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??-Secretase Inhibitors and Modulators for the Treatment of Alzheimer's

Disease: Disappointments and Hopes

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 Current Topics in Medicinal Chemistry, 2011, 11, 1555-1570 1555

-Secretase Inhibitors and Modulators for the Treatment of Alzheimer’s

Disease: Disappointments and Hopes

Bruno P. Imbimbo1,* and Giuseppe A.M. Giardina2

1
Research & Development Department, Chiesi Farmaceutici, Parma and 2NiKem Research, Baranzate, Italy

Abstract: According to the -amyloid (A) hypothesis, compounds that inhibit or modulate secretase, the pivotal en-
zyme that generates A, are potential therapeutics for Alzheimer’s disease (AD). Studies in both transgenic and non-
transgenic animal models of AD have indicated that secretase inhibitors, administered by the oral route, are able to
lower brain A concentrations. However, scanty data are available on the effects of these compounds on brain A deposi-
tion after chronic administration. Behavioral studies are also scarce with only one study indicating positive cognitive ef-
fects of a peptidomimetic compound acutely administered (DAPT). -Secretase inhibitors may cause abnormalities in the
gastrointestinal tract, thymus, spleen and skin in experimental animals and in man. These toxic effects are likely due to
inhibition of Notch cleavage, a transmembrane receptor involved in regulating cell-fate decisions. Some non-steroidal
anti-inflammatory drugs (NSAIDs) and other small organic molecules have been found to modulate secretase shifting
its cleavage activity from longer to shorter -amyloid species without affecting Notch cleavage. Long-term histopa-
thological and behavioral animal studies are available with these NSAIDs (mainly ibuprofen) but it is unclear if the ob-
served in vivo effects on A brain pathology and learning depend on their activity on -secretase or on other biological
targets. The most studied -secretase inhibitor, semagacestat (LY-450139), was shown to dose-dependently decrease the
generation of A in the cerebrospinal fluid of healthy humans. Unfortuantely, two large Phase 3 clinical trials of sema-
gacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of detrimental effects
on cognition and functionality in patients receiving the drug compared to those receiving placebo. These detrimental ef-
fects were mainly ascribed to the inhibition of Notch processing and to the accumulation of the neurotoxic precursor of
A (the carboxy-terminal fragment of APP, or CTF) resulting from the block of the -secretase cleavage activity on
APP. Two large Phase 3 studies in mild AD patients with tarenflurbil (R-flurbiprofen), a putative -secretase modulator,
were also completely negative. The failure of tarenflurbil was ascribed to low potency and brain penetration. New Notch-
sparing -secretase inhbitors and more potent, more brain penetrant -secretase modulators are being developed with the
hope of overcoming the previous setbacks.
Keywords: -secretase inhibitors, -secretase modulators, -amyloid, alzheimer’s disease.

INTRODUCTION disease. This hypothesis was conceptualized in 1991 by

Alzheimer’s disease (AD) is the most common cause of
dementia. Neuritic plaques, the characteristic lesions found
in the brain of AD patients, are composed mainly of aggre-
gates of a peptide with 40 or 42 amino acid residues known
as -amyloid (A) Fig. (1). The A peptide is the result of
the metabolic processing of a complex transmembrane gly-
coprotein known as amyloid precursor protein (APP). APP
may be metabolically processed according to two pathways
Fig. (1). In the so-called non-amyloidogenic pathway, the -
secretase enzyme cleaves APP within the A sequence and
releases extracellularly its soluble N-terminal fragment,
sAPP, that appears to exert neuroprotective activity. In the
amyloidogenic pathway, the -secretase enzyme releases
sAPP plus a 12 kDa protein fragment (C99 or CTF),
which in turn is cleaved by the -secretase enzyme giving
way to A. The correlation among A histopathologic
lesions, brain cell death and cognitive deficiency in AD
represents the so called “A cascade hypothesis” of the
*Address correspondence to this author at the Research & Development
Department, Chiesi Farmaceutici, Via Palermo 26/A, 43100 Parma, Italy;
Tel: +39 0521 279278; Fax:+39 0521 279579;
E-mail: b.imbimbo@chiesigroup.com
Hardy and Allsop [1]. The updated version of this theory
says that the oligomeric forms of A1-42 are the main cause
of neuronal death in AD [2,3].
-Secretase is formed by at least four proteins: presenilin
(PS), nicastrin, anterior pharynx-defective 1 (Aph-1) and
presenilin enhancer 2 (Pen-2). Presenilins are of exceptional
pathophysiological importance since more than 150 autoso-
mal dominant point mutations are known in these proteins,
all of which cause aggressive early-onset AD. These muta-
tions result in increased production of A142, the highly self-
aggregating and neurotoxic form of A, or an increased
A1-42 to A1-40 ratio. Thus, the inhibition of the catalytic
unit (presenilin) of the -secretase enzymatic complex ap-
pears to be a logical strategy for contrasting A accumula-
tion in the brain of AD patients and indeed many potent,
orally active and brain penetrant compounds have been syn-
thesized and developed [4]. Unfortunately, -secretase
cleaves many other important substrates other than APP [5],
one of the most relevant from toxicological point of view
being Notch. Thus, -secretase inhibitors block the process-
ing of other proteins and this is the main cause of toxicity in
preclinical testing and represents a major source of concern
in clinical trials. The discovery that some non-steroidal anti-

1568-0266/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.

1556 Current Topics in Medicinal Chemistry, 2011, Vol. 11, No. 12 Imbimbo and Giardina

Fig. (1). Schematic overview of APP processing. The top panel shows the APP region comprising the transmembrane sequence (underlined,
bold) and the sequences of A1-40 (D1-V40) and A1-42 (D1-A42) peptides. The -secretase cleaves at D1 and Y10. The
-secretase cleaves at
Lys16, and the -secretase cleaves at Val40 and/or Ala42. Below the sequence is a representation of APP with the residue numbers of interest
in - and -secretase cleavage. Panel A represents the non-amyloidogenic
-secretase pathway in which sAPP
and C83 are generated. Sub-
sequent hydrolysis by the -secretase produces a p3 peptide that does not form amyloid deposits. Panel B represents the amyloidogenic path-
way in which cleavage of APP by the -secretase to liberate sAPP and C99 is followed by -secretase processing to release -amyloid pep-
tides (A1-40 and A1-42) found in plaque deposits (from John et al, 2003).

inflammatory drugs (NSAIDs) may modulate the cleavage olytic event. Nicastrin is a 709- amino acid type 1 membrane
activity of -secretase on APP without interfering with the glycoprotein with a large ectodomain that may act
cleavage of other substrates [6], have lead to intensive efforts
in designing -secreatase modulators that appear much more
attractive from safety point of view than traditional -
secretase inhibitors [7]. This article reviews the profile of -
secretase inhibitors and modulators that have reached the
clinic and will discuss the pharmacological and clinical is-
sues of this new class of anti-AD compounds both in terms
of safety and efficacy.
THE STRUCTURE OF THE -SECRETASE COM-
PLEX
-Secretase is an unusual aspartyl protease that cleaves its
substrates within the transmembrane region. This enzyme
was shown to consist of four protein components: presenilin
(PS) 1 or 2 (which contains the catalytic domain), nicastrin
(which may serve to dock substrates), Aph-1 (anterior phar-
ynx-defective 1), and Pen-2 (presenilin enhancer-2) in a
1:1:1:1 ratio Fig. (2) [8]. Presenilin-1 (PS-1) and preseneni-
lin-2 (PS-2) are 476- and 448-amino acid proteins consisting
of nine transmembrane domains (TMDs) and are endoprote-
olytically cleaved into a 30 kDa N-terminal fragment and a
20 kDa C-terminal fragment, each of which contains an
Fig. (2). Schematic structure of the -secretase enzymatic complex
aspartate active site. The cleavage occurs in the large cyto-
and of its processing of the C99 substrate (nicastrin = green, Aph-1
plasmic loop between TMD6 and TMD7 within a short hy-
= blue, Pen-2 = red, presenilin N-terminal = yellow, presenilin C-
drophobic domain that is believed to dive into the mem-
terminal = light blue) (from Kreft et al, 2009).
brane. This endoproteolysis is believed to be an autoprote-

