Design, synthesis and biological evaluation of N-hydroxy-aminobenzyloxyarylamide analogues as novel selective κ opioid receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2020.127236

Aminobenzyloxyarylamide derivatives 1a-i and 2a-t were designed and synthesized as novel selective κ opioid receptor (KOR) antagonists. The benzoyl amide moiety of LY2456302 was changed into N-hydroxybenzamide and benzisoxazole-3(2H)-one to investigate whether it could increase the binding affinity or selectivity for KOR. All target compounds were evaluated in radioligand binding assays for opioid receptor binding affinity. These efforts led to the identification of compound 1c (κ K_i = 179.9 nM), which exhibited high affinity for KOR. Moreover, the selectivity of KOR over MOR and DOR increased nearly 2-fold and 7-fold, respectively, compared with (±)LY2456302.

Full text of DOI:10.1016/j.bmcl.2020.127236

Journal Pre-proofs
Design, synthesis and biological evaluation of N-hydroxy- aminobenzyloxyar‐
ylamide analogues as novel selective κ opioid receptor antagonists
Guangchao He, Qiao Song, Junwei Wang, Anhua Xu, Kewen Peng, Qihua
Zhu, Yungen Xu
PII:
S0960-894X(20)30341-3
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127236
BMCL 127236
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Bioorganic & Medicinal Chemistry Letters
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Accepted Date:
6 January 2020
28 April 2020
29 April 2020
Please cite this article as: He, G., Song, Q., Wang, J., Xu, A., Peng, K., Zhu, Q., Xu, Y., Design, synthesis and
biological evaluation of N-hydroxy- aminobenzyloxyarylamide analogues as novel selective κ opioid receptor
antagonists, Bioorganic & Medicinal Chemistry Letters (2020), doi: https://doi.org/10.1016/j.bmcl.2020.127236
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Graphical abstract

Design, synthesis and biological evaluation of N-hydroxy-
aminobenzyloxyarylamide analogues as novel selective κ opioid
receptor antagonists
Guangchao Hea,b,c, Qiao Songa,b,c, Junwei Wang , Anhua Xu , Kewen Peng , Qihua Zhu
a,b
a,b
a,b
a,b,*
and Yungen Xua,b,*
a
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University,
Nanjing 210009, China
b
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
*
Corresponding author. e-mail: zhuqihua@vip.126.com (Q. Zhu); xu_yungen@hotmail.com (Y.
Xu).
c
Both authors contributed equally to this work.
Abstract:
Aminobenzyloxyarylamide derivatives 1a-i and 2a-t were designed and
synthesized as novel selective κ opioid receptor (KOR) antagonists. The benzoyl
amide moiety of LY2456302 was changed into N-hydroxybenzamide and
benzisoxazole-3(2H)-one to investigate whether it could increase the binding affinity
or selectivity for KOR. All target compounds were evaluated in radioligand binding
assays for opioid receptor binding affinity. These efforts led to the identification of
compound 1c (κ K = 179.9 nM), which exhibited high affinity for KOR. Moreover,
i
the selectivity of KOR over MOR and DOR increased nearly 2-fold and 7-fold,
respectively, compared with (±)LY2456302.
Keywords: κ opioid receptor; LY2456302; N-hydroxy-aminobenzyloxyarylamide
antagonists; Novel; Selective
Depression has become a threat to human diminishing people’s living standard
[1-2]. The pathogenesis of depression is complicated, leading to a lack of effective
drugs. Opioid receptors, a family of G-protein coupled receptors (GPCRs) comprising
kappa (KOR or κ), mu (MOR or μ), delta ((DOR or δ), and opioid-like (ORL-1)
receptors, play an important role in multiple physiological activities, including pain
management, reward mechanisms, gastrointestinal (GI) motility, hormone release, and
eating behavior [3-5]. Numerous studies have demonstrated that activation of KOR
leads to depression and cocaine relapse, so blocking KOR activation may be effective
in treating depression and drug abuse [6-7].
Over the past few decades, increasing efforts have been made to develop KOR
antagonists for the treatment of depression. KOR antagonists such as norBNI, JDTic,
PF-04455242 and LY2456302 have showed anxiolytic and anti-depressant-like

