SAR-studies of γ-secretase modulators with PPARγ-agonistic and 5-lipoxygenase-inhibitory activity for Alzheimer's disease

Article abstract of DOI:10.1016/j.bmcl.2014.12.073

We present the design, synthesis and biological evaluation of compounds containing a 2-(benzylidene)hexanoic acid scaffold as multi-target directed γ-secretase-modulators. Broad structural variations were undertaken to elucidate the structure-activity-relationships at the 5-position of the aromatic core. Compound 13 showed the most potent activity profile with IC₅₀ values of 0.79 μM (Aβ42), 0.3 μM (5-lipoxygenase) and an EC₅₀ value of 4.64 μM for PPARγ-activation. This derivative is the first compound exhibiting low micromolar to nanomolar activities for these three targets. Combining γ-secretase-modulation, PPARγ-agonism and inhibition of 5-lipoxygenase in one compound could be a novel disease-modifying multi-target-strategy for Alzheimer's disease to concurrently address the causative amyloid pathology and secondary pathologies like chronic brain inflammation.

Full text of DOI:10.1016/j.bmcl.2014.12.073

Bioorganic & Medicinal Chemistry Letters 25 (2015) 841–846
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
SAR-studies of
c-secretase modulators with PPARc-agonistic
and 5-lipoxygenase-inhibitory activity for Alzheimer’s disease
a
b
a
c
c
a
Daniel Flesch , Julia Ness , Christina Lamers , Friederike Dehm , Sven Popella , Ramona Steri ,
b
a
d
c
b,
⇑
Isabella Ogorek , Martina Hieke , Gerd Dannhardt , Oliver Werz , Sascha Weggen ,
Manfred Schubert-Zsilavecz
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany
Department of Neuropathology, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany
Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, D-07743 Jena, Germany
a,
⇑
a
b
c
d
Institute of Pharmaceutical Chemistry, Johannes-Gutenberg-University Mainz, Staudingerweg 5, D-55128 Mainz, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
We present the design, synthesis and biological evaluation of compounds containing a 2-(benzyli-
dene)hexanoic acid scaffold as multi-target directed -secretase-modulators. Broad structural variations
were undertaken to elucidate the structure–activity-relationships at the 5-position of the aromatic core.
Compound 13 showed the most potent activity profile with IC50 values of 0.79 M (Ab42), 0.3
5-lipoxygenase) and an EC50 value of 4.64 M for PPAR -activation. This derivative is the first compound
exhibiting low micromolar to nanomolar activities for these three targets. Combining -secretase-mod-
ulation, PPAR -agonism and inhibition of 5-lipoxygenase in one compound could be a novel disease-
modifying multi-target-strategy for Alzheimer’s disease to concurrently address the causative amyloid
pathology and secondary pathologies like chronic brain inflammation.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 7 November 2014
Revised 17 December 2014
Accepted 19 December 2014
Available online 30 December 2014
c
l
lM
(
l
c
c
Keywords:
Alzheimer’s disease
c
c
c
-Secretase
-Secretase-modulator
Peroxisome-proliferator-activated-receptor
-Lipoxygenase
5
Alzheimer’s disease (AD) is the most prevalent form of demen-
GSIs reduce the overall enzymatic activity of c-secretase. In con-
tia, with an estimated 24 million affected individuals worldwide
and projected 81 million patients in 2040.1 AD is a progressive
neurodegenerative disease, resulting in loss of memory and cogni-
tive functions in the elderly, ultimately leading to death. According
to the amyloid hypothesis, the accumulation of Ab peptides in the
brain, in particular the longer and more hydrophobic Ab42 species,
leads to the formation of soluble, neurotoxic oligomers and the
characteristic extracellular amyloid plaques. These soluble and
insoluble Ab aggregates are believed to initiate pathological
changes in the AD brain like synaptotoxicity, neuronal death, and
chronic brain inflammation.2
trast, GSMs shift the Ab product spectrum from Ab42 towards
shorter and less aggregation-prone peptides like Ab38. Impor-
tantly, GSMs do not affect NOTCH receptor cleavage and signal-
5
,6
ling. Impairment of NOTCH signaling was likely at least in part
7
responsible for the reported clinical side-effects of GSIs. Thus,
modulation of c-secretase could be a safe approach to selectively
target Ab42 production and aggregation, and downstream patho-
logical changes.