-Secretase Inhibitors and Modulators for the Treatment of Alzheimer’s Disease
as a -secretase substrate receptor. It is hypothesized that the
free N-terminus of the -secretase substrate(s) first binds to
the ectodomain of nicastrin, which may facilitate its interac-
tion with the docking site on PS which is followed by reloca-
tion to the active site on PS where it is cleaved. Pen-2 is the
smallest component (10 kDa) of -secretase and is thought
to be required for the stabilization of the PS fragments in the
-secretase complex. Aph-1 is a seven-TMD protein ( 20
kDa) whose function in -secretase is currently unclear. It
has been found that Aph-1 can exist as two splice variants:
Aph-1a and Aph-1b [9]. Thus, several different -secretase
complexes are possible depending on whether they contain
PS-1 or PS-2 and whether they contain Aph-1a or Aph-1b. It
has been proposed that nicastrin and Aph-1 form an initial
complex that sequentially adds PS and Pen-2. The first high
resolution (12 Å) structure of -secretase have been recently
obtained [10] and revealed a globular structure with a num-
ber of cavities that are open to either the extracellular space
or the cytosol as well as an almost continuous surface groove
at the membrane region that could be a substrate entry site.
-SECRETASE INHBITORS THAT HAVE REACHED
CLINICAL DEVELOPMENT
In 2001 Eli Lilly firstly reported the in vivo inhibition of
brain A with DAPT, a peptidomimetic -secretase inhibitor
[11]. Several other non-peptidic, orally available, secretase
inhibitors have been synthesized [12]. Nevertheless, data on
the cognitive effects of single and prolonged administration
of -secretase inhibitors in animal models of AD are scanty,
the only published study being one on DAPT [13]. In this
study, single oral doses of DAPT (100 mg/kg) reversed the
contextual fear-conditioning deficit of Tg2576 mice only
when administered before training. Peak inhibitions of about
30% in soluble brain A140 and A142 levels were measured
at 4 and 8 hours, respectively, after dosing.
Historically, the first -secretase inhibitor publicly re-
ported to reach the clinic is a compound synthesized at Bris-
tol-Myers Squibb (BMS-299897). The drug was later aban-
doned. At least six other secretase inhibitors (LY-450139,
PF-3084014, MK-0752, BMS-708163, GSI-953 and
ELND006) reached the clinic (Table 1). For only one com-
pound (LY-450139) clinical data have been fully published.
Most of the information on the other compounds derives
from congress communications.
LY-450139 (Semagacestat)
The benzoazepinone derivative LY-450139 Fig. (3) is a
-secretase inhibitor developed at Eli-Lilly. LY-450139 is
only 3-fold selective in inhibiting APP and Notch cleavage
(APP IC50 = 15 nM, Notch EC50 = 49 nM) [14]. LY-450139
is the best documented -secretase inhibitor that has reached
clinical testing and for which clinical studies have been fully
published. In experimental animals, the effects of LY-
450139 on A levels in brain, cerebrospinal fluid (CSF) and
plasma were well characterized in transgenic mice [15], non-
transgenic mice [16], guinea pigs [17] and dogs [18]. Never-
theless, the drug failed to show a statistically significant ef-
fect on brain plaque deposition in chronic studies in trans-
genic mice expressing mutated human APPV717F (PDAPP
mice) [19]. More importantly, no data are available on the
Current Topics in Medicinal Chemistry, 2011, Vol. 11, No. 12 1557
cognitive or behavioral effects of the drug in animal models
of AD [20]. The lack of cognitive effects of semagacestat in
animals could be linked to the fact that the drug has neuro-
toxic effects in vivo. A study employing in vivo two-photon
imaging showed that dendritic spines get irreversibly lost in
the cerebral cortex of wild-type mice after only 4 days of
treatment with semagacestat (30 mg/kg s.c.). The same ex-
periments carried out in APP-deficient mice suggested that
APP-cleavage products (probably an accumulation of C-
terminal fragments), are critically involved [21].
Many studies with semagacestat have been conducted in
man. A Phase 1 study evaluated the safety and tolerability
and biomarker responses to single oral doses of 60, 100, or
140 mg in 31 healthy male and female volunteers (40 years
and older) [22]. No clinically significant adverse events or
laboratory changes were observed in this study. A dose-
proportional increase in drug exposure was observed in
plasma and in CSF with an estimated CNS penetration of
8%. Peak drug plasma levels occurred at 1 h and then de-
clined with a half-life of 2.5 h. A dose-dependent decrease in
plasma A1-40 levels was also demonstrated with maximum
inhibition (-73%) at 6 h after the administration of the 140-
mg dose. A rebound effect on plasma A1-40 levels was ob-
served at 8-12 hours after administration and lasted for at
least the 24 h. Cerebrospinal fluid concentrations of A were
unchanged 4 hours after drug administration. In a second
Phase 1 study, LY-450139 was administered to 37 healthy
men and women (45 years and older) for up to 14 days at
doses of 5, 20, 40 and 50 mg once daily [23]. Two subjects
in the 50-mg dose group developed possibly drug-related ad-
verse events and discontinued treatment. The first subject had
significant increases in serum amylase and lipase and com-
plained of moderate abdominal pain. The other subject re-
ported diarrhea that was positive for occult blood. The
plasma half-life of LY-450139 was found to be approxi-
mately 2.5 h and peak plasma concentrations were achieved
about 1 hour after administration. The 50-mg dose caused a
maximal 40% reduction in total plasma A that returned to
baseline within 8 hours. After returning to baseline, plasma
A levels increased to about 300% of baseline values at 15
hours before slowly declining again. At lower doses, smaller
and shorter decreases in plasma A were observed, although
the subsequent plasma A increases were similar. No signifi-
cant changes in cerebrospinal fluid A levels were detected.
LY-450139 has been extensively evaluated in AD pa-
tients. In a first randomized, placebo-controlled trial, 70 pa-
tients received the drug for 6 weeks (30 mg once a day for 1
week followed by 40 mg once a day for 5 weeks) [24]. Six
patients taking LY-450139 reported diarrhea. A 76-year-old
man on LY-450139 had gastrointestinal bleeding associated
to a Barrett esophagus, a clinical condition characterized by
the conversion of normal squamous cells into abnormal spe-
cialized columnar cells. Approximately 4 months after dis-
continuing treatment, the patient developed endocarditis and
approximately 1 month thereafter, died. In the LY-450139-
treated group, circulating CD69, T lymphocytes, eosinophils,
and serum concentrations of potassium and inorganic phos-
phorus showed statistically significant changes, although
these findings were reported as “clinically irrelevant”.
Plasma A1-40 concentrations of patients taking the com-
1558 Current Topics in Medicinal Chemistry, 2011, Vol. 11, No. 12 Imbimbo and Giardina

Table 1. -Secretase Inhibitors that have Reached Clinical Development for the Treatment of Alzheimer’s Disease (see Figure 3 for
Chemical Structures)

Compound Main Refer-

Pros Cons Development Company
Status ences

Worsens dose-dependly cognitive and

functional decay of AD patients.
Decreases production of newly syn- Increases skin cancer in AD patients.
Semagacestat
thesized A
in the CSF of healthy Is neurotoxic (reduced dendritic spine Discontinued Eli-Lilly [21-27]
(LY-450139)
humans density) in mice. Lack of data on
behavioral effects in animal models
of AD.

