Design and synthesis of potent β-secretase (BACE1) inhibitors with P1′ carboxylic acid bioisosteres

Article abstract of DOI:10.1016/j.bmcl.2006.01.108

Recently, we reported potent and small-sized β-secretase (BACE1) inhibitors KMI-420 and KMI-429 in which we replaced the Glu residue at the P₄ position of KMI-260 and KMI-360, respectively, with a 1H-tetrazole-5-carbonyl DAP (l-α,β-diaminopropi

Full text of DOI:10.1016/j.bmcl.2006.01.108

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2380–2386
Design and synthesis of potent b-secretase (BACE1) inhibitors
with P1 carboxylic acid bioisosteres
0
Tooru Kimura,a Yoshio Hamada,a Monika Stochaj,a Hayato Ikari,a Ayaka Nagamine,a
Hamdy Abdel-Rahman,a Naoto Igawa,a Koushi Hidaka,a Jeffrey-Tri Nguyen,a
Kazuki Saito,b Yoshio Hayashia and Yoshiaki Kisoa,*
aDepartment of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and 21st Century COE Program,
Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan
bLaboratory of Proteomic Sciences, 21st Century COE Program, Kyoto Pharmaceutical University,
Yamashina-ku, Kyoto 607-8412, Japan
Received 28 December 2005; revised 25 January 2006; accepted 27 January 2006
Available online 14 February 2006
Abstract—Recently, we reported potent and small-sized b-secretase (BACE1) inhibitors KMI-420 and KMI-429 in which we
replaced the Glu residue at the P4 position of KMI-260 and KMI-360, respectively, with a 1H-tetrazole-5-carbonyl DAP (L-a,b-dia-
minopropionic acid) residue. At the P1 position, these compounds contain one or two carboxylic acid groups, which are unfavor-
0
0
able for crossing the blood–brain barrier. Herein, we report BACE1 inhibitors with P1 carboxylic acid bioisosteres in order to
develop practical anti-Alzheimer’s disease drugs. Among them, tetrazole ring-containing compounds, KMI-570 (IC50 = 4.8 nM)
and KMI-684 (IC50 = 1.2 nM), exhibited significantly potent BACE1 inhibitory activities.
Ó 2006 Elsevier Ltd. All rights reserved.
Proteolytic processing of amyloid precursor protein
(APP)1,2 leads to the formation of amyloid b peptide
(Ab), which is the main component of senile plaques
found in the brains of Alzheimer’s disease (AD) patients.3
According to the amyloid hypothesis,4 BACE1 (b-site
APP cleaving enzyme, b-secretase) is considered as a
molecular target for therapeutic intervention in AD,5–8
because BACE1 triggers Ab formation by cleaving at
the N-terminus of the Ab domain.9–12 Recently, we
reported potent and small-sized BACE1 inhibitors,
KMI-420 (3) and KMI-429 (4),13 that contained phenyl-
norstatine [Pns: (2R,3S)-3-amino-2-hydroxy-4-phen-
ylbutyric acid] as a substrate transition-state mimic.14,15
From KMI-260 (1) and KMI-360 (2),16 KMI-420 and
KMI-429 were designed with a tetrazole ring as a carbox-
ylic acid bioisostere17 at the P4 position (Fig. 1). Accord-
ing to structure–activity relationship (SAR) studies of
KMI-compounds, we found that the acidic moieties at
BACE1 inhibitory activity. However, acidic moieties,
such as carboxylic groups, often possess low membrane
permeability across the blood–brain barrier. Herein, we
0
replaced one or two carboxylic acid groups at the P1 posi-
tion of KMI-compounds with some carboxylic acid bio-
isosteres in order to develop practical anti-AD drugs.
Naka and co-workers reported some bioisosteres of a tet-
razole ring and their applications in angiotensin II recep-
tor antagonists.18 Using tetrazole rings or acidic
0
heterocycles as carboxylic acid bioisosteres at the P1 po-
sition of KMI-420 and KMI-429, we designed and synthe-
sized novel potent BACE1 inhibitors, KMI-570 (24) and
KMI-684 (25), that do not possess carboxylic acid.
The synthesis of aniline derivatives 6, 8–10, 12, and 13,
which correspond to residues at the P1 position of
0
KMI-compounds, is shown in Scheme 1. 3,5-Bis(1H-tet-
razol-5-yl)-aniline 6a was synthesized from nitrile 5a by
cyclization using sodium azide and subsequent reduc-
tion using tin in hydrochloric acid. Aniline derivatives
8–10 were synthesized from amidoxime 7, which was
prepared by addition of hydroxylamine to the corre-
sponding nitrile 5b, according to Naka’s method.18
Compounds 12 and 13 were synthesized from benzoate
11 by cyclization using carbon disulfide19 and methyl
0
the P4 and P1 positions were important for improving
Keywords: Alzheimer’s disease; BACE1 inhibitor; b-Secretase;
Bioisostere.
*
Corresponding author. Tel.: +81 75 595 4635; fax: +81 75 591
9900; e-mail: kiso@mb.kyoto-phu.ac.jp
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.01.108