activity in clinical studies (Fig. 1) [8-12]. Among them, LY2456302 is a short-acting,
high-affinity selective KOR antagonist, which is currently in phase II trial for the
treatment of major depressive disorder [13-17]. However, the selectivity of
LY2456302 between KOR and MOR receptors is not good [18-21], which may
produce neither reliable antidepressant- nor anxiolytic-like effects in treatment. Thus,
developing selective KOR antagonist is a promising strategy to treat depression.
OH
CH3
CH3
CH3
N
CH3
CH3
NH
3
H C
HO
N
OH
O
O
HO
N
O
CH3
CH3
N
O
OH
NH2
O
S
O
N
H
O
NH
N
N
F
H
OH
nor-BNI
JDTic
PF-04455242
LY2456302
Fig. 1 Structures of representative KOR antagonists
In our previous work [22], a series of aminobenzyloxyarylamide derivatives were
designed, synthesized and evaluated as κ opioid receptor antagonists based on the
structural modification of LY2456302. We studied the effects on activity brought
about by different substituents on both ring A and ring B and obtained one potent and
selective candidate compound [22]. In this work, we continue to explore the chemical
space of LY2456302 in the hope to identify more potent KOR antagonists with better
selectivity profile. As shown in Fig 2, we mainly focus on the modification of its
terminal amide moiety. The benzamide moiety of LY2456302 was switched to
N-hydroxybenzamide and benzisoxazole-3(2H)-one bioisosterically, maintaining the
presence of a hydrogen bond donor while exploring possible influences on activity
and selectivity of the compounds associated with these structural changes.
R1
O
OH
N
N
A
B
H
R
O
R2
O
1a-i
N
NH2
A
B
O
R1
R1
O
N
A
B
NH
O
O
R2
R3
2a-t
Fig. 2 Rational design of novel KOR antagonists.
In order rationalize our design strategy, modeling studies of compound 1c and
LY2456302 in the ligand binding pocket of KOR (PDB code: 4DJH and depicted
using MOE 2013.08) were carried out. As predicted by the docking model, the
replacement of the amide moiety in LY2456302 with hydroxamic acid in 1c should
not compromise the key hydrogen bonding interaction with His291. Moreover, the

hydroxyl group of the hydroxamic acid moiety in 1c could form an additional
hydrogen bond with the carbonyl of His291, which may contribute to a higher binding
affinity.
Encouraged by the docking results, a series of N-hydroxybenzamide and
benzisoxazole-3(2H)-one derivatives containing an aminobenzyloxyarylamide
scaffold were synthesized as shown in Scheme 1 and Scheme 2. Benzoic acid
derivatives 3a-m were refluxed with thionyl chloride in ethanol to give intermediates
4
a-m, which were than coupled with N-Vinylpyrrolidone using sodium hydrogen as
base to form 5a-m. Intermediates 5a-m was heated in hydrochloric acid to give 6a-m.
Reduction of 6a-m with sodium borohydride provided intermediates 7a-m. The
reductive amination of aromatic aldehyde derivatives with 7a-m gave intermediates
8
a-m. Etherification of intermediates 8a-j with 9a-b provided 10a-i, which reacted
with hydroxylamine hydrochloride gave target compounds 1a-i.
Esterification of 4-fluoro-2-hydroxybenzoic acid derivatives 11a-c with ethanol
provided 12a-c, which reacted with hydroxylamine hydrochloride gave
4
-fluoro-N,2-dihydroxybenzamide derivatives 13a-c. 6-fluorobenzo[d]isoxazol-3(2H)
-ones 14a-c were synthesize through the intermolecular condensation of 13a-c under
the condition of N,N'-carbonyldiimidazole (CDI), and then reaction with
triphenylmethyl chloride gave 15a-c. Obtained N-protected products 15a-c were
etherified with 8a-m to give intermediates 16a-t. Finally, the target
benzisoxazole-3(2H)-one derivatives 2a-t were obtained by the deprotection of
triphenylmethyl group under the presence of zinc chloride. The synthesized
N-hydroxybenzamide and benzisoxazole-3(2H)-one compounds have been confirmed
1
13
by H-NMR, C-NMR, IR and HR-MS.
Fig. 3 Docking mode of 1c (A) and LY2456302 (B). The H-bonds were shown as black dot lines
and the key residues in the active site of KOR were shown as purple red. (A) The docking pose
of 1c in KOR crystal structure (PDB: 4DJH), and the ligand were shown as blue. (B) The
docking pose of LY2456302 in KOR crystal structure (PDB: 4DJH), and the ligand were shown
as yellow.