The first GSMs were discovered among non-steroidal anti-
inflammatory drugs (NSAIDs) and included sulindac sulfide,
,3
6,8
ibuprofen or flurbiprofen.
The drug candidate R-flurbiprofen
Ab-Peptides are formed by sequential cleavage of the amyloid
(tarenflurbil), which lacks undesired cyclooxygenase-(COX)-inhibi-
tion but exerts equivalent GSM activity compared to racemic flur-
biprofen, failed to show efficacy in a phase III clinical trial, possibly
2
precursor protein (APP) by b- and
c
-secretase. Based on this pro-
cess, approaches to modulate the proteolytic processing of APP and
the generation of Ab peptides include targeting of the aspartic pro-
due to substance specific limitations such as low penetration of the
blood brain barrier and weak GSM activity (IC50Ab42 = 307 lM).
-secretase.4 For
c
-secretase,
c
-secretase-inhibitors
9,10
teases b- and
c
(
GSIs) and -secretase-modulators (GSMs) have been developed.
c
Despite the failure of tarenflurbil, novel GSMs have been developed
that can be structurally divided in acidic, NSAID-like GSMs (e.g.,
5
the Cellzome GSM series) and non-acidic tetracyclic GSMs.
⇑
Corresponding authors. Tel.: +49 211 8104506; fax: +49 211 8104577 (S.W.);
tel.: +49 69 798 29339; fax: +49 69 798 29332 (M.S.-Z).
Potential future drug candidates have shown activity in the low
nanomolar range and are evaluated in early clinical trials (for
review see Ref. 11).
E-mail addresses: sweggen@hhu.de (S. Weggen), schubert-zsilavecz@
pharmchem.uni-frankfurt.de (M. Schubert-Zsilavecz).
http://dx.doi.org/10.1016/j.bmcl.2014.12.073
0
960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

8
42
D. Flesch et al. / Bioorg. Med. Chem. Lett. 25 (2015) 841–846
Table 1
mode of action. Epidemiological studies have suggested a positive
correlation between type 2 diabetes and the incidence of AD. In
addition, in vitro and in vivo investigations have demonstrated
other activities of PPARc agonists that might be beneficial in AD
including down-regulation of b-secretase-(BACE1) expression,
activation of insulin-degrading enzyme (IDE, which also degrades
Ab) and apolipoprotein E expression, enhancement of Ab phagocy-
tosis by microglia cells, improvement of hippocampus-dependent
Previously published compounds that act as dual
c
-secretase-modulators/PPAR
c
-
14
agonists1
2,13
Compound
c
-Secretase
PPAR
c
activation
5-LO-
modulation
inhibition
IC50
Ab42
EC50
Ab38
EC50
Max.
IC50
activation
cognition, anti-inflammatory actions as well as improved glucose
O
15–20
utilization of cerebral tissues.
Interestingly, an unbiased
O
N
S
OH
1
2
22.8
11.3
8.3
6.6
61%
71%
0.6
screen for suppressors of Ab-induced neuronal degeneration
recently identified the PPAR agonist 5-deoxy- 12,14-prostaglan-
din J2, indicating that Ab toxicity might, at least in part, be medi-
N
O
c
D
2
1
ated by inhibition of PPAR
c signaling. Common safety liabilities
of PPAR agonists in the clinic are edema, weight gain and changes
c
O
in lipid parameters. Rosiglitazone and Pioglitazone also showed
O
N
O
S
22
OH
substance-specific toxicity and their use was restricted.
