Synthesis and evaluation of aminopyridine derivatives as potential BACE1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2015.10.007

To identify a new non-peptidyl BACE1 inhibitor, we focused on the aminopyridine structure, which binds to the active sites of BACE1. Synthesis of aminopyridine derivatives and evaluation of inhibitory activity against rBACE1 are described. The 2-aminopyri

Full text of DOI:10.1016/j.bmcl.2015.10.007

Bioorganic & Medicinal Chemistry Letters 25 (2015) 5127–5132
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of aminopyridine derivatives as potential
BACE1 inhibitors
a
a
a
b
Hiroyuki Konno a, , Taki Sato , Yugo Saito , Iori Sakamoto , Kenichi Akaji
⇑
a Department of Biochemical Engineering, Graduate School of Science and Technology, Yamagata University, Yonezawa, Yamagata 992-8510, Japan
b Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
To identify a new non-peptidyl BACE1 inhibitor, we focused on the aminopyridine structure, which binds
to the active sites of BACE1. Synthesis of aminopyridine derivatives and evaluation of inhibitory activity
against rBACE1 are described. The 2-aminopyridine moiety and/or 3-methoxybenzaldehyde could be
converted to terminal acetylene derivatives by the Sonogashira method. Sonogashira or Glaser
cross-coupling reactions with the corresponding derivatives followed by hydrogenation could derive
the designed compounds. Although inhibitory activities of the synthetic compounds against rBACE1 were
weak, the aminopyridine motif has potential as a BACE1 inhibitor.
Received 11 September 2015
Revised 29 September 2015
Accepted 3 October 2015
Available online 9 October 2015
Keywords:
Sonogashira coupling
Glaser coupling
Amino pyridine
BACE1 inhibitor
Alzheimer’s disease
Ó 2015 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD)1–3 is caused by the aggregation of
amyloid-beta (Ab),4–6 which is produced from amyloid precursor
protein (APP) cleaved by proteases with b-secretase (b-site
amyloid precursor protein cleaving enzyme 1, BACE1)7,8 and
bioavailability. The typical aminopyridine type BACE1 inhibitors
by fragment screening are depicted in Figure 1. There are two types
of inhibitors; aminopyridine connected with the biphenyl moiety
(1) and a dipyridine derivative (2). 2-Aminopyridine binds to the
active sites of BACE1 and the principle interactions are between
the charged amino pyridine motif and the two catalytic aspartates
(Asp32 and Asp228) of the enzyme. The region adjacent to this
ligand is the S1 pocket, which is a highly hydrophobic area of the
active site, and thus is attractive to target. Moreover, the S3 pocket
is again rather hydrophobic in nature, and 3-methoxy biaryl or
3-pyridylphenyl groups make good contact with the target region
(Fig. 1).
c-secretase in the brain. Since BACE1 has been recognized as a
valuable target to inhibit production of Ab, a variety of BACE1 inhi-
bitors have been reported in past decades. However, BACE1 inhibi-
tors have not been approved as AD therapeutic agents to date.
Most peptidomimetic BACE1 inhibitors with potent activity are
based on the promising cleaving site of the APP sequence,9–13 but
these inhibitors tend to be P-glycoprotein substrates, digested by
proteases and have restricted brain penetration. Non-peptidyl nat-
ural products are promising bioactive libraries from which anti-AD
agents from microorganisms or food plants have been isolated,14
although they tend to offer low inhibitory activity and/or an
unknown mechanism of action for the target enzyme despite oral
bioavailability and brain penetration.
In contrast, aminopyridine derivatives are key components to
inhibit the active site of aspartyl protease as established by the
Murray group.15,16 The aminopyridine motif was found by
combination of fragment screening techniques and high through-
put X-ray crystallography against BACE1 as a new approach.15–18
These inhibitors are generated starting from small fragments and
are novel non-peptidyl fragments which take advantage of
In the course of our research program to find
a BACE1
inhibitor,19,20 we focused on the aminopyridine structure and
therefore needed to prepare a variety of aminopyridine derivatives.
For the reason, we aimed to verify the advantage of the C4 or C5
spacer connected with the amino pyridine moiety and 3-methoxy-
phenyl groups for potent inhibitory activities. Additionally,
connecting positions of aminopyridine were investigated. We
herein describe a synthetic study of aminopyridine derivatives by
Sonogashira21 and/or Glaser22–25 cross-coupling reactions as
potential BACE1 inhibitors.
The synthetic plan for aminopyridine derivatives as the target
molecules is depicted in Scheme 1. The 2-aminopyridine moiety
(A) and/or 3-methoxybenzaldehyde (B) could be converted to
terminal acetylene derivatives by the Sonogashira method.
Subsequently, Sonogashira or Glaser coupling reactions with the
⇑
Corresponding author. Tel./fax: +81 (0)238 26 3131.
E-mail address: konno@yz.yamagata-u.ac.jp (H. Konno).
http://dx.doi.org/10.1016/j.bmcl.2015.10.007
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

