) and
YF-012403 (Columbia University, a PDE5 inhibitor).
2.30. Drugs interacting with Phospholipase A2
and D2
Phospholipase A2 reduction ameliorated cognitive
deficits in a mouse model of AD [1567–1569]. These
findings were confirmed by genetic phospholipase A2
and D2 ablation studies [1570–1572].
Rilapladib (SB-659032; GSK using a technology licensed from Human Genome Science; Fig. 21)
is a lipoprotein-associated phospholipase A2 (LPPLA2) inhibitor for the potential oral treatment of
atherosclerosis and AD. In October 2011 a randomized, double-blind, placebo-controlled Phase II study
was initiated in 120 AD patients with evidence of
cardiovascular disease in Europe. The study was scheduled to complete in November 2012 (Thomson Reuters
Pharma, update of June 26, 2012).
Icosapent ethyl (AMR-101, SC-111, LAX-101;
MND-21; Epadel; ethyl-eicosapentaenoic acid;
Mochida Pharmaceutical and Amarin under license
from Scotia Holdings), a phospholipase A2 inhibitor,
was launched in Japan for the treatment of arteriosclerosis obliterans. The drug was in Phase IIa
clinical trials for the treatment of AD by Mochida,
which were completed in May 2007 and in Phase IIa
clinical trials for the treatment of memory disorders
in age-associated memory impairment in the UK by
Amarin, which started in May 2008. By 2011 the
development for age-associated memory impairment
was discontinued (Thomson Reuters Pharma, update
of August 29, 2012).
2.31. Drugs interacting with plasminogen
activator inhibitor (PAI)
PAI-1 (serpin E1) is a serine protease inhibitor
that functions as the principal inhibitor of tissue
591
plasminogen activator (tPA) and urokinase, the activators of plasminogen and hence fibrinolysis [1573].
Elevated serum PA1-1 was associated with a high
risk for cognitive dysfunction [1574]. PAI-1 promoted
synaptogenesis and protected against A␤1-42 -induced
neurotoxicity [7]. PAI-1 was also related to lower
speed and visuomotor coordination in elderly subjects
[1575]. PAI-1 may be a useful marker for vascular
dementia [1576]. The plasmin system of AD patients
was discussed [1577].
IMD-4482 (Institute of Medicinal Molecular
Design, IMMD) is an inhibitor of PAI-1 for the potential treatment of fibrotic diseases. The indication AD
is 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-ribose
polymerase (PARP)
Cognitive impairment can be prevented by PARP1 inhibitors administered after hypoglycemia [1578,
1579]. Cognitive and motor deficits were reduced in
mice deficient in PARP-1 [1580].
E-7016 (Eisai following the acquisition of MGI
Pharma, formerly Guilford; presumed to be GPI-21016
under license from Johns Hopkins University, Fig. 22)
is an orally active, brain-penetrable, PARP PAR synthase inhibitor currently in Phase II clinical trials
for the treatment of stage III/IV melanoma patients
[1581]. The indications AD and stroke were abandoned
2012).
MP-124 (Mitsubishi Tanabe Pharma) in a PARP
inhibitor for the potential treatment of acute ischemic
stroke 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 neuroprotective agent and PARP stimulator in preclinical
studies (Thomson Reuters Pharma, update of May 9,
2012).
2.33. Drugs interacting with prolyl endo peptidase
Several reviews on prolyl endo peptidase, also
known as prolyl oligopeptidase, as a potential target
for the treatment of cognitive disorders were published
[1582–1584]. Sustained efforts over many years have
gone into the discovery and characterization of potent
prolyl endopeptidase inhibitors for the treatment of
592
memory disorders [1585]. Potent prolyl endopeptidase
inhibitors, such as KYP-2047 and JTP-4819, did not
increase striatal dopamine, acetylcholine, neurotensin
and substance P levels [1586–1588].
Subchronic administration of rosmarinic acid, a
natural prolyl oligopeptidase inhibitor, enhanced cognitive performances [1589].