5.1
4.6
0.8
N
In addition to the potentially beneficial effects of modulating
c-
secretase and PPAR , 5-lipoxygenase (5-LO) could be another
c
attractive target with implications for Ab generation and brain
inflammation. Leukotrienes are products of the 5-LO-pathway,
CF
3
23
are well known mediators of inflammatory reactions and 5-LO
expression appears to be upregulated in patients with AD.24
recently published study also showed that 5-LO and leukotrienes
A
O
O
O
OH
28%
3
1.2
1.1
0.2
@10
lM
could promote Ab generation, likely by transcriptional upregula-
25
tion of
c-secretase subunits. In other reports, the potent and
selective 5-LO inhibitor zileuton reduced the amyloid and tau
CF
3
pathology as well as memory impairments in different mouse
2
6,27
models of AD.
However 5-LO inhibition as a novel approach
Values in
l
M; 100% maximal activation normalized to 1
lM pioglitazone.
for the treatment of AD is still subject to further investigations
evaluating its in vivo efficacy.
We have contributed to the field with an approach to combine
modulation of -secretase and of the peroxisome-proliferator-acti-
vated-receptor-
involved in the lipid-metabolism and the response of peripheral
tissues to glucose- and fatty acid uptake. PPAR agonists were
In summary, it could be a promising approach to combine GSM,
PPARc agonistic and 5-LO inhibitor activities in one compound to
obtain a broad and potentially synergistic range of beneficial
actions.
Our previous studies were based on the pirinixic acid derivative
(see Table 1), which is a moderately potent GSM with PPARc ago-
c
c
12,13
(PPARc).
PPARc is a nuclear receptor
c
widely used as antidiabetic drugs, due to their insulin-sensitizing
1
CF3
iia)
Ullmann
iib)
CF3
OH
O
ia)
O
Mitsunobu
iic)
O
Williamson
O
R
OH
OH
OH
OH
Williamson
O
iic)
ib)
O
O
Williamson
Suzuki
Br
OEt O
P
O
EtO
O
iii)
CF3
CF3
Horner-Wittig
O
O
iv)
O
R
O
OH
O
R
4-24
Scheme 1. Synthesis of cinnamic acid derivatives: Reagents and conditions: (ia) 4-(Trifluoromethyl) benzyl bromide (1.0 equiv), Cs
Arylboronic acid (1 equiv), Cs CO (2.5 equiv), Pd(PPh (0.1 equiv), toluene/EtOH 5:1, 80 °C, 2–3 h. (iia) Aryliodide (1.5 equiv), CuI (0.1 equiv), N,N-dimethylglycine
(2 equiv), DMF, 110 °C, 24 h. (iib) R-alcohol (1.3 equiv), TPP (1.3 equiv), DIAD or ADDP (1.3 equiv), THF, rt, 3–17 h. (iic) R-benzylhalide (1.3 equiv), Cs CO
1.3 equiv), DMF, 60 °C, 2 h. (iii) Ethyl-2-diethoxy phosphorylhexanoate (1.3 equiv), NaH (1.3 equiv), THF, rt, 3–17 h. (iv) LiOH (10 equiv), THF, H O, MeOH, 40–60 °C, 17–72 h.
2 3
CO (1.0 equiv), DMF, 60 °C, 2 h. (ib)
2
3
3 4
)
(
(
0.3 equiv), Cs
2
CO
3
2
3
2

D. Flesch et al. / Bioorg. Med. Chem. Lett. 25 (2015) 841–846
843
Table 2
In vitro pharmacological characterization I
CF
3
c
-Secretase modulation
PPAR
c
activation
Max. activation
5-LO-inhibition
IC50
IC50 Ab42
EC50 Ab38
EC50
Compound
O
R
O
OH
Hydrophobic residues and different linkers
4
5
11.9
12.0
15.6
26% @ 10
0.72
l
M
5.7
2.1
O
14.9
19.3
76%
O
6
7
14.1
2.5
11.7
12.9
108%
0.55
0.75
O
4.1
4.9
56%
ia.
