Novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P2 position

Article abstract of DOI:10.1016/j.bmcl.2012.05.089

Recently, we reported substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. We also designed and

Full text of DOI:10.1016/j.bmcl.2012.05.089

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4640–4644
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold
at the P2 position
Yoshio Hamada a,b, , Tomoya Nakanishi b, Kenji Suzuki b, Ryoji Yamaguchi b, Takashi Hamada b,d
,
⇑
Koushi Hidaka a,b, Shoichi Ishiura c, Yoshiaki Kiso a,b,d,
⇑
a Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Minatojima, Chuo-ku, Kobe 650-8586, Japan
b Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan
c Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Meguro-ku, Tokyo 153-8902, Japan
d Laboratory of Peptide Science, Nagahama Institute of Bio-Science and Technology, Tamura-cho, Nagahama 526-0829, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Recently, we reported substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcar-
bonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities
in enzymatic and cell assays. We also designed and synthesized non-peptidic and small-sized inhibitors
possessing a heterocyclic scaffold at the P2 position. By studying the structure–activity relationship of
Received 25 April 2012
Revised 23 May 2012
Accepted 24 May 2012
Available online 1 June 2012
these inhibitors, we found that the
r–p interaction of an inhibitor with the BACE1-Arg235 side chain
played a key role in the inhibition mechanism. Hence, we optimized the inhibitors with a focus on their
P2 regions. In this Letter, a series of novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the
P2 position are described along with the results of the related structure–activity relationship study. These
small-sized inhibitors are expected improved membrane permeability and bioavailability.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Alzheimer’s disease
b-Secretase
BACE1
BACE1 inhibitor
Amyloid b (Ab) peptide is a main component of senile plaques
in the brains of Alzheimer’s disease (AD) patients. According to
the amyloid hypothesis,1 b-secretase [BACE1: b-site APP (amyloid
precursor protein) cleaving enzyme 1] appears promising as a
molecular target for therapeutic intervention in AD,2–6 as BACE1
triggers Ab peptide formation by cleaving APP at the Ab domain
N-terminus.7–12 Potent peptidic BACE1 inhibitors13–19 (IC50
ꢀ1.2 nM) with a hydroxymethylcarbonyl (HMC) isostere as a sub-
strate transition-state mimic have been reported.20,21 Of these
inhibitors, KMI-429 exhibited effective inhibition of BACE1 activity
in cultured cells and significant reduction of Ab production in vivo
(via direct administration into the hippocampi of APP transgenic
and wild-type mice).14b Some natural amino acids in these inhibi-
tors seem to be required to improve both enzymatic stability
in vivo and permeability across the blood–brain barrier. Recently,
with the goal of developing a practical anti-AD drug, non-peptidic
and small-sized BACE1 inhibitors possessing a 2,6-pyridinedicar-
boxylic or chelidonic scaffold at the P2 position were designed
based on the conformer structure of a virtual inhibitor docked on
the enzyme (Fig. 1), so called ‘in silico conformational structure-
based design’.20 As these non-peptidic inhibitors exhibited lower
inhibitory activities than peptidic KMI-compounds, more potent
forms were desired and, thus, inhibitors possessing a halogen atom
on the P2-pyridine ring were designed by focusing on their interac-
tion with the guanidino
p-orbital of BACE1-Arg235 (Fig. 2), and
found to be more potent.23 In this study, we designed and synthe-
sized novel BACE1 inhibitors possessing a 5-nitroisophthalic scaf-
fold at their P2 position by focusing on the interaction with side
OSO2CH3
N
N
OH
H
N
H
NH
O
N
N
N
N
O
O
O
KMI-1036 IC50 = 96 nM
O
O
N
N
OH
H
N
H
NH
O
N
N
N
O
O
O
KMI-1027 IC50 = 50 nM
⇑
Corresponding authors. Tel.: +81 749 64 8113; fax: +81 749 64 8140.
E-mail address: y_kiso@nagahama-i-bio.ac.jp (Y. Kiso).
Figure 1. BACE1 inhibitors with a P2 heterocyclic scaffold.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.05.089