Notch sparing.
Lack of data on brain plaque deposi-
Good brain penetration.
tion in transgenic mice
Long-lasting effects on A
levels in
Lack of data on behavioral effects in Discontinued
PF-3084014 animals. Pfizer [38]
animal models of AD. for AD
No rebound effect on plasma
Unfavourable PK/PD profile. In hu-
A
in animals
mans

Decreases A
1 -40 levels in CSF of Inhibits Notch cleavage. Significant Discontinued
MK-0752 Merck [29]
healthy volunteers gastro-intestinal toxicity in humans for AD

Lack of data on brain plaque deposi-

Notch sparing. tion in transgenic mice. Bristol
BMS-708163 Decreases A
levels in CSF of Lack of data on behavioral effects in Phase 2 Myers [32,34,35]
healthy volunteers animal models of AD Squibb
Poor tolerability in AD patients

Lack of data on brain plaque deposi-

Notch sparing.
tion in transgenic mice.
Begacestat Good brain penetration
Does not decrease A
levels in CSF Phase 2 Wyeth [39,40]
(GSI-953) Improves memory in a transgenic
of AD patients. Causes rebounds on
mouse model of AD
plasma A
40 levels in man

Notch sparing. Produces late rebounds in plasma

Good brain penetration A
in animals.
ELND-006 Phase 1 Elan [44]
Decrease brain A
burden in trans- Lack of data on behavioral effects in
genic mice animal models of AD.

F
OH O
H H H
N N N
N N N
N
H Me H
O Me O F O N

Semagacestat (LY-450139) PF-3084014

CF3

CF3 O O
CF3 H2N S
N
OH O Cl
NH
Cl S S
N
O O F O
N
Begacestat (GSI-953) BMS-708163

MK-0752 (no structure disclosed) ELND-006 (no structure disclosed)

Fig. (3). Chemical structure of -secretase inhibitors that have reached clinical development.