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H. Konno et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5127–5132
Figure 1. BACE1 inhibitors (1) and (2) with an aminopyridine moiety.
Scheme 2. Preparation of amino ethynylpyridines.
Scheme 1. Synthetic plan for aminopyridine derivatives.
corresponding derivatives followed by hydrogenation could obtain
the designed compounds (C) (Scheme 1).
Preparation of 2-aminopyridylacetylene fragments to apply to
cross-coupling reactions were attempted using commercially
available 5-iodo-, 3-bromo- and 6-bromo-2-aminopyridines
(3a–c). After the acetylation of the amino group of 3a–c with
Ac2O/Et3N/catalytic DMAP in CH2Cl2, Sonogashira coupling was
performed. The results of the reaction are summarized in Table 1.
At first, we used the reaction conditions of the Murray group15 to
give 5-ethynylpyridine (5a) at a moderate yield (entry 1). After
switching of the base from Et3N to DIPEA, the reaction proceeded
smoothly to give 5a in 92% yield (entry 2). Although preparation
of 2-acetylamino-3-ethynylpyridine (5b) was attempted under
the conditions in entry 2, the reaction failed to recover 4b with
the complexed mixture (entry 3). We therefore examined the
Pd(II)Cl2(PPh3)2 catalyst in the presence of 10 mol % CuI and DIPEA
at room temperature to give 5b in 53% yield (entry 4). As for
2-acetylamino-6-bromo-pyridine (4c), additional optimization of
the reaction conditions was needed to obtain 2-acetylamino-6-
ethynylpyridine (5c) because the above-mentioned conditions
did not progress to the desired reaction (entries 5 and 6).
Fortunately, we found that treatment of a Pd(II) catalyst with
50 mol % KI26 under reflux conditions gave 5c. Under the condi-
tions using 10 mol % Pd(II)Cl2(PPh3)2/30 mol % CuI/50 mol % KI in
THF at reflux, 4c was converted to 5c in 43% yield (entry 9). 4c is
unfavorable for Pd catalyst insertion due to the m-orientation in
the amino group of 2-aminopyridine and therefore the reaction
was slow and yielded moderate results. Moreover, TBAF-mediated
Scheme 3. Preparation of phenylacetylene derivatives (8), (9) and (10).
deprotection of silyl compounds (5a–c) gave 6a–c at good yields
(Scheme 2) (Table 1).
3-Methoxyphenyl fragments (8), (9) and (10) were prepared
from commercially available 3-methoxybenzaldehyde (7). Corey–
Fuchs reaction27,28 was employed for 7 to give 8 in 69% yield (over
2 steps) and the alkynylation of 7 with lithium acetylide followed
by the deprotection of the silyl group afforded 9 in 62% yield (over
2 steps). Additionally, the 2 step sequences with methylene Wittig
and Corey–Fuchs reactions were conducted to give 10 at an ade-
quate yield (Scheme 3).
For the structure–activity relationship study of the biaryl
derivatives connected with C2 or C3 spacers, Sonogashira coupling
of the terminal alkyne with a pyridine fragment and aryl halide
Table 1
Palladium-catalyzed Sonogashira coupling of 2-aminopyridyl halide with trimethylsilylacetylenea
Entry
Substrate
Catalyst (mol %)
Additive (mol %)
Base (equiv)
Solvent
Temp
Time (h)
Productb (yield)
1
2
3
4
5
6
7
8
9
4a
4a
4b
4b
4c
4c
4c
4c
4c
Pd(PPh3)4 (3.5)
Pd(PPh3)4 (3.5)
Pd(PPh3)4 (5.0)
PdCl2(PPh3)2 (5.0)
Pd(PPh3)4 (5.0)
PdCl2(PPh3)2 (5.0)
Pd(dba)2 (5.0)
CuI (20)
CuI (20)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (30) KI (50)
CuI (50) KI (50)
CuI (30) KI (50)
Et3N (2.0)
THF
THF
THF
THF
THF
THF
Dioxane
THF
THF
rt
rt
rt
rt
rt
rt
Reflux
Reflux
Reflux
24
24
24
24
24
96
96
96
96
5a (69%)
5a (92%)
NIc
DIPEA (2.0)
DIPEA (3.0)
DIPEA (3.0)
DIPEA (3.0)
DIPEA (3.0)
DIPEA (2.0)
DIPEA (2.0)
DIPEA (3.0)
5b (53%)
NRd
NRd
5c (21%)
5c (12%)
5c (43%)
PdCl2(dppf) (10)
PdCl2(PPh3)2 (10)
a
b
c
Reactions of aminopyridines (4a–c) with trimethylsilylacetylene (6 equiv) were carried out with the conditions.
Isolation yield.
Not isolated.
No reaction.
d