T. Kimura et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2380–2386
2381
(Scheme 2) from aniline derivatives 8–10, 12, and 13,
respectively. Peptidic bonds were formed by 1-ethyl-3-
(3-dimethylaminopropyl)carbodiimideÆHCl (EDCÆHCl)
in the presence of 1-hydroxybenzotriazole (HOBt) as
coupling reagents. Protection groups Boc and Fmoc
(9-fluorenylmethoxycarbonyl) were removed using 4 M
HCl in dioxane and 20% diethylamine in DMF, respec-
tively. The final Boc deprotection was performed with
4 M HCl in dioxane and anisole. Subsequent purifica-
tion by preparative RP-HPLC afforded the desired
inhibitors 18–22, 26, and 27.
X
O
O
O
H
N
H2N
OH
N
H
N
H
N
H
O
OH
O
O
OH
1 X = H
2 X = COOH (KMI-360)
(KMI-260)
X
O
O
O
H
N
H2N
OH
N
H
N
H
N
H
HN
N
N
N
O
OH
O
NH
COOH
a,b
N
26
(KMI-696)
O
Boc DAP(Fmoc) OH
NH
3 X = H
(KMI-420)
4 X = COOH (KMI-429)
a,c
N
N
Boc Val OH
Boc Leu OH
Boc Pns OH
8
a,b
Figure 1. Structure of BACE1 inhibitors containing 3-aminobenzoic
0
a,b
acid derivatives at the P1 position.
a,b
isothiocyanate,20 respectively, and subsequent deprotec-
tion. BACE1 inhibitors 18–22, 26, and 27 were synthe-
sized by traditional solution-phase peptide methods
Scheme 2. Reagents: (a) EDCÆHCl, HOBt, DMF; (b) anisole, 4 M
HCl/dioxane; (c) 20% Et2NH/DMF.
N NH
X
N
N
a,b
5a
R
CN
N
H2N
NH
N
5a R = NO2, X = CN
N
6a
8
5b R = Boc-NH, X = H
d,e,f
5b
N
H2N
O
O
HN
HN
HN
c
g,h,f
N
H2N
H2N
N
S
Boc N
H
OH
NH2
9
O
7
i,f
N
N
O
S
10
j,k,f
j,l,f
OCH3
H2N
Boc N
H
NH
S
O
O
12
11
N
H2N
NH
N
CH3
13
S
Scheme 1. Reagents and conditions: (a) NaN3, n-BuOH-AcOH, reflux; (b) Sn, concd HCl; (c) NH2OHÆHCl, Et3N, DMSO, 75 °C; (d) pyridine,
2-ethylhexyl chloroformate, THF, 0 °C; (e) xylene, reflux; (f) anisole, 4 M HCl/dioxane; (g) TCDI, THF; (h) BF3ÆOEt2, THF; (i) TCDI, DBU,
MeCN; (j) NH2NH2ÆH2O, EtOH, reflux; (k) CS2, KOH, EtOH; (l) MeNCS, THF.