-Secretase Inhibitors and Modulators for the Treatment of Alzheimer’s Disease
pound decreased significantly by 38% compared to baseline.
The lowest concentration was achieved approximately 3
hours after administration of a 40-mg dose and returned to
baseline approximately 7 hours postdose. A140 concentra-
tions in cerebrospinal fluid did not decrease significantly.
Another study evaluated the safety, tolerability, and A
response to LY-450139 in 51 AD patients treated for 14
weeks [25]. Patients were randomized to receive placebo (n
= 15) or LY-450139 (n = 36). Patients on LY-450139 re-
ceived 60 mg/day for 2 weeks, then 100 mg/day for 6 weeks,
and then either 100 or 140 mg/day for 6 additional weeks.
Forty-three patients completed the study. There were 7 cases
of skin rashes and 3 reports of hair color change in the drug
treatment groups. There were 3 adverse event-related discon-
tinuations, including 1 transient bowel obstruction. Com-
pared to placebo, A140 plasma concentrations were reduced
by 58% in the 100-mg group and 65% in the 140-mg group.
No significant reduction was seen in cerebrospinal fluid A
levels. No differences were seen in cognitive or functional
measures between placebo-and LY-450139-treated patients.
The effects of semagacestat (100, 140 and 280 mg) on
A synthesis and clearance in CSF of 20 healthy volunteers
have been investigated with a relatively new technique,
based on the intravenous administration of a stable isotope-
labeled aminoacid (13C6-leucine) [26]. CSF was collected
hourly with a lumbar catheter. A dose-dependent decrease in
levels of newly-generated A was observed; this was statis-
tically significant at all doses versus placebo. The mean de-
crease in A generation was 47, 52 and 84% over a 12-h
period with doses of 100, 140 and 280 mg, respectively.
There was a significant inverse relationship between sema-
gacestat concentrations in the CSF and the amount of newly
generated A in CSF (r = -0.646; p = 0.002). Furthermore,
the AUC of CSF A (measured by ELISA) tended to de-
crease in this time period, with significance from placebo
achieved in the 280-mg group (48.2% decrease). Interest-
ingly, there was a rebound effect on CSF A142 concentra-
tions at later times (24 to 36 h); compared with placebo, a 2-
fold increase was observed at 30 h with the 280-mg dose.
Clearance of A was unaffected by semagacestat.
In April 2008, Eli Lilly has initiated its first Phase 3
clinical trial (IDENTITY) of semagacestat in about 1,500
mild to moderate AD patients with the hope of slowing dis-
ease progression. Patients would be treated with semagaces-
tat (100 or 140 mg po, qd) for 21 months, with the option of
enrolling in an open-label extension trial for further treat-
ment. Patients taking symptomatic treatments for AD were
permitted to continue treatment. The trial incorporated a
'randomized delayed start' design, which means that patients
initially assigned to the placebo arm will be administered
semagacestat sometime before the end of the 21-month pe-
riod to assess the effects on disease progression. The primary
outcome measures of efficacy were the ADAS-Cog scale for
cognition and the ADCS-ADL scale for functionality. Sec-
ondary endpoints include A levels in plasma and CSF and
other brain biomarkers determined by neuroimaging [20]. Eli
Lilly initially estimated the trial would be completed by
March 2012. A second Phase 3 trial, called IDENTITY-2,
was also started in about 1,100 patients with mild to moder-
ate AD. Patients would be treated with semagacestat (60 mg
Current Topics in Medicinal Chemistry, 2011, Vol. 11, No. 12 1559
po, qd, titrated to 140 mg po, qd) for 21 months, with the
option of enrolling in an open-label extension trial for further
treatment. Patients taking symptomatic treatments for AD
were permitted to continue treatment. The trial also incorpo-
rated a randomized delayed start design, similar to IDEN-
TITY. The primary outcome measures of efficacy were the
ADAS-Cog scale for cognition and the ADCS-ADL scale for
functionality. Secondary endpoints include other dementia
rating scales, A levels in plasma and CSF and other brain
biomarkers determined by neuroimaging. The dose titration
based on patient tolerability was designed to provide a more
'real-world simulation' of semagacestat. Eli Lilly estimated
the trial would be completed by June 2012 [20]. Unfor-
tunetly, on August 17, 2010, Eli Lilly announced that the
preliminary results from the two Phase 3 trials showed se-
magacestat worsened clinical measures of cognition and the
ability to perform activities of daily living compared to pla-
cebo. In addition, data showed semagacestat was associated
with an increased risk of skin cancer compared with those
who received placebo. The detrimental effects of semagaces-
tat appeared to be dose-dependent [27]. These negative find-
ings lead the company to interrupt the development of sema-
gacestat, although the two studies are still ongoing in double-
blind conditions to follow up the cognitive and clinical con-
ditions of the patients [27].
MK-0752
Merck is developing a -secretase inhibitor (MK-0752,
no structure disclosed) that does not distinguish between
APP and Notch. Doses of 30 or 60 mg/kg orally to rhesus
monkeys produced high plasma levels (Cmax of 32 or 88 M
and an AUC of 477 or 858 Mh, respectively) but unfortu-
nately spleen and ileum toxicity due to inhibition of Notch
signalling [28]. A Phase 1 study evaluated the safety, toler-
ability, pharmacokinetics and pharmacodynamics of single
oral doses (from 110 to 1000 mg) of MK-0752 in 27 healthy
young men [29]. The drug was generally well tolerated.
Drug plasma levels increased proportionally to the dose,
peaked at 3-4 hours and then declined with a half-life of
about 20 hours. MK-0752 CSF levels were similar to un-
bound plasma concentrations, suggesting a good penetration
of the drug into the CNS. MK-0752 Doses of 500 mg sig-
nificantly inhibited for 12 hours A
1-40 concentrations in
cerebrospinal fluid with a peak inhibitory effect of 35%. Af-
ter 1000 mg, cerebrospinal fluid A140 inhibition was sus-
tained over 24 hours. Plasma A
1-40 concentrations also
showed a dose-dependent decrease but were followed by a
later rebound over baseline levels.
Although MK-0752 was initially developed as a treat-
ment for AD, in mid 2005, Phase 1 trials in patients with
advanced breast cancer and in patients with T-cell acute
lymphoblastic leukemia (T-ALL) were initiated and results
were presented in June 2006 [30]. Indeed, there is increasing
interest in the applicability of -secretase inhibitors to the
treatment of cancer. MK-0752 has been shown to inhibit -
secretase-mediated cleavage of Notch with an IC50 of 55 nM.
Increasing evidence implicates the Notch pathway in normal
T-cell lymphopoiesis and the pathogenesis of several human
malignancies. Prolonged activation of the Notch signal
transduction pathway occurs in more than 50% of patients
1560 Current Topics in Medicinal Chemistry, 2011, Vol. 11, No. 12
with T-cell acute lymphoblastic leukemias and is important
in the pathogenesis of the disease. Preclinical studies indi-
cate that pharmacologic inhibition of -secretase activity
suppresses T-cell acute lymphoblastic leukemias cell growth
and induces apoptosis by preventing cleavage of Notch, thus
preventing prolonged activation in downstream pathways.
Unfortunately, studies with MK-0752 in pediatric and adult
patients with T-cell acute lymphoblastic leukemias and acute
myeloid leukemia reported that drug was associated with
gastrointestinal toxicity and fatigue without substantive
clinical activity [30].
An intermittent dosing schedule appears to reduce toxic-
ity while demonstrating adequate target inhibition, warrant-
ing further evaluation [31]. In February 2008, the Phase 1
trial of MK-0752 in combination with docetaxel began in 30
patients with locally advanced or metastatic breast cancer.
The primary outcome was dose limiting toxicity. At that time
the estimated study completion date was March 2012. In
May 2008, an open-label, uncontrolled pilot study was initi-
ated in 20 women with early stage, estrogen receptor positive
breast cancer to establish the safety and tolerability of MK-
0752 in the pre-surgical setting in combination with ta-
moxifen or letrozole. The study was expected to be com-
pleted in late 2010.
BMS-708163
The benzene sulfonamide BMS-708163 Fig. (3), in
which an oxadiazolylbenzyl group is attached to the sul-
fonamido nitrogen, is a potent, Notch-sparing, -secretase
inhibitor in development at Bristol-Myers Squibb. In vitro,
the drug shows a 193-fold selectivity versus Notch cleavage
(A1-40 IC50 = 0.3 nM and Notch EC50 = 58 nM) [32]. Stud-
ies in rats have shown that BMS-708163 dose-dependently
decreases CSF and brain A1-40 levels without causing
Notch-related gastrointestinal and lymphoid toxicity [33]. In
dogs receiving 2 mg/kg orally a decrease in brain and CSF
A1-40 levels were observed for at least 24 hours and peak
inhibition around 75% in CSF and 50% in the cortex [32].
Studies in healthy young subjects have indicated that
BMS-708163 is well tolerated up to 400 mg after single ad-
ministration and up to 150 mg/day after multiple doses for
28 days [33]. After oral administration, BMS-708163 ap-
pears to be quickly absorbed (Tmax = 1-2 h), to produce sys-
temic exposure proportional to the dose (up to 200 mg) and
to be slowly eliminated (terminal half-life  40 h). The ef-
fects of BMS-708163 in CSF A levels in humans were
evaluated after both single and multiple oral doses. Twelve
hours after a single administration, doses of 200 and 400 mg
to young subjects produced 37% and 40% reductions, re-
spectively in CSF A140 levels versus baseline. The corre-
sponding inhibitory values for CSF A142 levels were 32%
and 34%, respectively. Exposure for BMS-708163 in CSF
was much lower (< 1%) than in plasma [34]. After multiple
administrations for 4 weeks (50-150 mg/day), steady-state
trough CSF A140 levels were reduced dose-dependently
compared to baseline values [35]. A 24-week dose-range
(25, 50, 100 and 125 mg/day) finding Phase 2 study in 209
mild-to-moderate AD patients has been completed in June
2010 but data have not been released (ClincalTrials.gov
Identifier NCT00810147). A 104-week Phase 2 study in pa-
Imbimbo and Giardina
tients with prodromal AD was started in May 2009 and is
still recruiting patients (ClinicalTrials.gov Identifier
NCT00890890). Initially, the study was planned to last 52
weeks and later was amended to prolong treatment to 104
weeks. Dosing regimens were initially 50, 100 and 125
mg/day. Later due to tolerability problems, the two upper
doses were discontinued.
PF-3084014
The novel aminotetraline derivative PF-3084014 Fig. (3)
is a potent, Notch-sparing, -secretase inhibitor in develop-
ment at Pfizer. In a cell-free assay, PF-3084014 appears to
be a non-competitive but reversible inhibitor of human -
secretase activity with an IC50 of 6.2 nM [36]. In a whole-
cell assay, PF-3084014 displays an IC50 of 1.3 nM. In fetal
thymus organ culture assay, PF-3084014 appears to be a
weak inhibitor of Notch signaling with an IC50 of 1915 nM.
The APP to Notch selectivity ratio is 1,473. In guinea-pigs,
dose-response inhibition of total A levels was observed in
plasma, CSF and brain after subcutaneous administration
(0.03-10 mg/kg). At the highest dose (10 mg/kg), A
levels
were reduced by 70% in brain and plasma, and by 50% in
CSF, which was maintained at 30 hours post-dose. No late
rebound effects on plasma A
were observed. Drug levels in
the brain were similar to that measured in plasma. Studies in
young (plaque-free) Tg2576 transgenic mice showed that
brain, CSF, and plasma levels of A were inhibited dose-
dependently following doses of 1 to 18 mg/kg. At the highest
dose (18 mg/kg), A
levels were reduced by 78% in brain,
72% in CSF, and 92% in plasma. A
1-40 was most potently
inhibited in all compartments. A
1-42 showed approximately
20% less reduction than A
1-40 in all compartments [36].
However, dose-dependent increases in A11-40 and A1-43
were seen at doses that potently inhibited A1-40 and A1-42.
In addition, PF-3084014, like previously described gamma-
secretase inhibitors, preferentially reduced A1-40 relative to
A1-42 [36].
In healthy volunteers enrolled in a Phase 1 study, single
doses were associated with mild and self-limiting adverse
events, no apparent clinically relevant changes in vital signs
and no significant ECG trends [37]. Doses of 1-120 mg were
safe and well tolerated, and the maximum tolerated dose was
not identified. Mean pharmacokinetic variables with the sin-
gle 120 mg dose included an oral clearance of approximately
16 mL/min/kg, an half-life of approximately 19 hours, a
mean Cmax of approximately 21 nM and an average steady-
state concentration of approximately 4 nM [37]. However, an
analysis of pharmacokinetic/pharmacodynamic data from a
study of multiple oral dosing in humans led to the decision to
end development of the compound for AD [38]. Plasma drug
and A concentrations collected from 18 healthy volunteers
given 40 or 90 mg dose once daily for 14 days were used to
model the relationship between these concentrations. Phar-
macokinetic-pharmacodynamic profiles for these doses were
used to extrapolate the profile at higher doses. This popula-
tion pharmacokinetic-pharmacodynamic analysis yielded the
finding that exposure levels needed to reach the prespecified
area above the effect curve target for plasma inhibition of
A140 on Day 14 relative to Day 1 were 2- to 3-fold higher
than exposure limits based on animal toxicology data. As a