H. Konno et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5127–5132
5129
Table 2
Biaryl derivatives connected with C2 or C3 spacers and triacyl derivativesa
Entry
Pyridine
Benzene
Catalyst (mol %)
Productb (yield)
1
6a
Pd(PPh3)4 (3.5), CuI (50)
2
3
4
6a
6a
8
Pd(PPh3)4 (10), CuI (50)
Pd(PPh3)4 (3.5), CuI (20)
Pd(PPh3)4 (3.5), CuI (20)
4a
4a
13
5
6
10
8
Pd(PPh3)4 (3.5), CuI (20)
Pd(PPh3)4 (3.5), CuI (20)
7
9
13
Pd(PPh3)4 (3.5), CuI (100)
a
Coupling reactions of pyridyl compounds (1 equiv) and phenyl halides (1 equiv) were performed with a palladium catalyst, CuI, Et3N (2 equiv) in THF for 10 h at room
temperature.
b
Isolation yield.
Table 3
Glaser cross-coupling of pyridyl alkyne and phenyl alkynea
Entry
1
Pyridine
Benzene
Catalyst (mol %)
CuI (50)
Productb (yield)
6a
8
2
6a
9
CuI (50)
3
4
5
6b
6b
6b
9
9
9
CuI (100)
CuI (50), Pd2(dba)3 (3)
CuI (50), PdCl2(PPh3)4 (3)
NR
NR
NR
6
7
6c
6c
8
8
CuI (100)
CuI(50), Pd2(dba)3 (3)
20 (15%)
8
9
6c
22
9
8
CuI (60)
CuI (60)
NR
10
22
9
CuI (70)
a
Coupling reactions of pyridyl compounds (1 equiv) and phenyl compounds (1 equiv) were performed with catalyst(s) and base in THF for 10 h at room temperature.
Isolation yield.
b

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H. Konno et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5127–5132
Table 4
be briefly obtained by the method. Using a heterocycle terminal
Hydrogenation to afford alkyl aminopyridine derivatives
alkyne as a substrate has scarcely been reported in the literature
probably due to the interaction between copper and nitrogen of
the heterocyclic ligand. Although treatment of pyridyl alkyne and
phenyl alkyne under a variety of conditions predictably afforded
three products, a hetero-coupling product and two homo-coupling
products, it was an important tool to give the desired product
quickly. Because the aminopyridine derivatives have high polarity
and insolubility in organic solvents, another synthetic methods
with multi step reactions were often disadvantageous. In the initial
experiments, treatment of 6a and 8 or 9 with 50 mol % of CuI gave
18 or 19 with the homo-coupling products (entries 1 and 2).
Cross-coupling reactions of 6b under a variety of conditions were
attempted; however, the reaction did not proceed to give the
desired product probably because of steric hindrance with the
acetylamino group and terminal acetylene of 6b. In this case, the
homo-coupling diyne product derived from 9 was preferentially
obtained at high yields (entries 3–5). Although the coupling of 6c
and 8 with CuI as a sole reagent hardly proceeded to give the
desired hetero-coupling product, the reaction conditions in the
presence of a Pd2(dba)3 catalyst afforded diyne (20) in 15% yield
(entries 6 and 7). Using 9 as a coupling partner, 21 was obtained
(11%). Moreover, 2229 with 9 using CuI coupled to give diyne
(23) in 8% yield (entry 10). Thus, the designed compounds (18)–
(23) were given using 5-alkenyl- and 6-alkenyl-2-aminopyridine
(6a) and (6c) at low yields (Table 3).
Entry Substrate Condition Product (yield)
1
2
3
14
16
17
A
B
B
4
5
18
19
A
A
Subsequently, hydrogenation of the 1,3-diynes with H2/Pd–C
gave the corresponding alkanes (24)–(31) at moderate yields. It
is noted that the solubility of the aminopyridine derivatives in
organic solvents is an important factor to consume the substrate.
In addition, treatment of 21 or 23 in the hydrogenation condition
leads decomposed products. To attempt several conditions, a
Lindlar catalyst gave reasonable results (entries 7 and 8); purifica-
tion of crude final compounds was a laborious task because of its
high polarity and insolubility. Therefore, the chemical yields fre-
quently decreased (Table 4).
As shown in Table 3, a Glaser cross-coupling reaction of
3-alkynyl-2-aminopyridine (6b) with a variety of conditions was
attempted. However, the reactions did not proceed to give the
desired products because of steric hindrance with the acetylamino
group and terminal acetylene of 6b. For this reason, alkylation of
6b using a strong base was selected to afford the corresponding
diaryl derivative. Treatment of 6b and 7 with NaHMDS in THF gave
32 in 15% yield and subsequently hydrogenation with Pd–C in 20%
MeOH/CHCl3 solution was done to yield 33 quantitatively
(Scheme 4).
tPSA, C log P and inhibition value of compounds are summa-
rized in Table 5. The inhibition of rBACE1 activity was determined
by the previous procedure using a synthetic dodecapeptide with
the BACE1 cleavage sequence of the Swedish type as a substrate.
The inhibition potency of aminopyridine derivatives was screened
for rBACE1 inhibition at a 2.0 mM concentration. The fragment
molecules were investigated as potential BACE1 inhibitors in the
study and therefore these compounds showed relatively lower
potent inhibitory effects. For this reason, a high concentration of
inhibitors was needed for the assay. Biaryl derivatives connected
with C2 or C3 spacers and triaryl type compounds showed no
6
7
8
20
21
23
B
C
C
Condition A: H2/Pd-C/MeOH; B: H2/Pd-C/CHCl3; C: H2/Lindlar cat./MeOH.
with a Pd(0) catalyst and CuI were employed as depicted in Table 2.
All reactions used the Pd(0)(PPh3)4 catalyst, CuI and 2 equiv of Et3N
in THF at room temperature. Coupling of 5-ethynyl-2-aminopy-
ridine (6a) and iodobenzene derivatives gave biaryl derivatives
(11), (12) and (13) in 25%, 35% and 29% yields, respectively, (entries
1–3). On the other hand, the combination of aryl acetylene (8) and
iodopyridine (4a) gave 14 in 77% yield (entry 4). Unfortunately,
propargyl derivative (10) rarely afforded the desired compound
(15) (entry 5). When a biaryl compound (13) with aryl acetylene
(8) or (9) were employed, the yields of the respective triaryl
products (16) and (17) were 60% and 32% (entries 6 and 7). The
Sonogashira cross-coupling reactions as mentioned above resulted
the lower yields. Because the solubility of substrates, especially
pyridine type compounds, was excessively low. The reactions
hardly proceed to give desired products and additionally work-
up and purification by chromatography were in trouble (Table 2).
Glaser cross-coupling of pyridyl alkyne and phenyl alkyne are
depicted in Table 3. Glaser coupling is a prominent carbon–carbon
bond formation between terminal alkynes to give 1,3-diynes. In
most cases, copper and palladium salts are used as a mild catalytic
system for the homo-coupling of terminal alkynes. We employed
the reaction condition to give hetero-coupling products for BACE1
inhibitors. Biaryl derivatives connected with C4 or C5 spacers could
Scheme 4. Synthesis of 33.

