Novel Notch-sparing γ-secretase inhibitors derived from a peroxisome proliferator-activated receptor agonist library

Article abstract of DOI:10.1016/j.bmcl.2010.06.131

Screening of our library of peroxisome proliferator-activated receptor (PPAR) agonists yielded several phenylpropanoic acid-derived γ-secretase inhibitors (GSIs). Structure-activity relationship studies indicated that (R)-configuration of α-substituted phenylpropanoic acid structure and cinnamic acid structure is favorable to prepare Notch-sparing GSIs.

Full text of DOI:10.1016/j.bmcl.2010.06.131

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5282–5285
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel Notch-sparing c-secretase inhibitors derived from a peroxisome
proliferator-activated receptor agonist library
Motonori Kurosumi a, Yoshino Nishio a, Satoko Osawa b, Hisayoshi Kobayashi c, Takeshi Iwatsubo b,d,e
,
Taisuke Tomita b,d, Hiroyuki Miyachi a,
*
a Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-Naka, Kita-ku, Okayama
700-8530, Japan
b Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan
c Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
d Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo 113-0033, Japan
e Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Screening of our library of peroxisome proliferator-activated receptor (PPAR) agonists yielded several
Received 1 May 2010
Revised 24 June 2010
Accepted 28 June 2010
Available online 3 July 2010
phenylpropanoic acid-derived
cated that (R)-configuration of
is favorable to prepare Notch-sparing GSIs.
c
a
-secretase inhibitors (GSIs). Structure–activity relationship studies indi-
-substituted phenylpropanoic acid structure and cinnamic acid structure
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
c
c
-Secretase
-Secretase inhibitor
Notch-sparing
PPAR
c-secretase inhibitor
Alzheimer’s disease (AD) is a chronic neurodegenerative disor-
der characterized by memory loss, personality changes and a de-
cline in cognitive abilities, and is predicted to affect 20 million
people worldwide within 20 years.1 AD is pathologically character-
ized by the accumulation of senile plaques, neurofibrillary tangles,
synaptic loss, and neuronal death. Several lines of evidence suggest
that extracellular deposition of amyloid-b peptide (Ab) as senile
plaques is involved in the pathogenesis of AD. Ab is proteolytically
derived from amyloid precursor protein (APP) via sequential cleav-
Development of
c
-secretase inhibitors (GSIs) is a promising
therapeutic approach for AD.1 However, the
c-secretase cleaves
not only APP, but also several other transmembrane proteins,
including Notch, the latter being indispensable for the differenti-
ation and development of a variety of organs and tissues. Thus,
most of the reported GSIs cause severe adverse effects, because
these compounds are not substrate-specific and inhibit Notch
signalling.6–8 Recently, compounds capable of modulating the
-secretase activity to alter and/or block Ab production with lit-
tle or no effect on Notch cleavage have been identified.9–12 Such
compounds, called Notch-sparing GSIs (NS-GSIs) or -secretase
c
ages by b- and
duction of soluble APPb and the membrane-bound C-terminal
fragment C99. -Secretase, which is a membrane protein complex
c-secretases. b-Secretase-cleavage results in pro-
c
c
modulators (GSMs), would be good candidates for AD
consisting of at least four proteins (i.e., presenilin 1 (PS1), nicastrin,
anterior pharynx defective-1 and presenilin enhancer-2,2) cleaves
C99 within its transmembrane domain to generate Ab peptides
composed of 38-, 40- and 42-amino acids (designated as Ab38,
Ab40, Ab42). Among these, Ab42 is a highly amyloidogenic species
and is predominantly deposited in AD brains.3–5 Thus, increased
levels of Ab42 in the brain are considered to trigger a neuropatho-
logical cascade which ultimately leads to neurodegeneration and
dementia.
therapeutics.
Herein, we report structurally new GSIs with substrate selectiv-
ity. We have been engaged in structural development studies of
PPAR ligands for the treatment of metabolic syndrome, cancer
and so on, based on phenylpropanoic acid structure as a basic
framework (Fig. 1).13 PPAR ligands are constructed from three
components, that is, the acidic head group, the hydrophobic tail
group, and the linking group connected the acidic head group
and the hydrophobic tail group. Previous studies have indicated
that a subset of nonsteroidal anti-inflammatory drugs (NSAIDs),
such as indomethacin, sulindac sulfide and (R)-flurbiprofen, specif-
ically reduce the Ab42 production, acting as NS-GSIs independently
of their inhibitory activity for cyclooxygenases.9 Considering the
* Corresponding author.
E-mail address: miyachi@pharm.okayama-u.ac.jp (H. Miyachi).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.06.131