-Secretase Inhibitors and Modulators for the Treatment of Alzheimer’s Disease
result, much higher doses than those previously used would
be need to attain a high probability of technical success [38].
PF-3084014 has now entered clinical study as an anti-
cancer agent. A Phase 1 study in patients with advanced
solid tumors and leukemia, with an estimated enrollment of
60, is currently recruiting patients (ClinicalTrials.gov Identi-
fier NCT00878189).
Begacestat (GSI-953)
The thiophene sulfonamide GSI-953 Fig. (3) is a potent
-secretase inhibitor in development at Weyth. This com-
pound inhibits A production with low nM potency in both
cellular (1-40 EC50 = 14.8 nM, 1-42 EC50 = 12.4 nM) and
cell-free (IC50 = 8 nM) assays [39]]. The compound deter-
mines CTF elevation in cellular assay with an EC50 = 6.6.
nM. Cellular assays of Notch cleavage reveal that this com-
pound is 17-fold selective for the inhibition of APP cleavage
(Notch EC50 = 208.5 nM) [39]. In Tg2576 mice, a 100 mg/kg
doses of GSI-953 markedly reduced A1-40 and A1-42 levels
in both CSF (maximum  90% inhibition) and in brain
(maximum  60% inhibition). At 30 mg/kg, brain A levels
were significantly reduced for 24 h with maximum effects
between 4 and 6 h. The minimal efficacious doses were 1
mg/kg on brain A1-40 and 2.5 mg/kg on brain A1-42. Impor-
tantly, this compound has been reported to attenuate dose-
dependently contextual memory deficit in Tg2576 transgenic
mice with the effect being significant at 10 mg/kg [39]. In
mice, the drug showed a very good blood-brain barrier pene-
tration with brain-to-plasma exposure ratios ranging from 1.1
to 1.3. Interestingly, CSF drug levels were lower than those
measured in plasma (5-10%) [39]. No behavioral studies are
available on begacestat.
In a first-in-man study in healthy human volunteers, oral
administration of single doses of begacestat (3-600 mg) pro-
duced dose-dependent transient reductions in plasma A1-
40 levels with maximum inhibition of 40% with 600 mg at 2
h. Rebounds in plasma A1-40 levels were visible at later
times [39]. Other studies have described the pharmacoki-
netic, pharmacodynamic and tolerability profile of GSI-953
after single oral administration in young subjects and in AD
patients [40]. GSI-953 was well-tolerated and no dose-
limiting adverse events were observed. Begacestat was rap-
idly absorbed in both young subjects and AD patients (Tmax =
1-2 h). Drug plasma levels increased proportionally to the
dose. Plasma elimination half-life was also similar in the two
populations (7-8 h). Drug concentrations in CSF were 10-
fold lower than in plasma in both young and AD subjects
[40]. For both young healthy subjects and AD patients, a
biphasic pattern of plasma A140 concentrations was ob-
served, with an initial reduction below baseline for approxi-
mately 4 hours, followed by a second phase of increased
concentrations above baseline lasting up to 48 h before re-
turning to baseline. Maximum inhibition in plasma A140
concentrations was observed at 2 h with a 28% reduction in
AD subjects and 33% reduction in young subjects. Notably,
initial reductions in plasma concentrations were less pro-
nounced for A142 than A140. Maximum reductions in
plasma A142 were only 7% in AD subjects and 17% in
young subjects. Subsequent increases in A142 above base-
Current Topics in Medicinal Chemistry, 2011, Vol. 11, No. 12 1561
line were similar to those of A1-40 in magnitude and dura-
tion. No significant effects of the drug on CSF A1-40 levels
were observed in either AD patients or young volunteers
[40].
A translational medicine study was subsequently per-
formed on begacestat, comparing pharmacokinetic/ pharma-
codynamic biomarker relationships in Tg2576 mice and hu-
mans [41]. It was found that a 10 mg/kg dose in Tg2576
mice produces different drug exposures and inhibitiory ef-
fects on  in plasma (AUC0-3 = 5951 ng·h/mL, 9-20% 
inhibition), brain (AUC0-3 = 9338 ng·h/mL, 22-33%  inhi-
bition) and CSF (AUC0-3 = 350 ng·h/mL, no  inhibition).
In AD patients receiving a 450 mg dose, drug exposures and
 inhibitory effects in plasma (AUC0-3 = 2334 ng·h/mL,
28%  inhibition) and CSF (AUC0-3 = 240 ng·h/mL, no 
inhibition) were correlated with the Tg2576 results and sug-
gested that the exposure in human brain would lead to AUC0-
3 = 2400 ng·h/mL, which should produce brain  inhibition
similar to what was observed in plasma. The apparent dis-
connect between CSF and brain  lowering in Tg2576
mice may be explained by the lower drug levels observed in
CSF compared to brain [41].
No clinical trials of begacestat in AD patients are pres-
ently registered in ClinicalTrials.gov web site.
ELND-006
ELND-006 is a -secretase inhibitor in development at
Elan Pharmaceuticals. The chemical structure of ELND-006
is still undisclosed. Like BMS-708163, ELN-006 is claimed
to be a “APP-selective” -secretase inhibitor. These com-
pounds are thought to interact with -secretase outside the
catalytic site, but the precise binding site and mode of action
is not known. The potency and in vivo characterization of the
agent after oral administration was recently described. In
cellular and enzymatic assays, ELND-006 displayed selectiv-
ity for APP, inhibiting APP and Notch cleavage with IC50
values of 0.34 and 5.3 nM, respectively, and inhibiting A
production and Notch signaling in cells with IC50 values of
1.1 and 81.6 nM, respectively [42]. Brain/plasma ratios ex-
ceeded 1 in both rodents and non-human primates, indicating
a very good brain penetration [42, 43]. After oral administra-
tion (0.3-30 mg/kg) to wild-type mice, PDAPP mice, wild-
type rats or wild-type guinea pigs, ELND-006 was associ-
ated with significant reductions in CSF A [42]. In cynomol-
gus monkeys, an oral dose regimen of 0.3 mg/kg/ day for 13
weeks produced a decrease of brain A levels of at least 25%
for approximately 24 h [43]. ELND-006 concentrations in
plasma needed to reduce A in brain were consistent across
species. Similarly to other -secretase inhibitors, ELND-006
administration determined late rebounds in plasma A levels
in both rodent and non-human primate [42, 43]. Studies in
PDAPP transgenic mice indicated that treatment with 12.5
mg/kg/day for 13 weeks significantly reduced hippocampal
amyloid burden and brain A levels but not of dystrophic
neurites [44]. More prolonged treatment with the same dose
significantly reduced both plaque burden and dystrophic
neuritis but not brain A levels measured by Elisa [44]. Ac-
cording to Elan, ELND-006 is currently being evaluated in
Phase 1 studies.
1562 Current Topics in Medicinal Chemistry, 2011, Vol. 11, No. 12 Imbimbo and Giardina

-SECRETASE MODULATORS THAT HAVE REAC-
HED OR ARE APPROCHING CLINICAL DEVEL-
OPMENT
Based on the initial observation that some NSAIDs pref-
erentially inhibit A1-42 secretion without affecting Notch
processing [6], a new class of drugs called -secretase modu-
lators with both NSAID-like and non-NSAID structure has
been developed in the last 5 years [7]. At least three of these
-secretase modulators have entered clinical trials (tarenflur-
bil, E2012, CHF5074) Table 2, Fig. (4). It has been proposed
that NSAID-like -secretase modulators interact with the
substrate (APP) rather than with the enzyme (-secretase)
[45]. However, the Merck group has shown that tarenflurbil
and sulindac sulfide could non-competitively block binding
of -secretase inhibitors to -secretase [46]. An additional
level of complexity recently uncovered is that APP binds to
-secretase as a dimer and must partially unwind for -
secretase processing [47].
Tarenflurbil
Tarenflurbil Fig. (4) is a biphenylpropionic acid single
isomer developed by Myriad Genetics. The drug is the R
entantiomer of flurbiprofen. Tarenflurbil has been developed
with the rationale of maintaining the A1-42 lowering proper-
ties of flurbiprofen while removing its anti-COX activity that
is ascribable only to the S entantiomer and thus reducing
gastro-intestinal toxicity of the original drug. Preclinical
studies have shown that tarenflurbil has quite low potency in
inhibiting the secretion of A1-42 in vitro (IC50  250 M)
[48] as well as a poor CNS penetration in rodents (cerebro-
spinal fluid to plasma ratio of 1.3%) [49] with inadequate
brain concentrations achieved in vivo ( 2 M) [50, 51]. The
promising pharmacological results obtained with tarenflurbil
by the Mayo Clinic group after short-term administration in
transgenic mice [50] have never been confirmed by other
groups [52,49]. The neuropathological and behavioral effects
of tarenflurbil after chronic administration in the transgenic
mouse [51] are inconsistent and questionable from a meth-
odological point of view. In these studies [51], the control
groups of three different experiments using animals of dif-
ferent ages (12 and 19 months) were pooled. In addition,
several animals from control and drug-treated groups were
excluded from the analyses. The positive behavioral effects
of tarenflurbil observed in two pooled experiments of 16-
week duration, were not coupled with significant lowering
effects on A plaque burden or on A1-40 or A1-42 brain lev-
els [51]. The positive effects of the drug on A deposition in
a third experiment of only 2-week duration, were not cou-
pled with any behavioral effect [51].
In healthy elderly human subjects, a three-week treat-
ment with tarenflurbil (200, 400 or 800 mg b.i.d.) did not
modify A1-40 or A1-42 levels in CSF [53]. Overall, there
were no significant effects of the drug on plasma A levels,
although an inverse relationship was found between peak