R1
COOH
R1
COOC2H5
R1
O
N
HN
R1
a
b
c
d
e
O
OH
N
R1
R1
R2
N
3a-m
4a-m
5a-m
6a-m
7a-m
8a-m
R1
R1
O
O
O
O
CH3 8a-j
g
OH
N
O
CH3
N
N
F
H
R2
f
O
O
R2
R2
9a-b
10a-i
1a-i
2
Synthesis route for target compounds 1a-i. Regents and conditions: (a) SOCl , EtOH, reflux, 2 h, 94.4~98.8%; (b)
o
N-Vinylpyrrolidone, NaH, THF, r.t.-60 C, 3 h, 85.7~94.2%; (c) HCl, THF, reflux, 12 h, 82.8~87.2%; (d) NaBH
4
,
AcOH, MeOH, r.t., 1 h, 43.7~55.6%; (e) Aldehyde, NaBH
3
CN, AcOH, MeOH, r.t., 12 h, 72.7~86.7%; (f) K
2
CO3,
o
o
DMF, N
2
, 120 C, 12 h, 38.4~55.7%; (g) NH
2
OH•HCl, KOH, MeOH, 40 C, 10 h, 38.4~55.7%.
Cmpd
R1
3,5-CH
H
R2
H
H
H
H
1e
1f
4-Cl
3-Cl
F
F
F
F
F
1
a
3
1
b
1g
1h
1i
3-F
1
c
4-OCH
3-OCH
3
3
3-OCH
4-OCH
3
3
1
d
Scheme 1. Syntheses of N-hydroxybenzamide derivatives 1a-i
O
O
O
O
O
h
i
j
k
Ph
Ph
OH
NHOH
OEt
OH
NH
N
O
O
F
OH
F
OH
F
F
F
Ph
R3
1a-c
R3
13a-c
R3
R3
R3
1
12a-c
14a-c
15a-c
R1
R1
8a-m
O
m
O
Ph
Ph
Ph
N
N
l
N
NH
O
O
O
O
R2
R3
R2
R3
16a-t
2a-t
2
Synthesis route for target compounds 2a-t. Regents and conditions: (h) SOCl , EtOH, reflux, 18 h, 72.5~78.3%; (i)
NH
2
OH•HCl, NaOH, H
2
O/Dioxane, r.t., 12 h, 72.2~80.3%; (j) CDI, THF, reflux, 2 h, 82.2~86.2%; (k)
o
Triphenylmethyl chloride, CHCl
3
, reflux, 12 h, 40.8~48.4%; (l) K
2
CO
3
, DMF, N
2
, 120 C, 12 h; (m) ZnCl
2
,
acetone, reflux, 1 h, 15.2~34.8% in two steps.
Cmpd
R1
R2
H
R3
H
H
H
H
2k
2l
3-OCH
3-OCH
3-F
3
3
H
H
H
H
H
F
Cl
F
2
a
3, 5-CH
3
2
b
4-OCH
4-Cl
3
H
2m
2n
2o
2
c
H
3-F
Cl
F
2
d
3, 5-CH
3
Cl
4-Cl

2
e
3, 5-CH
3, 5-CH
3-Cl
3
3
OCH
F
3
H
H
F
2p
2q
2r
2s
2t
4-Cl
H
H
H
Cl
F
Cl
F
2
f
4-OCH
4-OCH
3
3
2
g
H
Cl
F
2
h
3-Cl
H
Cl
F
3, 5-CH
3, 5-CH
3
3
2
i
3, 5-CH
3, 5-CH
3
3
H
F
2
j
H
Cl
Scheme 2. Syntheses of benzisoxazole-3(2H)-one derivatives 2a-t
In order to evaluate the in vitro receptor binding affinity of above two series
compounds, we used the radioligand binding assays analysis for MOR, KOR and
3
3
3
DOR, using [ H]-DAMGO, [ H]-U69,593 and [ H]-DPDPE, respectively [22-24]. As
showed in Table 1 and Table 2, compounds 1a-i, 2a-g and 2t exhibited moderate
binding affinities with KOR inhibition rates > 50% at the concentration of 10 μM,
while the KOR inhibition rates of compounds 1b, 1c and 2a-c were greater than 50%
at the concentration of 1 μM. Among them, compound 2a exhibited the strongest
binding affinity, with KOR inhibitory rate > 90% at 10 μM and > 70% at 1 μM. It is
noteworthy that the binding affinities of all compounds for MOR and DOR were
much weaker compared with KOR, with inhibition rates constantly below 50% at 1
μM.
According to the above receptor binding affinity results, the compounds of 1c,
1
3
g, 1h and 2a were selected to further test their K values for opioid receptors (Table
i
3
). The affinities of these four compounds for MOR ([ H]-DAMGO was used), KOR
3
3
([ H]-U69,593 was used) and DOR ([ H]-DPDPE was used) were weaker than those
of (±)LY2456302. Although the binding affinities were less than satisfactory, we
found that the KOR selectivity of 1c over MOR and DOR was 12.8- and >55-fold,
respectively, which eclipsed that of (±)LY2456302.
The above results indicate that changing the benzamide moiety into
benzisoxazole-3(2H)-one did not improve the activity or selectivity. However, the
replacement of benzamide with N-hydroxybenzamide increased the selectivity of
KOR over MOR and DOR, especially over DOR. Among compounds 1a-i, when R2
group was fluorine, 3-methoxy substituted derivative 1g exhibited more potent KOR
binding affinity and higher KOR selectivity than 4-methoxy substituted derivative 1h.
1
However, when R group was 4-methoxy, fluorine substituted derivative 1h showed
weaker KOR binding affinity and lower KOR selectivity than its unsubstituted
counterpart 1c.
Table 1
In vitro receptor binding affinity of N-hydroxybenzamide derivatives 1a-i and (±)LY2456302.