The development of many prolyl endopeptidase
inhibitors was terminated, of eurystatin A (BristolMyers Squibb [1590–1593]), JTP-4819 (Japan
Tobacco [1594–1597]), KYP-2047 (Univ. of Kuopio
and Finncovery [1598]), ONO-1603 (Ono Pharmaceuticals [1599, 1600]), S-17092 (Servier [1601–1605])
and S-19825 (Servier [1606]), SUAM-1221 (Chinoin
and sanofi [1598, 1607–1610]), Y-29794 (Yoshitomi, now Mitsubishi Pharma Corp. [1611, 1612]),
Z-321 (Zeria Pharmaceutical [1613–1615]) and ZTTA
[1616].
2.34. Drugs interacting with prostaglandin D & E
synthases
Reviews on the biochemical, structural, genetic,
physiological, and patho-physiological features of
lipocalin-type prostaglandin D synthase were disclosed [1617, 1618]. The three prostaglandin E
synthases were described [1619] as was prostaglandin
E2 synthase inhibition as a therapeutic target [1620]
and the COX-1 mediated prostaglandin E2 elevation
and contextual memory impairment [1621]. Deletion
of microsomal prostaglandin E synthase-1 protected
neuronal cells from the cytotoxic effects of A␤
[1622].
HF-0220 (7-beta-hydroxy-epiandrosterone; Newron Pharmaceuticals; Fig. 22) is a cytoprotective
steroid, which stimulated prostaglandin D synthase
for the potential treatment of AD. A Phase IIa multicenter, double-blind, placebo-controlled, biomarker
trial (NCT00357357) in AD patients was initiated in
April 2007. The randomized, double-blind, placebocontrolled pilot study enrolled 42 patients in the UK,
Sweden, and India. Subjects received 1 to 220 mg/day
of the drug and were allowed to continue with their
current AD treatment. Results were reported in October 2008. HF-0220 was well tolerated at all doses
2012).
AAD-2004 (GNT Pharma, formerly Neurotech and
US subsidiary AmKor, Fig. 22) is a prostaglandin E
synthase-1 inhibitor for the treatment of AD, Parkinson’s disease, and amyotrophic lateral sclerosis. A
Phase I study was initiated in April 2010. By December
2011, the Phase Ia single ascending dose trial had been
successfully completed. In April 2012, it was reported
that a Phase Ib multiple ascending-dose trial to evaluate safety and biomarker profiles was planned for
that 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␤ elevation, and cognitive deficits in AD transgenic mice
[1623, 1624]. The pharmacology of PKC activators
was extensively reviewed [1625–1629].
APH-0703 (Aphios Corp.), a potent PKC activator, enhanced the generation of non-amyloidogenic,
soluble A␤PP in fibroblasts from AD patients. It
reduced brain amyloid plaques (A␤40 and A␤42 ) in
double-transgenic mice. The drug, formulated using
Aphios’s hydrophobic-based and SFS-PNS polymer
nanospheres technologies, is in Phase II clinical trials
since May 2010 (Thomson Reuters Pharma, update of
July 5, 2012). The structure was not communicated.
Potent activators of PKC are indirect activators of ␣secretase [1630–1632].
Bryostatin-1 (Blanchette Rockefeller Neurosciences Institute) is a naturally occurring PKC
activator isolated from the Californian marine
bryozoan Bugula neritina. In February 2012, the
Institute was preparing to initiate clinical trials in
neurological disorders. Dual effects of bryostatin-1
on spatial memory and depression were described
[1633–1635]. Postischemic PKC activation to rescue
long-term memory was investigated [1636, 1637]. The
chemistry and biology of bryostatins was reviewed
[504] (Thomson Reuters Pharma, update of February
24, 2012). See also Section 2.2. Drugs interacting
with ␣-secretase.
DCP-LA (Hyogo College of Medicine; Fig. 22)
is an activator of PKC␧ for the potential treatment
of stroke and cognitive disorder (Thomson Reuters
PKC epsilon activators (Blanchette Rockefeller
Neurosciences Institute) are evaluated for the potential treatment of cognitive disorder (Thomson Reuters
Pharma, update of February 17, 2012). The structures
The development of FR-236924 (Fujisawa, now
Astellas; an activator of PKC␧ [1638–1641]) and of
K-252c (Kyowa Hakko Kogyo; a PKC inhibitor) was
terminated.
593
Fig. 22. A poly ADP-ribose polymerase inhibitor, prostaglandin D and E modulators, a protein kinase C ␧ activator, a Rac1 GTPase inhibitor
and a ras farnesyl transferase inhibitor.