Table 2. -Secretase Modulators that have Reached or are Approaching Clinical Development for the Treatment of Alzheimer’s
Disease (see Figure 4 for Chemical Structures)

Compound Main
Pros Cons Development Company
Status References

Poor in vitro potency. Poor brain

Tarenflur-
Good safety profile in AD patients penetration Discontinued Myriad Genetics [54-56]
bil
Not effective in two Phase 3 trials

Lenticular opacity in rats Lack of data

Notch sparing
on brain plaque deposition in trans-
E2012 No accumulation of CTF No re- Discontinued Eisai [57,58,60]
genic mice.
bound effects on human plasma
A Lack of data on behavioral effects

Notch sparing
No accumulation of CTF Low micromolar inhibitory potency
CHF5074 Attenuates brain pathology in tg mice on A1-42 Phase 2 Chiesi [61-64]
Improves cognitve deficit in tg mice Limited brain penetration
Neuroprotective activity in vivo

Lack of data on brain plaque deposi- ClinicalTri-

Good safety margin in animals
E2212 tion in transgenic mice. Lack of data Phase 1 Eisai als.gov Identifier
High inhibitory potency on A142.
on behavioral effects NCT0122125

Notch sparing
Decreases brain A aggregates in
Cognitive effects in transgenic mice
EVP-15962 transgenic mice. Preclinical En Vivo [66,67]
occur at relatively high doses
Improves cognitve deficit in trans-
genic mice.

Nanomolar potency.
Neuro Genetic
NPG-328 Notch-sparing Lack of data on behavioral effects Preclinical [68]
Pharmaceuticals
Attenuates brain pathology in tg mice

-Secretase Inhibitors and Modulators for the Treatment of Alzheimer’s Disease
Me
O N
F HO
Tarenflurbil (R-Flurbiprofen)
Cl
O N
Cl F HO
CHF5074
Cl
CF3
O S
O
HO
Possible structure of EVP-15962
Fig. (4). Chemical structure of -secretase modulators that have reached or are approaching clinical development.
tarenflurbil concentrations and A
1-42 levels in plasma (r =
0.38, p = 0.016) suggesting that at concentrations around 180