O
O
O
8
9
4.4
3.2
ia.
ia.
ia.
ia.
11.9
8.5
ia.
ia.
10
1.8
ia.
ia.
O
Haloaromatic substitution pattern
O
1
1
7.0
13.8
5.17
2.11
76%
0.5
F
O
1
1
2
3
2.0
3.2
1.0
56%
0.3
0.3
Cl
Cl
O
0.79
4.64
103%
F
3
C
CF
3
ia. = inactive; values in
lM; 100% maximal activation standardized to 1
l
M pioglitazone.
nistic activity.12 Improvement of activity was achieved through
different substituents at the central pyrimidine core, with com-
pound 2 being the most potent of this set. In addition to their func-
ecule. Based on 2,5-dihydroxybenzaldehyde, a four-step-synthesis
incorporating mono-benzylation at position 2, derivatization of
position 5 and formation of the conjugated acidic headgroup with
subsequent hydrolysis was carried out to yield the compounds of
this study (Scheme 1). Structural modifications of the 5-substitu-
ents were focused on hydrophobic moieties, different linkers, sev-
eral haloaromatics and heteroaromatic mono- and multicyclic
systems.
tion as GSMs and PPARc-agonists, these structures are also known
inhibitors of 5-LO and microsomal prostaglandin E2 synthase-1
2
8
(
mPGES-1). Through additional structural optimization,13 we
were able to establish a 2-[2,5-(phenalkoxy)benzylidene] hexanoic
acid scaffold for further investigations in structure–activity-rela-
tionships (SAR). Compound 3 was the most potent GSM of this
The synthetic procedures used in this work are described in
1
3
class, but activity toward PPAR
c
was nearly absent. In previous
Hieke et al. 2011. In the first step, mono-benzylation of 2,5-dihy-
droxybenzaldehyde was done under Williamson-like conditions
(step ia). Derivatization of position 5 resulted from a consecutive
Williamson ether-synthesis, Mitsunobu-reaction or Ullmann
ether-synthesis of the respective phenalkoxy halo gens, -alcohols
and aryliodides (steps iia/b/c). Formation of the 2-(benzyli-
dene)hexanoic acid derivatives was carried out in a Horner–Wittig
studies, we showed an important influence of the lipophilic back-
bone on the pharmacological activity profile of this class of com-
1
2,13
pounds.
As the most potent GSM, compound 3 served as a
structural template for all the presented derivatives. The 2-[(4-tri-
fluoromethyl)benzyl]oxy-substituent was kept constant and the 5-
position was varied to investigate the SAR of this part of the mol-

8
44
D. Flesch et al. / Bioorg. Med. Chem. Lett. 25 (2015) 841–846
Table 3
In vitro pharmacological characterization II
CF
3
c
-Secretase modulation
PPAR
c
activation
Max. activation
5-LO-inhibition
IC50
IC50 Ab42
EC50 Ab38
EC50
Compound
O
R
O
OH
Heterocyclic residues
O
1
4
5
32.1
4.6
23.2
2.1
2.56
ia.
120%
ia.
2.3
0.7
N
O
1
S
O
N
16
17
18
19
S
2.3
10.7
1.17
2.2
ia.
ia.
0.9
0.2
6.7
0.2
3
F C
O
O
0.63
20.2
5.0
17% @ 10 lM
N
CF3
O
ia.
ia.
ia.
ia.
N
O
S
4.5
O
N
O
20
2.2
0.97
3.77
66%
0.9
O
N
O
Miscellaneous
2
1
2
OH
>40
>40
48% @ 10
1.26
lM
ia.
O
2
11.4
11.2
97%
0.25
O
*
2
2
3
4
1.0
1.5
1.1
1.3
2.16
158%
1.7
0.5
CF
3
O
21% @ 3
2% @ 6
l
l
M
M
7
3
F C
ia. = inactive; values in
l
M; 100% maximal activation standardized to 1
lM pioglitazone.