H. Konno et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5127–5132
5131
Table 5
rBACE1 inhibitory activity of aminopyridine derivatives (27)–(33)
Compd
tPSAa
C log Pa
Inhibitionb (%)
Compd
tPSAa
C log Pa
Inhibitionb (%)
27
28
29
50.69
70.92
50.69
3.915
2.687
3.915
20
20
21
30
31
33
70.92
41.82
70.92
2.687
2.840
0.759
56
19
18
a
tPSA and C log P were calculated by Chem 3D Ultra 12.0 (PerkinElmer).
Inhibitory activity was measured with 2.0 mM.
b
(A)
(C)
(B)
Figure 2. Docking simulation of inhibitor (30) bound to BACE1 (PDB code 1FKN) using GOLD from CCDC. Molecular graphics image using PyMOL from Schrödinger; oxygen
(red), nitrogen (blue) and carbon (skyblue) of 30; oxygen (red) of BACE1. (A) Cartoon mode with the side chains of BACE1. (B) Surface mode; Asp32 and Asp228 (red). (C)
Model of interaction.
inhibitory activities. Alkenyl compounds (18)–(23), synthetic inter-
mediates, were also inactive (data not shown). On the other hand,
biaryl derivatives connected with C4 or C5 spacers (24)–(31)
showed relatively weak inhibitory effects on rBACE1 activity. This
suggested that biaryl derivatives connected with C4 or C5 spacers
are effective and consequently the aminopyridine motif reported
by the Murray group has potential as a BACE1 inhibitor although
a structure–activity relationship study needs to show an increase
in inhibitory activity. In addition, 6-alkyl-2-aminopyridine (30)
exhibited greater inhibitory activity in comparison with 5-alkyl-
2-aminopyridines (27) and (28). Surprisingly, aminopyridine
derivatives, which had an acetyl group removed, tended to show
similar activities to the corresponding compounds (data not
shown). There was no correlation between the inhibition value,
tPSA and C log P in this case (Table 5).
small molecules derived from fragment screening and further
studies will be developed to investigate potent active inhibitors.
Acknowledgements
This work was supported in part by Yamagata University
Research Fund and The Foundation for Japanese Chemical
Research.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2015.10.
007.
The binding mode of 30 to BACE1 (PDB code 1FKN30) was pre-
References and notes
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