Y. Hamada et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4640–4644
4641
KMI-1303, was designed, which possessed a halogen atom on the
P2-pyridine scaffold, and proved to be quite potent (Fig. 2). The
electron-rich halogen atom appeared able to interact with the elec-
tron-poor
p-orbital of guanidino-plane by Coulomb’s force. With
the goal of identifying other forms of potent inhibitors by optimiz-
ing the inhibitor P2 regions, we investigated the effect of other P2
regions substituents which allowed to interact with the guani-
dino-plane of BACE1-Arg235. A 5-isophthalic scaffold was adopted
as a P2 residue for the synthesis of a series of BACE1 inhibitors.
BACE1 inhibitors 1–34 were synthesized with the plan to con-
nect in tandem the blocks corresponding to the P3–P2 residues
0
and P1–P1 residues (Scheme 1A) or to connect sequentially from
the P10 residues to P3 residues (Scheme 1B). Amide bonds were pro-
duced by common solution-phase synthesis methods using 1-
ethyl-3-(3-dimethylaminopropyl)carbodiimideꢁHCl (EDCꢁHCl) in
the presence of 1-hydroxybenzotriazole (HOBt) as a coupling
agent. For examples, in the synthesis of inhibitors 10 and 32
(Scheme 1), P3 amine 37 and 5-nitroisophthalic acid were coupled
to produce the P3–P2 residue 38, with the former compound, pos-
sessing an oxazolidine ring, prepared from the corresponding ami-
Figure 2. BACE1 inhibitors with a halogen atom on the P2 aromatic ring.
no alcohol, itself previously prepared from
L
-amino acid
0
chain of BACE1-Arg235. In addition, the results of their structure–
activity relationship are discussed.
derivatives. Other amines were commercially available. P1–P1 res-
idue 40 was synthesized from Boc-Apns-OH 39 [Apns: (2S,3S)-3-
amino-2-hydroxy-4-phenylbutyric acid] and 5-(3-aminophe-
When the publicly-available X-ray crystal structures of BACE1-
inhibitor complexes are compared, surprisingly, the guanidino-
planes of Arg235-BACE1 show similar features in terms of flopping
over the P2 region of the inhibitors, and the nearest distances be-
tween the P2 region and guanidino-plane show similar values of
about 3 Å in the X-ray crystal structures of most BACE1-inhibitor
complexes.23 It was hypothesized here that the guanidino-plane
of Arg235 pushes down on the P2 region of the inhibitors, causing
them to be affixed in the BACE1 active site, and that a slightly
0
nyl)tetrazole. Eventually, P3–P2 residue 38 and P1–P1 residue 40
were coupled to produce inhibitor 10. Alternatively, some inhibi-
tors, 32 for example, were synthesized from compound 40 by
sequential connection with the P2 residue and P3 amine. BACE1
inhibitor 2 was synthesized from its methyl ester, by alkaline
hydrolysis, which was prepared from monomethyl ester of ben-
zene-1,3,5-tricarboxylic acid as a starting material. BACE1 inhibitor
4 was synthesized from compound 9 by catalytic hydrogenation
using 5% Pd-C catalyst. All inhibitors were purified by preparative
reversed phase-high performance liquid chromatography. BACE1
inhibitory activities of the synthesized inhibitors were determined
attractive force from a quantum effect, such as stacking or
r–p
interactions, plays a significant role for packing down the inhibi-
tors effectively in the active site of BACE1. Hence, an inhibitors,
A
F
F
F
NO2
d
a,b
e,b
c
F
O
OH
NH
OH
N
O
Boc
Boc
N
H
COOCH3
35
OH
H2N
H2N
O
O
36
37
38
NO2
N
N
OH
H
H
N
NH
N
N
OH
N
OH
H
N
H
N
NH
f
F
O
N
N
O
O
N
O
O
P1-P1' unit
O
39
40
10 (KMI-1309)
B
NO2
NO2
N
N
N
OH
N
OH
d
g
H
H
H
N
H
N
NH
NH
40
HO
N
N
N
N
N
O
O
O
O
O
O
41
32 (KMI-1731)
Scheme 1. Reagents and conditions: (a) LiBH4/THF-MeOH; (b) 4 N HCl/dioxane; (c) HCHO, water; (d) 5-nitroisophthalic acid, EDCꢁHCl, HOBt/DMF; (e) 5-(3-
aminophenyl)tetrazole, EDCꢁHCl, HOBt/DMF; (f) 38, EDCꢁHCl, HOBt/DMF; (g) azocane, EDCꢁHCl, HOBt/DMF.