*
Mixture of cis and trans.
reaction to the ester intermediate (step iii) with subsequent hydro-
lysis (step iv). It has been successfully established to merge steps iii
and iv into a one-pot-synthesis, without isolation of the ester inter-
mediate. Synthesis of the biphenyl-derivative started with a
Suzuki-coupling of 5-bromosalicyl aldehyde to introduce the
biphenyl-backbone (step ib). The phosphonate-precursor for step
Ab42 peptides were measured by ELISA in a previously described
1
2
cell-based assay.
Transactivation of all PPAR subtypes was
assessed with a cell-based luciferase assay. 5-LO inhibition was
tested in a cell-based assay using polymorphonuclear leukocytes,
and 5-LO enzymatic activity was measured by HPLC analysis of
formed 5-LO products. Detailed procedures and conditions of syn-
thesis and biological evaluation are provided in the Supporting
information.
iii) was prepared in an arbuzov reaction of the
and triethylphosphite.
a-bromo-ester
The methods for the biological characterization are described in
To determine the GSM activity of novel
derivatives, changes in the amounts of secreted Ab38, Ab40 and
First, we varied the aliphatic spacer between the aromatic core
and the phenyl residue in compounds 4 to 7 (see Table 2) com-
pared to the parental compound 3. Compound 6 showed the
previous reports.1
2,13,28

D. Flesch et al. / Bioorg. Med. Chem. Lett. 25 (2015) 841–846
845
weakest IC50Ab42 activity in this subgroup, and shorter and longer
not detrimental. PPAR
c
activation, in contrast, was considerably
residues improved the GSM activity. Shortening to the biphenyl
derivative (4) increased activity almost two-fold. Elongation (com-
pound 7) led to even higher potency with respect to GSM activity.
There seemed to be a trend for higher GSM activity of less rigid
structures when comparing IC50Ab42 data of the biphenylmeth-
oxy-substituent (9) to hydrophobic residues of corresponding
lower, except for compound 14 and 20. Only the latter showed a
balanced but not remarkably potent activity profile.
In the miscellaneous fourth subset, the 5-hydroxy-derivative
(21) showed no GSM activity, weak PPARc agonism and a lack of
5-LO inhibition. In comparison to the benzyl derivative 6 the
branched diphenylethoxy-derivative (compound 22) showed a
nearly two-fold higher GSM activity and 5-LO inhibition as well
length (compound 8). With regard to PPAR
inhibition, optimal activity was obtained for the diarylether
5, PPAR ) and benzyl derivative (6, 5-LO). The biphenyl analogue
showed a decreased activity for both targets. For longer residues,
the PPAR agonism and 5-LO inhibition was completely lost
8 to 10).
The haloaromatically substituted compounds showed a clearly
c activation and 5-LO
as a ten-fold increase in PPAR
23 displayed an interesting pharmacological profile with its potent
and balanced activity at all three targets (Ab42: 1.0 M, PPAR
2.16 M, 5-LO: 0.9 M). The maximal PPAR activation was excep-
c agonism. The cyclohexyl analogue
(
c
4
l
c:
c
l
l
c
(
tionally high with 158%. In comparison with the structural tem-
plate of this study (compound 3), derivative 24 showed a slightly
weaker GSM activity and 5-LO inhibition, but higher potency for
higher potency at all three targets than compound 6. A gradual
increase of potency was observed with substituents providing a
higher negative inductive effect at the aromatic system (11 to
PPARc agonism.
Previous studies had shown that 5-LO inhibitors often also
1
1
3). Based on its activity profile at all three targets, compound
3 showed the best overall pharmacological profile with consider-
affect mPGES-1 and/or COX enzymes, in particular pirinixic acid
2
9,30
derivatives and derivatives of compound 3,
suggested a role of PGE
2
and recent data
and mPGES-1 in AD. Therefore, we ana-
lyzed the ability of selected compounds that inhibited 5-LO (with
IC50 <2 M) to suppress mPGES-1 and COX-1 and -2 (see Table 4).