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T. Kimura et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2380–2386
BACE1 inhibitors 14, 16, 17, and 23–25 were synthe-
sized by Fmoc-based solid-phase peptide synthesis
methods using previously reported procedures.13a As
an example, the synthesis of inhibitors 14, 24 and 25 is
outlined in Scheme 3. Namely, N-Fmoc-3-aminobenzoic
acid was attached to the deprotected Rink amide resin
using diisopropylcarbodiimide (DIPCDI) in DMF. N-
Fmoc-protected compounds, which were obtained from
tetrazole derivatives (6a and 6b) by treatment with
Fmoc-OSu [N-(9-fluorenylmethyloxycarbonyl)succini-
mide] in THF–water, were attached to 2-chlorotrityl
chloride resin using diisopropylethylamine (DIPEA) in
dichloromethane (DCM). The Fmoc group was
removed with 20% piperidine in DMF and peptide
bonds were formed using DIPCDI in the presence of
HOBt as coupling reagents. After elongation of the pep-
tide chain, cleavage from the resin was achieved using
trifluoroacetic acid (TFA) in the presence of m-cresol
and thioanisole. The crude peptide was purified by pre-
parative RP-HPLC. BACE1 inhibitor 15 was synthe-
sized from compound 18 by catalytic hydrogenation
(Scheme 4) and purified by preparative RP-HPLC.
To evaluate carboxylic acid bioisosteres on BACE1 inhi-
bition, we selected inhibitor 1 (KMI-260), containing a
Glu residue at the P4 position, as the reference com-
pound and replaced its carboxylic acid functional group
0
at the P1 position with different moieties. The inhibitory
activity against BACE1 for the compounds 14–22 is
summarized in Table 1. In inhibitors 14 and 15, the car-
boxamide and amidine functional groups, similar in size
to that of a carboxylic acid, induced low BACE1 inhib-
itory activities, suggesting that the acidic property of the
0
P1 side chain is essential for improving BACE1 inhibito-
ry activity. On the other hand, inhibitors 16–21, which
contained one or two tetrazole rings, or acidic heterocy-
cles (5-oxo-1,2,4-oxadiazole, 5-oxo-1,2,4-thiadiazole,
0
and 2-thioxo-1,3,4-oxadiazole)18,19 at P1 position,
respectively, showed significantly higher BACE1 inhibi-
tory activities than their lead compound 1. This finding
supported the fact that acidic heterocycles18 act as bio-
isosteres of carboxylic acid, as well as tetrazole ring.
However inhibitor 22, which contained N-methyl
0
heterocycle (4-methyl-3-thioxo-1,2,4-triazole)20 at P1
position, possessed low BACE1 inhibitory activity,
H
N
a
Fmoc
N
COOH
Fmoc
N
H
H
O
O
H
(b,c) x 4
N
Fmoc Glu(OtBu) Val Leu Pns
N
H
b,d
X
14 (KMI-409)
= Rink Amide resin
X
e,f
N
N
N
N
N
N
H2N
Fmoc
NH
H
N
N
N
NH
N
6a X =
6b X = H
N
X
(b,c) x 4
N
N
N
N
Boc DAP(Fmoc) Val Leu Pns
N
H
X
O
H
Boc
N
N
N
N
N
Val Leu Pns
N
H
b,g
HN
N
O
= 2-chlorotrityl resin
NH
N
N
24 (KMI-570) X = H
25 (KMI-684) X =
d
N
N
NH
N
Scheme 3. Reagents and conditions: (a) deprotected Rink amide resin, DIPCDI, DMF; (b) 20% piperidine/DMF; (c) Fmoc-AA-OH, DIPCDI,
HOBt, DMF; (d) TFA, m-cresol, thioanisole; (e) Fmoc-OSu, K2CO3, THF-H2O (1:1); (f) 2-chlorotrityl chloride resin, DIPEA, DCM; (g)
1H-tetrazole-5-carboxylic acid, DIPCDI, HOBt, DMF.

T. Kimura et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2380–2386
2383
N
H Glu Val Leu Pns
N
O
H
HN
O
18 (KMI-596)
NH
NH2
a
H Glu Val Leu Pns
N
H
15 (KMI-654)
Scheme 4. Reagents: (a) H2, Pd/C, MeOH.
Table 1. BACE1 inhibitory activity of P4 glutamic compounds
Y
O
O
O
H
H2N
N
N
N
N
X
H
H
H
O
OH
O
OH
Compound (KMI No.)
X
Y
BACE1 inhibition (%)
at 2 lM at 0.2 lM
IC50 (nM)
14 (KMI-409)
15 (KMI-654)
CONH2
H
H
62.1
—
—
—
NH
29.2
—
NH2
N N
16 (KMI-569)
17 (KMI-597)
18 (KMI-596)
19 (KMI-683)
20 (KMI-879)
21 (KMI-666)
22 (KMI-686)
H
92.2
99.7
94.4
91.9
94.5
92.0
74.2
73.7
94.0
66.3
63.2
68.4
72.3
—
—
NH
N
N N
N N
6.4
NH
NH
N
N
N O
H
H
H
H
—
—
—
—
—
O
O
S
N
H
N S
N
H
N O
N
H
N NH
S
S
O
N NH
H
H
N
CH3
1 (KMI-260)
2 (KMI-360)
COOH
COOH
83.7
98.3
44.4
84.3
—
55
COOH
0
suggesting that the N-methyl group might prevent
hydrogen bond formation to the S1 site of BACE1.
be preserved for non-carboxylic acid P1 residues. Con-
sequently, we synthesized compounds possessing a P4
tetrazole ring while replacing P1 carboxylic acid in 3
0
0
Previously, we reported that replacing the carboxylic
acid at the P4 position with a tetrazole ring enhanced
inhibitory activity against BACE1.13 In the current re-
port, we wanted to observe if such enhancements would
(KMI-420) and 4 (KMI-429) with a carboxamide, one
or two tetrazole rings, 5-oxo-1,2,4-oxadiazole or
5-thioxo-1,2,4-oxadiazole. As shown in Table 2,
BACE1 inhibitors possessing a P4 tetrazole ring 23–27