R1
O
OH
N
N
A
B
H
O
R2
1a-i
Binding (%)
μa
κb
δc
Compd
1
0 μM
1 μM
10 μM
1 μM
10 μM
6.5±0.5
1 μM
0
1
a
36.0±1.3
45.9±1.3
40.4±3.1
31.6±2.0
25.8±1.6
57.3±0.3
73.2±0.2
64.4±0.1
43.1±2.3
87.2±1.2
10.7±2.7
21.9±2.8
12.8±0.6
13.5±1.4
0
84.7±0.3
85.3±0.8
86.0±0.6
84.3±0.4
74.3±1.4
54.7±1.9
80.6±0.5
80.4±0.8
77.4±0.9
100±0.3
39.5±0.5
51.6±1.1
52.3±0.1
33.8±0.1
46.1±0.8
30.9±0.7
45.8±0.8
42.5±1.1
34.9±0.6
96.2±0.8
1
b
13.8±2.5
24.4±1.8
7.1±1.7
0
1
c
3.9±0.3
0
1
d
1
e
34.4±2.0
26.4±0.4
28.4±2.1
17.1±1.5
15.8±0.4
90.2±1.1
25.6±1.4
0
1f
16.5±0.4
25.8±1.5
22.6±0.1
11.0±0.4
52.7±0.4
1
g
16.8±1.1
7.0±1.0
6.2±0.8
49.5±0.4
1
h
1i
(±)LY2456302
a
[3
b
3
c 3
H]-DAMGO was used; [ H]-U69,593 was used; [ H]-DPDPE was used.
Table 2
In vitro receptor binding affinity of benzisoxazole-3(2H)-one derivatives 2a-t and (±)LY2456302.
R1
O
NH
N
A
B
O
O
R2
R3
2a-t
Binding (%)
μa
κb
δc
Compd
1
0 μM
1 μM
10 μM
1 μM
10 μM
1 μM
2
a
74.0±1.4
50.6±0.7
54.5±1.6
49.4±0.5
42.2±0.1
47.0±0.1
91.6±0.4
66.9±0.7
83.5±0.3
70.6±0.5
55.7±0.1
57.6±1.6
54.8±2.0
40.7±0.9
35.9±0.6
33.9±1.0
33.3±0.7
15.7±1.1
2
b
2
c