M, tarenflurbil may decrease A
1-42 levels in plasma as
expected by its in vitro potency (IC50  250
M). Unfortu-
nately, the drug reached much lower concentrations in CSF
samples collected 2-4 hours from the last dose (1.2
M after
800 mg b.i.d.) and no significant effects were detected on
CSF A
1-42 levels even at peak levels [53]. It cannot be ex-
cluded that later CSF sampling could allow the detection of
some effects of tarenflurbil on CSF A
levels as occurred
with traditional -secretase inhibitors [26].
From a clinical point of view, an accurate examination of
the results of a 12-month Phase 2 study with tarenflurbil in
AD patients [54] reveals that the apparent positive effects of
the drug at a dose of 800 mg b.i.d. in mildly affected patients
were likely due to an anomalous deterioration rate observed
in patients treated with placebo, rather than to the drug itself.
On the ADCS-ADL (Alzheimer’s Disease Cooperative
Study Activities of Daily Living) scale, mild patients had a
mean decay in 12 months of 8.57 ± 1.32 points on placebo vs
4.60 ± 1.30 points on tarenflurbil 800 mg b.i.d., the differ-
ence being statistically significant (p = 0.033). However, the
decay observed in the placebo-treated mild patients (8.57 ±
1.32 points) was very similar to that observed in the moder-
ately affected patients treated with placebo (8.31 ± 3.03
points). This is abnormal since it is expected that mildly af-
fected patients have less decline than moderately affected
patients. On the CDR-SB (Clinical Dementia Rating Sum of
Boxes) scale, mild patients had a mean decay of 2.13 ± 0.28
points on placebo vs 1.33 ± 0.28 points on tarenflurbil 800
Current Topics in Medicinal Chemistry, 2011, Vol. 11, No. 12 1563
O Me
N
F
N
O
Me E2012
N N
CF3
N
N
N
O
Possible structure of E2212
Me
O
N
N H
N
N
O
Me
NGP-328
mg b.i.d. (p = 0.042) but again, the decay in the placebo-
treated patients (2.13 ± 0.28 points) was unexpectedly simi-
lar to that observed in moderate patients (2.20 ± 0.58 points).
The cognitive measure ADAS-Cog (Alzheimer’s Disease
Assessment Scale Cognitive Subscale) showed the expected
mean decays in mild and moderate patients treated with pla-
cebo (4.02 ± 0.99 and 6.86 ± 1.79 points, respectively) and
no significant effects of tarenflurbil were observed. There
were no effects at all of tarenflurbil on MMSE (Mini-Mental
State Examination), another measure of cognition. Moder-
ately affected patients who received the same dose of taren-
flurbil (800 mg b.i.d.) had highly significant greater clinical
deterioration compared to placebo on the CDR-SB scale
(4.63 ± 0.57 vs 2.20 ± 0.58 points, p = 0.003).
The detrimental effects of tarenflurbil on the global clini-
cal status of the AD patients were again observed in a 18-
month, placebo-controlled, Phase 3 study in 1,684 patients
with mild AD [55]. Patients receiving 800 mg b.i.d. had a
significantly higher deterioration than placebo on the CDR-
SB scale at the end of the 18-month treatment period (p =
0.004). There were no significant differences in all the other
cognitive, functional and behavioral variables between taren-
flurbil and placebo. Another large 18-month Phase 3 study
confimed that tarenflurbil is not effective in mild AD pa-
tients [56].
E2012
The imidazylbenzyliden derivative E2012 Fig. (4) is a -
secretase developed by Eisai in a partnership with TorreyPi-
1564 Current Topics in Medicinal Chemistry, 2011, Vol. 11, No. 12
nes Therapeutics. E2012 represents the first -secretase
modulator with a non-NSAID structure entering clinical de-
velopment. In 2005, Eisai disclosed a novel chemical class
of -secretase modulators characterized by the presence of an
arylimidazole moiety as exemplified by E2012. This chemi-
cal backbone has prompted intense research activity
throughout the industry. In in vitro studies, MALDI-TOF
analysis showed that E2012 decreased A
1-40 and A
1-42 and
increased A
1-38 without changing total A
levels [57]].
E2012 did not induce the accumulation of APP-CTFs and
did not inhibit Notch processing up to 3
M [57]. In rat cor-
tical neurons, E2012 inhibited A
1-42 and A
1-40 with an IC50
of 92 and 330 nM, respectively [58]. In rats, a 30 mg/kg dose
maximally decreased CSF and brain A
1-42 levels by 47%
and 43%, respectively [58]. Treatment of dogs with E2012
(20 and 80 mg/kg) led to a dose-dependent increase in CSF
levels of A
1-37, while A
1-39, A
1-40 and A
1-42 decreased
[59]. In mid 2006, E2012 entered Phase 1 clinical develop-
ment. In February 2007, the Phase 1 study was put on hold
because lenticular opacity was observed in a high-dose group
of a 13-week safety preclinical study in rats. At the time
when the study was suspended, no medical concerns were
reported. Lenticular opacity was not observed in a later 13-
week safety study in monkeys. An additional 13-week mul-
tiple dosing study in rats did not reveal ocular toxicity and
the clinical hold on E2012 was lifted in April 2008. The re-
sults of a Phase 1 study were recently reported [60]. Single
doses ranging from 2.5 to 400 mg were studied. Dose-
dependent reductions in plasma A
1-42 and A
1-40 levels were
observed with maximal inhibitions with the 400 mg dose of
50% and 30%, respectively without a rebound effect [60].
Eisai recently reported that E2012 will not be developed
further in favor of an improved compound, E2212.
CHF5074
CHF5074 Fig. (4) is a novel dichloro substituted
biphenyl spirocyclopropyl acetic acid derivative in which the
anti-cyclooxygenase activity has been removed and anti-
A
1-42 secretory properties potentiated [49]. In human neuro-
glioma cells overexpressing the Swedish mutant form of
APP (H4swe), CHF5074 lowered A
1-42 secretion with an
IC50 of 3.6
M [61]. At 5
M, no effects were observed on
Notch intracellular cleavage in human embryonic kidney 293
APPswe cells [61]. In 14-month-old Tg2576 mice expressing
human mutated APP with point mutations at the
-secretase
cleavage sites (K670N/M671 or “Swedish mutations”),
chronic treatment with CHF5074 in the diet (375 ppm for 4
months) markedly reduced brain A
burden (-52% in the
cortex; -77% in the hippocampus) without any histological
sign of peripheral Notch-mediated toxicity [61]. In another
transgenic mouse model of AD (hAPPswe+lon), expressing
human APP with mutations at both
-secretase (K670N/
M671) and -secretase (V717I or “London mutation”) cleav-
age sites, chronic treatment with CHF5074-supplemented
diet (375 ppm for 6 months) decreased brain A
plaques (-
32% in the cortex; -42% in the hippocampus) as well as mi-
croglia activation (-54% in the cortex; -59% in the hippo-
campus) [62]. The same treatment also attenuated spatial
memory deficit (-35%) evaluated with the Morris water
maze test [62]. Long-term treatment of 6-month-old Tg2576
mice with CHF5074 for 9 months mitigated neurogenesis
Imbimbo and Giardina
impairment in the hippocampus, normalized synaptophysin
levels in the cortex and completely reversed contextual
memory deficit [63]. In October 2009 CHF5074 has been
advanced into Phase 1 clinical trials and the results of a First-
in-Man study in 84 healthy mal subjects has been reported at
ICAD 2010 [64]. The maximum tolerated dose was found to
be 800 mg. The pharmacokinetics of CHF5074 appeared
linear in the studied dose range (25-1000 mg) with plasma
exposure increasing in a predictable dose-proportional man-
ner [64]. A safety and tolerability mutiple ascending dose
study has been completed (ClinicalTrials.gov Identifier:
NCT01203384) and the drug has recently started Phase 2
clinical development.
E2212
Eisai recently reported that E2012 will not be developed
further in favor of an improved compound, E2212 whose
structure has not been disclosed [65]. Based on the analysis
of Eisai’s patent literature, E2212 could have a quite original
phenyldihydrobenzotriazole group replacing the benzylpyri-
done moiety of E2012 in the right end side of the molecule
and an imidazylpyridinyliden instead of the imidazylben-
zyliden group in the left end side Fig. (4). Indeed, the com-
pany has published in the past few years several patent ap-
plications on interesting arylimidazole derivatives. E2212
was claimed to be more potent both in vitro and in vivo than
E2012 and to have a wider safety margin [65]. An IND for
E2212 was submitted in November 2009, and a First-in-Man
study was started in January 2010. On October 25, 2010 the
study was still recruiting subjects (ClinicalTrials.gov Identi-
fier: NCT01221259).
EVP-15962
EVP-15962 is a -secretase modulator in development at
EnVivo Pharmaceuticals. The chemical structure of EVP-
15962 has not been disclosed, but based on analysis of En-
Vivo’s patent literature a biphenyl cyclopropyl propionic
acid derivative structure could be hypothesized Fig. (4).
EVP-15962 could derive from the linear propionic acid de-
rivatives like tarenflurbil or CHF5074 by shifting the distal
phenyl group from the para to the meta position while re-
placing the steric hindrance in para with the lipophilic -
OCH2CF3 group. In rat cortical neurons, EVP-15962 inhib-
ited A
1-42 production (IC50 = 0.42
M) and increased A
1-38
secretion without affecting Notch signalling [66]. Similar
effects on A
levels were observed in wild-type C57/BL6
mice and Sprague-Dawley rats following single oral admini-
stration of the agent [66]]. Chronic administration of EVP-
15962 as a diet supplement (equivalent to 20 or 60 mg/kg/
day) to Tg2576 mice was associated to a significant decrease
in the brain concentrations of A
1-42 levels and to a reduction
of A
aggregates [67]. Behavioral tests of cognitive ability
were performed using the contextual fear conditioning and
the Morris water maze paradigms. Sub-chronic treatment (
3 months) of young Tg2576 mice (4-5 months of age) at-
tenuated contextual memory at both 20 and 60 mg/kg/day
doses. On the other hand, chronic treatment with EVP-15962
( 12 months) of young Tg2576 mice (4-6 months) up to the
age of 16-18 months did not show significant improvements
of contextual memory at both doses. In the Morris water