2.36. Drugs interacting with protein tyrosine
phosphatase
The role of striatal-enriched protein tyrosine phosphatase in cognition was described [1642] as was the
involvement of PTPN5, the gene encoding the striatalenriched protein tyrosine phosphatase in schizophrenia
and cognition [1643]. A genome-wide association
study in 700 schizophrenic patients found that three
intronic SNPs in the protein tyrosine phosphatase
receptor type O were associated with learning and
memory [1644]. Knockout mice revealed a role for
protein tyrosine phosphatase in cognition [1645].
LDN-33960 (Yale University) is a striatal-enriched
protein tyrosine phosphatase inhibitor, which
increased the phosphorylation of NMDA receptors
and of ERK in a dose dependent manner. The drug
restored memory in a novel object recognition test in
triple transgenic mice. It appears that the development
of LDN-33960 was terminated (Thomson Reuters
Pharma, update of June 19, 2012).
2.37. Drugs interacting with Rac1 GTPase
The role of Rac1 GTPase in cognitive impairment
following cerebral ischemia in the rat was described
[1646]. The modulation of synaptic function by Rac1
may be a possible link to fragile X syndrome pathology
[1647, 1648].
Cytotoxic Necrotizing Factor 1, a modulator
of Rho GTPases including Rac, Rho, and Cdc42
subfamilies improved object recognition in mice
[1649].
Sanquinarinium chloride (ExonHit; Fig. 22) is an
selective Rac1/1b GTPase nucleotide binding inhibitor
with IC50 ’s of 58 ␮M and 4.6 ␮M for Rac1 and Rac1b,
respectively in nucleotide binding inhibition assays in
preclinical development (Thomson Reuters Pharma,
update of July 20, 2011).
The development of EHT-1864 (EHT-206, EHT101; ExonHit), an orally active small molecule Rac1
GTPase inhibitor capable of crossing the blood brain
barrier was discontinued [1650–1652].
594
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 Farnesyl
Transferase
Inhibiting farnesylation, but not geranylgeranylation, replicated the enhancement of LTP caused by
simvastatin via the activation of Akt [1653].
LNK-754 (OSI-754, CP-609754; AstraZeneca
following the acquisition of Link Medicine’s neuroscience assets under license from OSI Pharmaceuticals, a subsidiary of Astellas Pharma, and Pfizer;
Fig. 22) is an orally active inhibitor of ras farnesyl
transferase. Two Phase I clinical trials were initiated
in the US, one in May 2009 in 40 healthy elderly
subjects and one in November 2009 in 110 healthy
elderly subjects and in patients with mild AD. Treatment of transgenic mice at 6 months of age for 3 months
showed a clear reduction of plaques caused by either
␣-synuclein or A␤ [1654] (Thomson Reuters Pharma,
update of July 13, 2012).
S-adenosylhomocysteine hydrolase
Homocysteine potentiated A␤ neurotoxicity [1655].
The S-adenosyl homocysteine hydrolase inhibitor
3-deaza-adenosine prevented cognitive impairment
following folate and vitamin E deprivation in mice
[1656].
L-002259713 (Merck, Fig. 23) is a potent inhibitor
of S-adenosylhomocysteine hydrolase for the potential
treatment of AD. The development was discontinued
2012).
2.40. Drugs interacting with sirtuin
The neuronal protection by sirtuins in AD was
described [1657] as were details on the sirtuin pathway
in aging and AD [1658].
Resveratrol (Fig. 23) is a natural phyto compound,
which activates Sirtuin-1 [1659–1664]. It reduced
A␤ accumulation [1665–1668]. It remodeled soluble oligomers and fibrils of A␤ into off-pathway
conformers [1669]. Resveratrol is not a direct activator of SIRT1 enzyme activity [1670]. Resveratrol
improved memory deficits in mice fed a high-fat diet
[1671]. Subchronic oral toxicity and cardiovascular
safety pharmacology studies were carried out [1672].
The biosynthesis of resveratrol in yeast and in mammalian cells was worked out [1673]. The Georgetown
University Medical Center started at Phase II, randomized, double-blind, placebo-controlled study in
patients with mild to moderate AD (expected n = 120)
in the US in May 2012 (NCT015048549). A novel
application in Huntington’s disease was discussed
recently [1674] (Thomson Reuters Pharma, update of
June 22, 2012).