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T. Kimura et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2380–2386
Table 2. BACE1 inhibitory activity of P4 tetrazole compounds
Y
O
O
O
H
H2N
N
N
N
N
X
H
H
H
O
OH
NH
N
O
NH
N
N
Compound (KMI No.)
X
Y
BACE1 inhibition (%)
IC50 (nM)
at 2 lM
at 0.2 lM
23 (KMI-419)
24 (KMI-570)
CONH2
H
H
97.3
78.1
—
N N
100
100
100
99.8
98.1
100
4.8
NH
N
N N
N N
NH
25 (KMI-684)
26 (KMI-696)
27 (KMI-808)
1.2
6.6
6.4
NH
N
N
N O
H
94.2
97.2
O
S
N
H
N O
H
H
N
H
3 (KMI-420)
4 (KMI-429)
COOH
COOH
99.1
100
87.1
98.1
8.2
3.9
COOH
demonstrated vastly greater inhibitory activities in com-
parison with inhibitors possessing at P4 carboxylic acid
14–21. In particular compounds containing tetrazole
rings at P1 position, 24 (IC50 = 4.8 nM) and 25
(IC50 = 1.2 nM) exhibited highest BACE1 inhibitory
activities.
philic side chain group at the P2 position (Asn). Howev-
er, our compounds contained a hydrophobic amino acid
(Leu) at the same position. Hence, we repeated the
docking simulation study using another structure of
the BACE1 enzyme (PDB ID: 1W51) in which the li-
gand had a hydrophobic group (benzene ring) at the
P2 position. For the case of the 1FKN BACE1 enzyme,
Arg235 formed hydrogen bonds with Gln326 and the
co-crystallized ligand’s P2 Asn side chain. On the other
hand, for the case of the 1W51 BACE1 enzyme,
Arg235 assumed a different orientation to repel the co-
crystallized inhibitor’s P2 benzene ring and had hydro-
gen bond interaction with Asn233. As shown in Figure
2B, docking simulation study to BACE1 enzyme (PDB
ID: 1W51) gave a similar result to our previous repor-
t.13a These findings suggested that the docking simula-
tion which absolutized crystal structures by X-ray
diffraction method might have given irrelevant output,
because enzymes often changed their three-dimensional
structure depending on the nature of the ligands.
0
Computer-assisted simulated docking experiments were
carried out in a BACE1 enzyme (PDB ID: 1FKN),21
in order to correlate affinity with activity. In all com-
pounds listed in Tables 1 and 2, the most energy-favored
conformations assumed similar poses with excellent
hydrogen bond interactions between the inhibitor’s
Pns anchor and BACE1’s Asp32 and Asp228. More-
over, the inhibitor is firmly secured throughout its back-
bone by strong hydrogen bond interactions coming
from Gly11, Thr232, Gly230, Gln73, and Thr72, which
coincided with the previously reported modeling study
of KMI-429 (4).13a As an example, the results for
KMI-684 (25) is shown in Figure 2A. Previously, we
predicted that the tetrazole carbonyl group at the P4 po-
sition of KMI-429 (4) formed hydrogen bonds to both
Arg235 and Arg307 residues to explain its enhanced
BACE1 inhibitory activity upon replacing the P4 car-
boxylic acid with a tetrazole ring.13 However, docking
simulation to BACE1 enzyme (PDB ID: 1FKN) showed
that the tetrazole carbonyl group at P4 position formed
hydrogen bonds to Arg307, Gly264, and Asn233 as
shown in Figure 2A. The inhibitor which was used to
co-crystallize this BACE1 enzyme contained a hydro-
Docking simulation using two structures of BACE1 en-
zyme (0PDB ID: 1FKN and 1W51) gave similar results at
the P1 position. Alpha sphere pharmacophore predic-
tions suggest that 0an anionic group or hydrogen-bond
ac0ceptor at the P1 carboxylic acid’s coordinates in the
S1 pocket would improve inhibitor–site interactions.
Carboxylic acids are excellent hydrogen-bond acceptors;
carboxamides have partial hydrogen-bond-accepting
and -donating properties; while amidines are mainly