2
d
9.8±2.3
59.2±0.2
9.5±1.7
0
0
69.8±0.2
73.2±0.1
85.2±0.9
57.2±0.1
45.4±2.0
36.4±0.4
11.6±1.9
29.0±0.9
0
23.8±0.9
16.9±1.8
49.1±0.9
10.7±0.4
38.2±0.4
44.9±1.2
33.3±0.2
22.3±0.0
28.4±0.3
60.6±1.6
52.5±0.6
37.9±4.5
9.6±1.0
0
2
e
14.3±1.4
38.4±0.3
11.6±0.4
0
2
f
0
37.2±0.9
2
g
0
20.0±0.3
0
2
h
32.5±1.0
21.1±2.6
0
19.2±0.1
0
0
2
i
0
0
0
0
2
j
0
0
2
k
6.2±0.3
0
0
9.7±0.2
0
2
l
0
0
19.7±0.8
20.7±0.1
8.5±0.5
0
2
m
0
0
24.8±2.4
16.2±0.3
39.2±0.2
0
0
2
n
0
0
0
0
2
o
p
q
35.8±0.1
41.1±0.5
41.0±2.3
32.2±1.6
45.7±0.1
37.3±0.8
22.5±3.8
21.7±3.2
19.2±2.5
17.7±0.3
21.4±1.6
9.4±0.1
52.7±0.4
2
0
52.2±2.2
49.7±6.2
39.3±0.3
32.9±0.1
49.3±2.1
90.2±1.1
23.9±3.9
23.7±2.3
18.0±0.2
18.0±0.4
17.2±1.5
49.5±0.4
2
19.1±4.3
39.9±2.1
47.4±3.8
56.9±1.8
100±0.3
0
2
r
18.8±0.1
20.1±0.2
26.7±0.3
96.2±0.8
2
s
2
t
(
±)LY2456302
87.2±1.2
a
[3
b
3
c 3
H]-DAMGO was used; [ H]-U69,593 was used; [ H]-DPDPE was used.
Table 3
The binding affinities K values of 1c, 1g, 1h, 2a and (±)LY2456302.
i
K
i
(nM)
Selectivity
Compd
μa
κb
δc
µ/κ
12.8
4.6
2.2
1.0
6.7
δ/κ
>55.5
>20.0
>4.6
3.5
1
c
2311±43.5
2797±17.0
4763±178.0
1481±23.0
93.7±8.1
179.9±6.7
497.6±34.7
2154±27.0
1411±125.8
14.0±0.7
>10000
>10000
>10000
5008±45.5
105.2±5.6
1
g
1
h
2
a
(
±)LY2456302
7.5
a
[3
b
3
c 3
H]-DAMGO was used; [ H]-U69,593 was used; [ H]-DPDPE was used.
Furthermore, to further evaluate compound 1c in vitro antagonist activity, we
3
5
utilized inhibition of agonist stimulated [ S]GTP-γ-S binding with cloned human
opioid receptors expressed in CHO cells for MOR and KOR or HEK293 cells for

3
5
DOR [16,22]. According to the [ S]GTP-γ-S binding assays results showed in Table
, 1c with κ IC = 178 nM and μ IC = 201.5 nM that showed moderate κ antagonist
4
5
0
50
potency and selectivity. Although its potency proved to be much weaker than
±)LY2456302, the result demonstrates intriguingly that 1c is an antagonist of KOR
(
and MOR but not of DOR.
Table 4
3
5
In vitro [ S]GTP-γ-S binding values of 1c and (±)LY2456302.
Compd
µ IC50 (nM)a
κ IC50 (nM)b
δ IC50 (nM)c
> 5000
µ/κ
1.1
3.8
δ/κ
1
c
201.5±10.61
178.0±22.80
>28
14.1
(
±)LY2456302
29.4±3.54
7.7±1.27
108.9±5.36
a
b
c
DAMGO was used; U69,593 was used; DPDPE was used. The IC50 is reported as the mean ± SEM of
at least three independent experiments.
In summary, a series of N-hydroxybenzamide derivatives 1a-i and
benzisoxazole-3(2H)-one derivatives 2a-t were designed and synthesized to search
novel KOR antagonists. All compounds were evaluated the binding affinities of
towards opioid receptors, and typical compounds were biologically evaluated the
antagonist potency for opioid receptors in vitro. The results showed that
N-hydroxybenzamide may be an effective pharmacophore to improve the selectivity
of KOR. Although the KOR binding affinity of compound 1c (κ K =179.9 nM) was
i
weaker than that of (±)LY2456302 (κ K = 14.0 nM), the KOR selectivity of 1c over
i
MOR and DOR was nearly improved 2-fold and 7-fold, respectively. Meanwhile, in
GTP-γ-S functional assays, compound 1c also showed moderate KOR antagonist
potency in vitro.
Acknowledgments
We thank the Excellent Science and Technology Innovation Team Projects of
Jiangsu Province Universities in 2015 for support.
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Highlights:
•
•
•
Opioid receptors are a family of G-protein coupled receptors and involved in
multiple physiological activities.
A series of κ opioid receptor antagonists were designed and synthesized based on
the scaffold of aminobenzyloxyarylamide.
All target compounds were evaluated in radioligand binding assays for opioid
receptor binding affinity.

•
•
Compound 1c exhibited high affinity for KOR.
The selectivity of compound 1c for KOR was improved, compared with
(±)LY2456302.