Whereas the parental compound 3 was a moderate mPGES-1
inhibitor (IC50 > 10 M), several compounds (i.e., 7, 11, 12, 17,
23, 24) efficiently inhibited mPGES-1 with IC50 values in the range
of 1.6 to 5.0 M, being equally potent as the well-recognized
mPGES-1 inhibitor MK-886 (IC50 = 2.4
compounds were much less active in inhibiting COX-1 and COX-
2 (IC50 >10 M) suggesting that these compounds might preferen-
3
1
ably increased activities (Ab42: 0.79
.3 M) and a potent triple-target effect in the submicromolar to
low-micromolar range.
l
M, PPAR
c
: 4.64
lM, 5-LO:
0
l
l
In the heteroaromatic subset (see Table 3), the most potent
GSMs were found with electron-poor terminal heterocycles (com-
pounds 16, 17 and 20 with 2.3, 0.63 and 2.2 lM for IC50Ab42). The
most potent GSM of this study (compound 17) showed the combi-
nation of an electron-deficient heterocycle with an attached tri-
fluoromethyl group. The most potent GSM of this study
l
l
3
2
lM). Interestingly, the
(
compound 17) showed the combination of an electron-deficient
heterocycle with an attached trifluoromethyl group. Furthermore,
it exhibited the highest inhibition of 5-LO, but lacked potent PPAR
l
tially suppress the synthesis of pro-inflammatory PGE
2
rather than
c
blocking formation of all COX-derived prostanoids.
agonism. 5-LO inhibition was not exceptionally high throughout
the heterocyclic-residue-subset, but in contrast to compounds 8
to 10 with large residues, the bulkier heterocyclic moieties were
A cell-based NOTCH-1 reporter assay was used to investigate
potential adverse effects of compounds 17 and 23 on NOTCH pro-
cessing and signaling. Reporter activity was not affected in a con-
centration range of 5–50
lM. In contrast, treatment of cells with
0
.5 M of the -secretase inhibitor LY-411575 reduced reporter
l
c
Table 4
activity by >75%. The evaluation of cell viability of the compounds
in Jurkat cells showed low overall toxicity at concentrations up to
Effects of test compounds on mPGES-1 and COX1/2 in cell-free assays
Compound mPGES-1
IC50 (or remaining
activity at 10 M)
>10
5.1 ± 5.4%
COX-1
COX-2
30
4 reduced cell viability at 30
tigation of toxicity in CHO cells for compounds 13, 17 and 23
l
M for most compounds of this study. Only compounds 15 and
2
l
M by more than 50%. Further inves-
IC50 (or remaining
activity at 10
IC50 (or remaining
activity at 10 lM)
l
lM)
showed at least 50% cell viability up to 30
information).
lM (data in Supporting
3
6
7
1
1
1
1
1
1
1
2
2
2
2
>10
82.6 ± 4.7%
>10
>10
102.0 ± 5.5%
>10
84.8 ± 2.6%
>10
77.7 ± 8.8%
>10
84.2 ± 4.2%
>10
73.3±0.5%
>10
77.3 ± 4.1%
>10
91.7 ± 4.3%
>10
84.4 ± 3.3%
>10
84.2 ± 2.3%
>10
91.1±2.8%
>10
95.0 ± 2.6%
>10
79.5 ± 1.9%
>10
75.3 ± 1.7%
>10
5
5.6
5.0
4.9
1.6
>10
9.2
>10
3.0
10.0
8.7
>10
2.5
3.1
In summary, the substitution at position 5 of the aromatic core
contributed significantly to the potency and selectivity of the
presented compounds. Shortening of the benzyl-motif to
diarylether- and biphenyl-derivatives (compounds 4 to 6) resulted
in enhanced GSM activity, a decline in 5-LO inhibition and remark-
8
6.6 ± 8.5%
>10
6
9.5 ± 6.9%
1
2
3
5
6
7
9
0
2
3
4
>10
7
8.4 ± 3.0%
>10
ably higher potency of PPARc agonism for the diarylether deriva-
5
9.4±6.3%
tive. There was an overall benefit of activity for electron-deficient
aromatic systems, especially halogen-substituted (compounds 11
to 13), as well as branched moieties at the 5-position (22). With
the exception of compound 20, structural elongation of the resi-
dues through para-substitution with additional aromatic and
>10
6
2.4 ± 5.5%
>10
6
7.4 ± 3.3%
>10
7
3.5 ± 3.1%
aliphatic systems resulted in a loss of PPARc activity. With intro-
>10
duction of more polar heterocyclic structures we were in part able
to decrease the high lipophilicity of the compounds and to main-
tain or enhance activity at the targets of this study (17, 20).