-Secretase Inhibitors and Modulators for the Treatment of Alzheimer’s Disease
maze test, a partial recovery/blockade of the cognitive deficit
of Tg2576 animals was seen following treatment with the 60
mg/kg/day dose [67]. Intitial clinical testing of EVP-15962 is
expected to start in 2011.
NPG-328
The imidazylphenyl 2-thiazoleamine derivative NGP-328
Fig. (4) has been recently selected at NeuroGenetic Pharma-
ceuticals as a clinical candidate for the development in AD.
The compound presents the same fragments in the left hand
side of both E2012 and E2212 Fig. (4). In cell cultures,
NPG-328 selectively inhibited the production of A1-42,
while favoring the generation of the shorter A1-37 and A1-38
species. The compound did no show effects on the prote-
olytic processing of Notch [68]. After oral dosing, NGP-328
reduced the levels of A1-42 and increased the amount of
A1-38 in the plasma, cerebrospinal fluid and brains of trans-
genic animals [68].
DISCUSSION
-Secretase Inhibitors
While a number of highly potent inhibitors of secretase
have been identified [12], serious concerns about their toxic-
ity have been raised since -secretase can cleave several
other membrane proteins other than APP [5], the most phar-
macologically relevant being the Notch receptor. Secretase
inhibitors block proteolysis of Notch by inhibiting cleavage
at site 3 [69]. Physiological cleavage of Notch leads to re-
lease of the Notch intracellular domain (NICD), a protein
fragment that is translocated to the nucleus where it regulates
transcription of target genes involved in cell development
and in differentiation of adult self-renewing cells. The in-
hibitory effects of -secretase inhibitors on Notch activation
in embryonic and fetal development may not be of concern
for the treatment of AD patients. However, it is known that
Notch signaling plays an important role in the ongoing dif-
ferentiation processes of the immune system [70]], gastroin-
testinal tract [71] and epidermis [72]. Treatment of mice with
-secretase inhibitors can cause severe gastrointestinal toxic-
ity and compromise the proper maturation of B- and T-
lymphocytes [73,74]]. Notch signaling is also present in the
mature brain where its activation influences structural and
functional plasticity including processes involved in learning
and memories [75]. Mice heterozygous for a null mutation in
the gene encoding Notch1 display deficits in spatial learning
[76] and mice overexpressing Notch1 antisense mRNA have
about 50% of the normal levels of Notch protein in the hip-
pocampus and do not display long-term potentiation (LTP)
in response to high-frequency stimulation [77]. Thus, the
detrimental cognitive and functional effects of semagacestat
observed in the interrupted Phase 3 clinical trials may be
ascribed to its interference activity on Notch signaling. The
increased rate of skin cancer observed with semagacestat in
AD patients could be also linked to the drug inhibitory activ-
ity on Notch1 signaling that may have a role as tumor sup-
pressor in certain type of non-melanoma skin cancer [71].
Another possible reason for the faster clinical decline of
semagacestat-treated AD patients could be linked to the abil-
ity of the drug to accumulate the neurotoxic C-terminal
fragment of APP (CTF or C99) in response to the block of
Current Topics in Medicinal Chemistry, 2011, Vol. 11, No. 12 1565
-secretase activity [19]. Indeed, an in vivo study indicated
that semagacestat is neurotoxic in mice [21]. This study em-
ployed in vivo two-photon imaging and showed that den-
dritic spines get irreversibly lost in the cerebral cortex of
wild-type mice after only 4 days of treatment with sema-
gacestat (30 mg/kg s.c.). The same experiments carried out
in APP-deficient mice suggested that APP-cleavage products
(probably an accumulation of C-terminal fragments), are
critically involved [21]. Recent studies have shown that a
number of proteins regulate -secretase activity, including
secretase activating protein (GSAP) [78], the member of
the p24 cargo protein family TMP21 [79] and the orphan G-
protein coupled receptor 3 (GPR3) [80]. These proteins rep-
resent potential therapeutic target for the treatment of AD
because their inhibition appear to affect A production with-
out affecting the cleavage of Notch.
However, even Notch-sparing -secretase inhibitors (PF-
3084014, BMS-708163, begacestat) could have neurotoxic
effects due to their inhibitory activity on amyloid precursor
protein intracellular domain (AICD) release from either C-
terminal fragments of APP (C83 in the non-amyloidogenic
pathway and C99 in the amyloidogenic pathway). AICD
may have important physiological role in gene expression,
apoptosis, and cytoskeletal dynamics [81].
Another possible explanation for the detrimental effects
of semagacestat in AD patients is the higher inhibitory po-
tency displayed by the drug on A1-40 production compared
A1-42 [17], a characteristic shared with other secretase
inhibitors. Recent studies in double transgenic mice have
shown that A1-40 inhibits amyloid deposition while A1-42
increases it [82]. In addition, increasing A1-40 levels pro-
tected transgenic mice from the premature death. The protec-
tive properties of A1-40 with respect to amyloid deposition
suggest that drugs preferentially targeting A1-40 may actu-
ally worsen the disease course. Studies in guinea-pigs [17]]
and in normal men [26] have indicated that semagacestat
may cause rebound effects on A1-42 levels in the CNS.
Whatever is the mechanism of the detrimental effects of se-
magacestat on cognition in AD patients, it has to be pointed
out that no studies have been published showing positive
cognitive or behavioral effects of the drug in animal models
of AD, neither after acute or chronic administration [20].
This is a problem shared by other -secretase inhibitors in
clinical developemt: there are no studies showing that the
chronic aministration of these drugs produce positive effects
on memory in animal models of AD.
-Secretase Modulators
Modulation of -secretase appears to be a logical strategy
to selectively decrease A142 accumulation in AD patients
without causing an accumulation of the potentially neuro-
toxic CTF, interfering with Notch signaling and AICD re-
lease. In the last two years, significant progresses have been
made in designing and developing -secretase modulators
with improved potency for lowering the production of A1-42.
However, the increase in A1-42 inhibitory potency may im-
ply the loss of selectivity versus other -secretase substrates.
It has been shown that at high concentrations -secretase
modulating NSAIDs may inhibit the S3 cleavage site of
Notch-1, an effect reminiscent of classical -secretase inhibi-
1566 Current Topics in Medicinal Chemistry, 2011, Vol. 11, No. 12
tion [83]. It appears that the separation of the inhibitory ef-
fects on the various cleavage sites is concentration dependent
leaving a “window of modulation”. The positive neuropa-
thological and behavioral effects observed for some NSAIDs
(the best documented being ibuprofen) in different trans-
genic mouse models of AD, could be not linked to their abil-
ity to modulate -secretase (quite unlikely at the drug con-
centrations reached into the brain) but rather to a plethora of
other mechanisms that include inhibition of microglia-
mediated release of cytokines [84], inhibition of microglia
peroxidase [85], inhibition of neuronal cell cycle events [86],
stimulation of neurotrophin synthesis or expression [87],
inhibition of mitochondrial Ca2+ overload [88], effects on
astrocyte motility [89].
The major issue for NSAIDs-like -secretase modulators
is brain penetration. NSAIDs per se show good blood-brain
barrier permeability, but their high plasma protein binding
reduces the unbound fraction to less than 3-5% of the total
concentration, thus limiting the amount of drug available to
reach CNS. -Secretase modulators with non-NSAID struc-
ture tend to have high molecular weight and lipophilicity and
this may represent an issue since mounting evidence in the
literature indicate that large, lipophilic compounds have a
higher incidence of off-target and non-selective pharmacolo-
gies. Finally, it will be important to gain a better understand-
ing of the specific target(s) that these -secretase modulators
interact with in order to facilitate future drug design efforts.
CONCLUSIONS
The recent failure of semagacestat has fueled the con-
cerns on the safety and the efficacy of -secretase inhibitors,
not to mention questions about the A
hypothesis for AD in
general. The semagacestat failure echoes a previous observa-
tion that immunization with pre-aggregated A
1-42 (AN1792)
resulted in almost complete clearance of amyloid plaques
from the brain of patients with AD but did not alter disease
progression [90]. It has been argued that the accumulation of
A
in the brain of AD patients is simply a downstream mani-
festation of the disease rather then its cause [91]. Brain
plaques may represent a defensive mechanism in response to
a neuronal damage process [92]. The reason for the presence
of A
in the normal brain and its physiological role is not
fully understood but it may regulate neuroplasticity [93].
Electrophysiological studies in rodent hippocampal prepara-
tions have shown that endogenously released A
peptides
positively regulate the release ability of synapses without
altering postsynaptic function or intrinsic neuronal excitabil-
ity [94]. Other in vivo studies have shown that intra-
hippocampal injections of picomolar concentrations of A
1-42
monomers and oligomers to normal mice cause a marked
increase of hippocampal LTP and enhancement of reference
and contextual memory [95]. More recently, it has been
shown that low doses of A
enhance memory retention and
acetylcholine production in the hippocampus of normal mice
[96]. Blocking endogenous A
with antibodies or decreasing
A
expression with antisense directed at APP, all resulted in
impaired learning in a spatial memory test [96]. Interest-
ingly, A
1-42 facilitated induction and maintenance of LTP in
hippocampal slices, whereas antibodies to A
inhibited hip-
pocampal LTP [96]. All these studies indicate that in normal
healthy young animals the presence of A
is important for
Imbimbo and Giardina
normal synaptic function and for normal learning and mem-
ory. Thus, it may be plausible that indiscriminate and com-
plete inhibition (with -secretase inhibitors) or removal (with
anti-A
antibodies) of endogenous A
could be detrimental
in AD patients rather than beneficial. A significant propor-
tion (20-30%) of cognitively intact individuals shows a sig-
nificant amount of pre- or post-mortem amyloid [97, 98].
Collectively, these obvservations question the hypothesis
that A
is the key pathologic factor affecting AD process. It
has been recently proposed that a decline in brain metabolic
activity or synaptic activity is the underlying cause of the
disease [99]. Decreased metabolic activity, which can be
consequent to decreased synaptic activity, increases
-
secretase expression or activity which, in turn, increases A

deposition as a secondary response [99]. If this is true we
should assist to other failures of -secretase inhibitors or
other A
-lowering agents, especially those for which no
proofs of neuronal rescue and attenuation of memory deficit
have been documented in preclinical model of AD.
CONFLICT OF INTEREST
Bruno P. Imbimbo is an employee at Chiesi Farmaceutici
and is involved in the development of CHF5074. He is listed
between the inventors of a number of Chiesi Framaceutici’s
patents of anti-AD drugs, including -secretase modulators.
Giuseppe Giardina has no conflict of interest to declare.
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Received: November 28, 2010 Accepted: March 22, 2011

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