4642
Y. Hamada et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4640–4644
Table 1
compound 5, 6, and 7, possessing a halogen atom or methyl group
on the P2 aromatic ring, also exhibited high BACE1 inhibitory activ-
ities, suggesting that a small-sized and hydrophobic substituent on
the P2 aromatic ring was preferential for BACE1 inhibition. Having
previously reported the nature of a series of BACE1 inhibitors pos-
sessing a halogen atom on the P2-heterocyclic scaffold, the focus
here was on the nitro-group as a P2-substituent, resulting in the
design of inhibitors 10–34. Inhibitors 10–24 possessed a 5-mem-
bered oxazolidine ring (Table 2) and, of these, compound 10 exhib-
ited the highest BACE1 inhibitory activity, followed in activity by
compounds 17–19 and 22. The results also showed that compound
16, with a small-sized group and compounds 13, 15, and 24, with
bulky oxazolidine ring substituents, showed low inhibitory activi-
ties, suggesting that size—being the length of as phenyl group—and
planarity for an inhibitor P2-substituent are important. In particu-
lar, a p-fluorophenyl group appeared to interact tightly with the
BACE1 S3 sub-pocket.
Next, inhibitors 25–34, with no oxazolidine ring at the P3 posi-
tion were synthesized (Table 3). Inhibiters 26 and 27, with a P2-
benzylamino type group, exhibited relatively high BACE1 inhibi-
tory activities and, although compound 28 with a P3-pyrrolidine
ring, showed low inhibitory activity, inhibitor 29, possessing a sub-
stituent on the P3-pyrrolidine ring, showed superior inhibitory
activity. This suggested that there was an empty space between
the P3-pyrrolidine ring and S3 pocket of BACE1. Hence, inhibitors
30–34 were produced with cyclic amines at the P3 position and,
of these, compound 32 (KMI-1731), with an 8-memberd ring,
showed the highest inhibitory activity. To understand these re-
sults, a docking simulation study was performed using MOE soft-
BACE1 inhibitors possessing a chelidonic scaffold at the P3 position
R
N
N
OH
H
H
NH
O
N
N
N
N
O
O
O
Compound (KMI-No.)
R
BACE1 inhibition %
IC50 (nM)
at 2
l
M
at 0.2 lM
1 (KMI-1662)
2 (KMI-1767)
3 (KMI-1298)
4 (KMI-1307)
5 (KMI-1280)
6 (KMI-1287)
7 (KMI-1325)
8 (KMI-1277)
9 (KMI-1214)
–H
–COOH
–OCOCH3
–NH2
–Br
–I
–CH3
–C(CH3)3
–NO2
85
91
79
49
98
98
95
63
98
46
60
—
192
122
—
—
—
84
78
65
—
25
34
67
—
88
19
by an enzymatic assay using a recombinant human BACE1 and
FRET (fluorescence resonance energy transfer) substrate as previ-
ously reported.5,13–19,22,23
First, BACE1 inhibitors 1–9 were synthesized possessing an iso-
phthalic scaffold at the P2 position and diverse groups on its aro-
matic ring (Table 1). Of these inhibitors, compound 9, with a
nitro group, exhibited the highest BACE1 inhibitory activity and
Table 2
BACE1 inhibitors possessing a 2,6-pyridinedicarboxylic scaffold at the P3 position
NO2
N
OH
N
H
H
NH
O
N
N
N
R
N
O
O
O
Compound
(KMI-No.)
R
BACE1 inhibition %
IC50 (nM)
at 2
99
lM
at 0.2
91
lM
10 (KMI-1309)
13
F
F
F
F
11
81
41
—
12
13
Benzyl
Cyclohexylmethyl
89
50
45
—
—
—
OH
14
80
—
—
NH
15
57
—
—
16
17
18
19
20
–CH3
–Et
–n-Pr
–n-Bu
Isopropyl
33
92
93
92
88
—
54
57
59
44
S
21
86
45
22
23
24
sec-Butyl
Isobutyl
tert-Butyl
94
85
71
62
42
—