M. Kurosumi et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5282–5285
5283
F
MeO
O
O
OH
OH
OH
N
OH
O
O
O
N
H
MeO
F3C
F
MeS
Cl
O
3
1
Indomethacin
2
Sulindac Sulfide
(R)-Flurbiprofen
4
Figure 1. Structures of the representative
c
-secretase modulators 1–3, and our representative PPAR ligand 4.
similar structural profile of NSAID-type NS-GSIs, which contain a
highly lipophilic component in combination with an acidic func-
tional group, we searched for compounds that inhibit or modulate
sulindac sulfide for Ab40, Ab42 and Notch are 215
and 53.0 M respectively). These results indicated the importance
of the shape and/or nature of the linking group for inhibition of the
Ab-generating -secretase activity.
The central methoxy group could be replaced with a fluorine
atom. Compound 10 exhibited similar activity to 9, but with a re-
duced Notch-inhibitory activity. The steric hindrance of the distal
benzene substituent R1 might be important for substrate specific-
ity. Increasing steric bulkiness decreased the inhibitory activity
for Ab secretion (10 > 11 > 12), but increased that for Notch cleav-
age (12 > 11 > 10).
lM, 82.5 lM
l
c
-secretase activity by screening our PPAR agonist library. Cell-
based -secretase assay was performed using an HEK293 cell line
(NLNTK) stably co-overexpressing enhanced green fluorescent pro-
c
c
tein (EGFP), Swedish mutant APP, truncated Notch (NotchDE) and
Notch-responsive CSL-luciferase reporter.14 Using this cell line, we
are able to analyze simultaneously the effect of compounds on Ab
secretion and Notch signaling. The activities were expressed as rel-
ative percentage inhibitory activity compared to that of 10 lM
DAPT (N-[N-(3,5-difluorophenylacetyl)-
L
-alanyl]-S-phenylglycine
Based on the initial screen, we concluded that phenylpropanoic
acid structure with a CH2NHCO linker was effective, as in 9. How-
ever, this compound had been assayed as a racemate. In order to
ascertain the stereochemistry–activity relationship, we then as-
sayed both enantiomers of 9. Its cinnamic acid derivatives 18a–c
were also assayed, because in the case of PPAR, both frameworks
are effective as PPAR agonists. Compounds 18a–c were prepared
from 5-formylsalicylic acid (13) in five steps. Compound 13 was
benzylated with 4-methoxybenzyl bromide, followed by methyla-
tion of the phenolic hydroxyl group to afford the benzaldehyde
derivative (15). Compound 15 was treated with trialkyl 2-phos-
phonoalkylate in the presence of tBuOK as a base, followed by