In conclusion, this study describes the first series of triple-tar-
6
9.0 ± 5.1%
>10
7
5.7 ± 4.2%
>10
9
1.3 ± 1.8%
get-directed
c-secretase-modulators and gives valuable insights
>10
6
1.1 ± 1.3%
into the SAR of the 5-position of the aromatic core. Compound
13 was the first derivative that displayed activities at low micro-
molar to nanomolar levels at the desired targets, with substantial
increases in activity compared to the lead structure of this study
>10
5
8.0 ± 4.3%
>10
6
6.3 ± 2.9%
72.2 ± 3.0%
(
compound 3), particularly with regard to PPAR
c activation.
Values in lM, remaining activity in%.
Compound 17 showed even higher activity for Ab42 and 5-LO

8
46
D. Flesch et al. / Bioorg. Med. Chem. Lett. 25 (2015) 841–846
7. Imbimbo, B. P.; Panza, F.; Frisardi, V.; Solfrizzi, V.; D’Onofrio, G.; Logroscino, G.;
inhibition, but PPARc agonism was rather weak and therefore can
be considered as a selective GSM/5-LO inhibitor. Compound 23
showed an overall balanced and potent pharmacological profile
with high maximal activation of PPARc. The lead compounds of
this study are promising as a platform for optimization and pre-
clinical investigations in AD animal models. The presented multi-
target directed approach could be efficacious in AD by targeting
different stages of the amyloid cascade and secondary pathological
events like chronic brain inflammation.
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Acknowledgments
This study was supported by the Competence Network Degen-
erative Dementias of the German Federal Ministry of Education
(
grant number 01 GI 1004B to S.W.) and the Else Kröner-Fresenius
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Foundation (EKFS), Research Training Group Translational
Research Innovation – Pharma (TRIP). We thank Dr. Jan Näslund
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(
Karoliska Institute, Sweden) for the NOTCH reporter plasmids,
1
9. Denner, L. A.; Rodriguez-Rivera, J.; Haidacher, S. J.; Jahrling, J. B.; Carmical, J. R.;
Hernandez, C. M.; Zhao, Y.; Sadygov, R. G.; Starkey, J. M.; Spratt, H.; Luxon, B.
A.; Wood, T. G.; Dineley, K. T. J. Neurosci. 2012, 32, 16725.
0. Yamanaka, M.; Ishikawa, T.; Griep, A.; Axt, D.; Kummer, M. P.; Heneka, M. T. J.
Neurosci. 2012, 32, 17321.
and Drs. Karlheinz Baumann and Manfred Brockhaus (F. Hoff-
mann-La Roche AG, Switzerland) for carboxyl terminus-specific
Ab antibodies.
2
2
1. Ofengeim, D.; Shi, P.; Miao, B.; Fan, J.; Xia, X.; Fan, Y.; Lipinski, M. M.;
Hashimoto, T.; Polydoro, M.; Yuan, J.; Wong, S. T.; Degterev, A. J. Biol. Chem.
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2012, 287, 8714.
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data and assay descriptions) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.bmcl.
Agents Med. Chem. 2012, 10, 124.
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