Y. Hamada et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4640–4644
4643
Table 3
BACE1 inhibitors possessing 2,6-pyridinedicarboxylic scaffold at the P3 position
NO2
N
N
OH
H
N
H
N
NH
R
N
O
O
O
Compound (KMI-No.)
R
BACE1 inhibition %
Compound (KMI-No.)
R
BACE1 inhibition %
at 2
lM
at 0.2
l
M
at 2
lM
at 0.2
lM
25-(KMI-1211)
26 (KMI-1212)
–N(n-Pr)2
79
—
30 (KMI-1729)
31-(KMI-1730)
49
—
N
H
N
83
87
44
50
60
80
—
N
F
H
N
27 (KMI-1213)
32 (KMI-1731)
38
N
N
28 (KMI-1728)
29 (KMI-1219)
24
89
—
33 (KMI-1769)
34 (KMI-1732)
28
0
—
—
N
O
O
N
57
N
Figure 3. (A) Configurations of some cyclic amides. (B) Inhibitor 32 (KMI-1731) docked in BACE1. (C) Inhibitor 10 (KMI-1309) docked in BACE1 (PDB ID: 2B8L). Space-filing
models and green lines indicate inhibitors and BACE1 hydrophobic pockets, respectively, and stick models indicate BACE1 amino acid residues around each inhibitor.
ware (Chemical Computing Group Inc., Canada, Figure 3). The con-
figurations of cyclic acetyl amides from 5- to 9-membered rings
after energy minimization under the MMFF94x force field are
shown in Figure 3A. The molecular sizes of these cyclic acetyl
amides appeared to be similar in the direction of the amide bonds
regardless of their ring-sizes, because the larger rings present more
greatly curved configurations. When inhibitor 32, with an 8-mem-
bered ring, was docked in BACE1, this ring appeared to interact
tightly with the S3 pocket of BACE1 due to its very bent structure
(Fig. 3B). However, compound 33, with a 9-membered ring,
showed surprisingly low inhibitory activity. In general, an odd-
membered, medium-sized ring has higher strain energy and no
symmetric properties, resulting in a bulky configuration (Figure
3A). Consequently, compound 33 might not have been able to bind
to the S3 pocket of BACE1. On the other hand, compound 34, with a
P3-morpholine ring, exhibited no inhibitory activity, suggesting
that a hydrophilic moiety, such as an oxygen atom, could not inter-
act with the hydrophobic S3 pocket of BACE1. For comparison,
BACE1 docked inhibitor 10 is shown in Figure 3C. Inhibitor 32’s
P3 moiety could have interacted with the S3 pocket of BACE1, while
inhibitor 10’s P3-benzene ring appeared able to interact effectively
with the S3 sub-pocket lying behind the S3 pocket.
As described above, inhibitors with a nitro group on the P2-
isophthalic scaffold exhibited the highest inhibitory activities
among the present inhibitors possessing an isophthalic scaffold.
To better understand this finding, a docking simulation performed
using MOE software. As inhibitor 5–7 exhibited potent BACE1
inhibitory activities, a halogen and methyl groups were speculated

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Y. Hamada et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4640–4644
Figure 4. Interaction between BACE1-Arg235 and inhibitors docked in BACE1 (PDB ID: 2B8L). (A) Merck’s compound. (B) Compound 10 (KMI-1309). Inhibitors and Arg235
were depicted by space-filling models. Stick models indicate BACE1 amino acid residues around each inhibitor.
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and effectively bound to the guanidino-plane of BACE1-Arg235
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group of Merck’s inhibitor appears to interact with the
a-amino
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is fixed on the P2-isophthalic ring and might bind effectively to the
BACE1-Arg235 by CH–p interactions. Considering the nitro group
on the P2-isophthalic ring of inhibitor 10 (Fig. 4B), the rotation of
a nitro group on an aromatic ring is restricted by resonance effects
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p
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inhibitor 10 (KMI-1309) was shown to have potent BACE1 inhibi-
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inhibitors are expected to provide improvement of clinical inhibi-
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brain barrier.
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Acknowledgments
This study was supported in part by the Grants-in-Aid for Scien-
tific Research (A) and (C) from MEXT (Ministry of Education, Cul-
ture, Sports, Science and Technology), Japan. (KAKENHI
No.21249007 and No.23590137, respectively) We thank T. Hamada
and Dr. J.-T. Nguyen for performing the in vitro enzyme assays and
his help in preparing the manuscript, respectively.
17. Hamada, Y.; Abdel-Rahman, H.; Yamani, A.; Nguyen, J.-T.; Stochaj, M.; Hidaka,
K.; Kimura, T.; Hayashi, Y.; Saito, K.; Ishiura, S.; Kiso, Y. Bioorg. Med. Chem. Lett.
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Lett. 2012, 22, 1130.
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23. Hamada, Y.; Ohta, H.; Miyamoto, N.; Sarma, D.; Hamada, T.; Nakanishi, T.;
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