hydrolysis with trifluoroacetic acid and amidation with 4-trifluo-
romethylbenzylamine to afford alkyl cinnamate derivatives (17a–
c). Alkaline hydrolysis of 17a–c and recrystallization afforded the
desired 18a–c. The E-stereochemistry was assigned based on the
coupling constant (in the case of 18a, Scheme 1) or the presence
of the NOESY correlation peak between Ha and Hb (in the cases
of 18b and 18c, Scheme 1). The correlation peak between Ha and
t-butyl ester), an authentic potent GSI.15 In each set of experi-
ments, the assay was performed in duplicate or triplicate.
Our initial screening results are summarized in Table 1. The
CONHCH2 linker compound 4,16 which exhibits potent dual
PPARa/d agonistic activity with EC50 values in the low nanomolar
range, did not exhibit any apparent effect on APP, while it exhib-
ited NOTCH cleavage-inhibitory activity at the concentration of
1
l
M. At 100
a concomitant increase of Notch signaling was observed, suggest-
ing that this compound differentially modulated the -secretase
activity in a substrate-specific manner. This differential modula-
tion was affected by the shape of the substituent at the -position
lM, Ab secretion was increased by twofold. Notably,
c
a
of the carboxyl group (5, 6) and the steric bulkiness of the 4-posi-
tion substituent on the distal benzene ring of the molecule (7, 8). In
contrast, compound 9,17 a weaker PPAR agonist than 4 with a re-
versed CH2NHCO linker, exhibited inhibition of Ab secretion as
well as Notch signaling at both assay concentrations. The potency
of 9 seems comparable to that of sulindac sulfide (IC50 values of
Table 1
Cleavage activities of compounds 4–12
L
COOH
R3
R1
R2
No.
L
R1
R2
R3
Ab40
Ab42
Notch
100 lM
1
lM
100
l
M
1
l
M
100
lM
1
lM
4
5
6
7
8
9
10
11
12
CONHCH2
CONHCH2
CONHCH2
CONHCH2
CONHCH2
CH2NHCO
CH2NHCO
CH2NHCO
CH2NHCO
CF3
CF3
CF3
OCH2CF3
OPh
CF3
CF3
OCF3
OPh
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
F
CH2CH3
CH3
H
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
89.5
114
104
118
103
82.0
77.6
90.6
89.8
186
132
112
136
119
41.0
13.0
42.6
63.2
101
109
102
119
103
88.5
63.3
87.4
99.7
220
139
104
133
145
15.2
0.00
55.7
106
31.2
190
178
170
200
102
53.8
67.2
6.30
0.00
190
162
84.0
162
8.90
38.5
0.00
6.80
F
F
DMSO
DAPT
Sulindac sulfide
100
100
100
0.00a
98.4b
0.00a
97.1b
0.00a
90.7b
88.6c
60.3c
43.9c
a
b
c
The relative
M sulindac sulfide was used.
M sulindac sulfide was used.
c-secretase activity elicited with 10 lM DAPT was designated as 0%.
3
30
l
l