Selisistat (SEN-196, EX-527, SEN-0014196; Siena
Biotech under license from Elixir Pharmaceuticals;
Fig. 23) is a sirtuin-1 inhibitor for the potential
treatment of Huntington’s disease in Phase II trials (PADDINGTON, NCT01485965) in Europe since
April 2011 (Thomson Reuters Pharma, update of May
29, 2012).
INDUS-815C (Indus Biotech) is a natural NADdependent deacetylase sirtuin-2 (SIRT-2) inhibitor
for the potential treatment of Huntington’s disease.
In addition, the drug is evaluated for the potential
treatment of age-related macular degeneration and
retinopathy (Thomson Reuters Pharma, updates of
August 19, 2011 and August 16, 2011, respectively).
2.41. Drugs interacting with steroid sulfatase
Steroid sulfatase is a potential modifier of cognition in attention deficit hyperactivity disorder
[1675].
DU-14 (Dusquesne University, Fig. 23) is a
steroid sulfatase inhibitor for the potential enhancement of cognitive function via enhanced levels of
plasma dehydro-epiandrosterone and brain acetylcholine [1676–1679]. Its development was terminated.
2.42. Drugs interacting with transglutaminase
(TG2)
Tissue transglutaminase catalyzes protein crosslinking, an important molecular process in AD.
Accumulation of insoluble proteins with isopeptide
bonds, products of tissue transaminase activity, correlated with cognitive impairment [1680].
CHDI-00339864 (Fig. 23) and CHDI-00316226
(Evotec in collaboration with the CHDI Foundation) are selective TG2 inhibitors (IC50 = 7 nM for
TG2 for CHDI-00316226) for the potential treatment of Huntington’s disease. It displayed an 85
fold greater selectivity for TG2 over Factor XIIIA
(Thomson Reuters Pharma, update of February 10,
2012).
595
2.43. Drugs interacting with ubiquitin
carboxyl-terminal hydroxylase (Usp14)
Inhibitors of this enzyme could accelerate the degradation of neurodegenerative disease-related proteins,
such as tau, TDP-43, and ataxin-3. Changes in hippocampal synaptic transmission were observed in
Usp14-deficient mice [1681].
Usp14 inhibitors (Proteostasis Therapeutics under
license from Harvard University) are investigated for
the potential treatment of neurodegenerative diseases
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 and
BChE), three valuable medications are available for
the treatment of patients with mild to moderate AD.
Huperzine A was launched in China in 1995, but the
four times a day administration makes it less attractive,
a problem which will be solved by a transdermal patch
currently in Phase I evaluation as XEL-001HP by Xel
Pharmaceuticals.
The development of ten Phase III compounds tested
for the indication AD was terminated, of the AChE
inhibitors amiridin (Nikken), eptastigmine (Mediolanum), metrifonate (Bayer), phenserine (Anonyx),
and velnacrine (HMR, now sanofi), of the ␥-secretase
inhibitors begacestat (Pfizer) and semagacestat (Lilly),
the ␥-secretase modulator tarenflurbil (Myriad Genetics), and of the MAO inhibitors rasagiline (Teva) and
safinamide (Merck Serono).
Currently there is one compound interacting with
enzymes in the pre-registration phase (WIN-026,
WhanIN, an AChE inhibitor), one compound in
Phase III trials (masitinib, AB Science, a kinase
inhibitor), 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 NIC515 (␥-secretase inhibitors), CHF-5074 (␥-secretase
modulator), tideglusib (GSK-3␤ inhibitor), EVP0334 (HDAC inhibitor), RG-1577 (MAO-B inhibitor),
PF-02545920 (PDE10A inhibitor), rilapladib (PLA2
inhibitor), HF-0220 (prostaglandin D synthase stimulator), APH-0703 (PKC activator), and selisistat
(sirtuin-1 inhibitor).
It may be that positive results will be obtained from
the masitinib Phase III trials within the next two to
596
three years, whereas results from the Phase II trials
will be available only within the next five to six years.
[17]
DISCLOSURE STATEMENT
[18]
Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=1508).
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