T. Kimura et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2380–2386
2385
Figure 2. 3D Views of docked inhibitor KMI-684. (A) Docking simulation of 25 (KMI-684, white line) in BACE1 enzyme (PDB ID: 1FKN, red
lines). (B) Docking simulation of 25 (KMI-684, white line) in BACE1 enzyme (PDB ID: 1W51, red lines). In both A and B, three stable conformers of
inhibitor 25 were superimposed. White dashed lines depict hydrogen bond interactions. Two docking simulations using 1FKN and 1W51 gave similar
results at the lower omitted part in B.
hydrogen-bond donors. As a result, the observed
inhibitory potency trend can be correlated with the
hydrogen-bond-accepting ability of the functional
group. The nature of tetrazole rings and other acidic
heterocycles, which are slightly larger than a carboxylic
acid and possessed a delocalized negative charge around
the rings,22 is thought to favor the binding to hydrogen-
bond donors. Moreover, the partially hydrophobic
regions above and below these heterocycles may interact
favorably with the partially hydrophobic inner walls of
activity than their carboxylic acid counterparts and
may also be more efficient in crossing the blood–brain
barrier. 5-Oxo-1,2,4-oxadiazole and its sulfur-substitut-
ed derivatives have been reported to be converted meta-
bolically to their corresponding amidoximes, which
released NO by cytochrome 450 isoenzymes.23 The use
of these acidic heterocycles in drug development might
become an issue in point of the formation of NO,
although this problem had not exposed in the case of
the antihypertensive agents, angiotensin II receptor
antagonists,18 that served a common bioactivity to
blood pressure.
0
the S1 pocket, which consists of Tyr71, Pro70, Tyr198,
Ile126, Ser35 (a- and b-carbons), Thr329, Ile226, and
Val332.
In conclusion, novel series of BACE1 inhibitors were de-
signed and synthesized using bioisosteres of carboxylic
acid at the P1 position. In particular, compounds 24
BACE1 inhibitors bearing tetrazole ring and acidic het-
erocycle bioisosteres were synthesized and some inhibi-
tors demonstrated more potent enzyme inhibitory
0
(KMI-570) and 25 (KMI-684), which contained

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T. Kimura et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2380–2386
10. Yan, R.; Bienkowski, M. J.; Shuck, M. E.; Miao, H.;
Tory, M. C.; Pauley, A. M.; Brashier, J. R.; Stratman, N.
C.; Mathews, W. R.; Buhl, A. E.; Carter, D. B.;
Tomasselli, A. G.; Parodi, L. A.; Heinrikson, R. L.;
Gurney, M. E. Nature 1999, 402, 533.
11. Sinha, S.; Anderson, J. P.; Barbour, R.; Basi, G. S.;
Caccavello, R.; Davis, D.; Doan, M.; Dovey, H. F.; Frigon,
N.; Hong, J.; Jacobson-Croak, K.; Jewett, N.; Keim, P.;
Knops, J.; Lieberburg, I.; Power, M.; Tan, H.; Tatsuno, G.;
Tung, J.; Schenk, D.; Seubert, P.; Suomensaari, S. M.;
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tetrazole rings, demonstrated significantly more potent
BACE1 inhibitory activities. These modifications are
expected to enhance blood–brain barrier permeability,
which is one of the greatest challenges to overcome dur-
ing the development of drug against AD.
Acknowledgments
This study was supported in part by the Frontier Re-
search Program and the 21st Century COE Program
of the Ministry of Education, Culture, Sports, Science
and Technology (MEXT) of Japan, Japan Society for
the Promotion of Science’s Post-Doctoral Fellowship
for Foreign Researchers, and grants from MEXT.
13. (a) Kimura, T.; Shuto, D.; Hamada, Y.; Igawa, N.; Kasai,
S.; Liu, P.; Hidaka, K.; Hamada, T.; Hayashi, Y.; Kiso, Y.
Bioorg. Med. Chem. Lett. 2005, 15, 211; (b) Asai, M.;
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