5284
M. Kurosumi et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5282–5285
H
O
O
O
O
H
O
H
a
c
b
O
O
O
OR5
HO
O
O
O
R4
MeO
MeO
Ha'
MeO
15
MeO
16a; R4 = H, R5 = Me
16b; R4 = Me, R5 = Me
16c; R4 = Et, R5 = Et
MeO
HO
HO
13
14
O
O
O
O
COOH
Hc
COOH
e
d
N
OR5
N
OH
H
H
R4
R4
Hb'
Ha Hb Hc
F3C
MeO
F3C
MeO
Hc
Ha': = 7.6 (d, 1H, J = 16 Hz)
Hb': = 6.4 (d, 1H, J = 16 Hz)
δ
δ
17a; R4 = H, R5 = Me
17b; R4 = Me, R5 = Me
17c; R4 = Et, R5 = Et
18a; R4 = H
18b; R4 = Me
18c; R4 = Et
NOE
NOE
18a
18c
Scheme 1. Synthesis of the c-secretase modulator 18s. Reagents and conditions: (a) 4-methoxybenzylamine, KHCO3, DMF, rt, 24 h, quant.; (b) MeI, K2CO3, DMF, 24 h, 93%; (c)
(1) tBuOK, trialkylphosphonoalkylate, dehydrated THF, rt, 6 h, 61–82%, (2) trifluoroacetic acid, rt, 24 h, 77–84%; (d) 4-(trifluoromethyl)benzylamine, DEPC, TEA, DMF, rt, 24 h,
77–89%; (e) (1) 2 mol/L NaOH, EtOH, 60 °C, 24 h, (2) recrystallization from n-hexane/AcOEt, 28–54% (two steps).
Hc was also observed in the case of 18c (Scheme 1). The prepara-
ues for de novo generation of Ab40 and Ab42 are 15.2
10.1
M, respectively),18 indicating that these compounds act di-
rectly on the -secretase.
lM and
tion of the optically active
a-ethylphenylpropanoic acid deriva-
l
tives, (S)-9 and (R)-9, was reported previously.17
c
The inhibitory activities of these compounds are summarized in
It is very important to note the contrasting results that effective
Figure 2. Compound (S)-9 did not inhibit Ab-generating
activity at the high concentration of 100 M, for either Ab40 or
Ab42. On the other hand, the antipodal (R)-9 inhibited -secretase
activity leading to both Ab40 and Ab42 at 100 M. These results
c-secretase
Notch-inhibitory activity was seen at the low concentration of
l
1
lM (S)-9, whereas (R)-9 did not exhibit apparent Notch-inhibi-
c
tory activity at the higher concentration of 100 M. This suggests
l
l
that inhibitory activities for Ab generation and Notch signaling
clearly indicated that inhibitory activity of 9 towards Ab genera-
might be separated by controlling the stereochemistry of the sub-
tion resides mainly in the (R)-enantiomer. Notably, the PPAR-ago-
stituent at the
IC50s of (S)-9 for Ab40, Ab42 and Notch are >100
24.0 M, respectively, while those of (R)-9 are 37.8
and >100 M, respectively.
a
-position of phenylpropanoic acid derivatives. The
M, >100 M and
M, 34.2 lM
nistic activity of
9
resides mainly in the (S)-enantiomer17
l
l
suggesting that the inhibition of Ab-generating activity occurs
independently of the modulation of the transcriptional activity of
l
l
l
PPAR. In accordance with this notion, (R)-9 inhibited the
c
-secre-
The cinnamic acid derivatives (18a–c) exhibited similar phar-
tase activity in in vitro assay using recombinant substrate (IC50 val-
macological character to (R)-9. That is, 18a–c exhibited dose-
O
O
H
O
R
N
(A)
H
OH
OH
R =
F3C
MeO
H
Aβ40
100
50
0
Aβ42
Notch
100 (μM)
1
10
1
100
1
Cont.
DAPT
R4
(S)-9
(R)-9
O
COOH
(B)
N
H
MeO
R4 = H
R4 = Me
R4 = Et
F3C
100
50
0
1
10
1
100
1
100
1
100
(μM)
Cont.
DAPT
18a
18b
18c
Figure 2. Cleavage activities of DAPT, (S)-9, (R)-9, and 18a,b,c. Relative c-secretase activities are shown as the ratio (%) to the control (left), taken as 100%, and 10 lM DAPT as
0%.

M. Kurosumi et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5282–5285
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a
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than 18a. The IC50s for Ab40,
and Notch are calculated to
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In conclusion, we found that the phenylpropanoic acid with a
CH2NHCO linker and cinnamic acid with a CH2NHCO linker can
be employed as scaffolds for the creation of structurally novel
NS-GSIs. Moreover, we identified phenylpropanoic acid with a
CONHCH2 linker as a Notch-specific GSI. Notch inhibition is consid-
ered to be effective against cancer cell induction and/or prolifera-
tion in
a
subset of malignant neoplasms.19 Therefore, such
compounds could be useful as a scaffold for developing agents to
treat Notch-dependent cancer. Further chemical modification
studies are on-going.
Acknowledgements
This work is supported in part by Grants-in-Aid for Young Sci-
entists (S) from Japan Society for the Promotion of Science (JSPS),
Scientific Research on Priority Areas ‘Research on Pathomecha-
nisms of Brain Disorders’ from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), by Targeted Proteins Re-
search Program of the Japan Science and Technology Corporation
(JST) and by Core Research for Evolutional Science and Technology
of JST, Japan.
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