Synthesis, structure-activity relationships, and biological evaluation of a series of benzamides as potential multireceptor antipsychotics

Article abstract of DOI:10.1016/j.bmcl.2016.04.087

In the present study, a series of benzamides, endowed with potent dopamine D₂, serotonin 5-HT_1A and 5-HT_2A receptors properties, was synthesized and evaluated as potential antipsychotics. Among them, 3-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl)butoxy)-N-methylbenzamide (21) and its fluoro-substituted analogue (22) held the best pharmacological binding profiles. They not only presented potent activities for D₂, 5-HT_1A, and 5-HT_2A receptors, but were also endowed with low activities for 5-HT_2C, H₁ receptors and hERG channels, suggesting a low propensity of inducing weight gain and QT prolongation. In animal models, compounds 21 and 22 reduced phencyclidine-induced hyperactivity with a high threshold for catalepsy induction. It thus provides potential candidates for further preclinical studies.

Full text of DOI:10.1016/j.bmcl.2016.04.087

Accepted Manuscript
Synthesis, structure-activity relationships, and biological evaluation of a series
of benzamides as potential multireceptor antipsychotics
Feipu Yang, Xiangrui Jiang, Jianfeng Li, Yu Wang, Yongjian Liu, Minghao Bi,
Chunhui Wu, Qingjie Zhao, Weiming Chen, Jingjing Yin, Jian Zhang,
Yuanchao Xie, Tianwen Hu, Mingshuo Xu, Shuang Guo, Zhen Wang, Yang He,
Jingshan Shen
PII:
S0960-894X(16)30475-9
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.04.087
BMCL 23849
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 March 2016
27 April 2016
29 April 2016
Please cite this article as: Yang, F., Jiang, X., Li, J., Wang, Y., Liu, Y., Bi, M., Wu, C., Zhao, Q., Chen, W., Yin,
J., Zhang, J., Xie, Y., Hu, T., Xu, M., Guo, S., Wang, Z., He, Y., Shen, J., Synthesis, structure-activity relationships,
and biological evaluation of a series of benzamides as potential multireceptor antipsychotics, Bioorganic &
Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.04.087
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Synthesis, structure-activity relationships,
and biological evaluation of a series of
benzamides as potential multireceptor
antipsychotics
Leave this area blank for abstract info.
Feipu Yang, Xiangrui Jiang, Jianfeng Li, Yu Wang, Yongjian Liu, Minghao Bi, Chunhui Wu, Qingjie Zhao,
Weiming Chen, Jingjing Yin, Jian Zhang, Yuanchao Xie, Tianwen Hu, Mingshuo Xu, Shuang Guo, Zhen Wang
,Yang He, Jingshan Shen

Bioorganic & Medicinal Chemistry Letters
Synthesis, structure-activity relationships, and biological evaluation of a series of
benzamides as potential multireceptor antipsychotics
Feipu Yanga, Xiangrui Jianga, Jianfeng Lia, Yu Wanga, Yongjian Liu b, Minghao Bib, Chunhui Wub,
Qingjie Zhao a, Weiming Chenb, Jingjing Yinb, Jian Zhangb, Yuanchao Xie a, Tianwen Hua, Mingshuo Xu
a, Shuang Guo a, Zhen Wanga, , Yang He a, , and Jingshan Shena
aCAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203,
China
bTopharman Shanghai Co., Ltd., 1088 Chuansha Road, Shanghai 201209, China
A RT ICL E INFO
A BST RA CT
Article history:
Received
Revised
Accepted
Available online
In the present study, a series of benzamides, endowed with potent dopamine D2, serotonin 5-
HT1A and 5-HT 2A receptors properties, was synthesized and evaluated as potential
antipsychotics. Among them, 3-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl)butoxy)-N-
methylbenzamide (21) and its fluoro-substituted analogue (22) held the best pharmacological
binding profiles. They not only presented potent activities for D2, 5-HT 1A, and 5-HT 2A receptors,
but were also endowed with low activities for 5-HT2C, H1 receptors and hERG channels,
suggesting a low propensity of inducing weight gain and QT prolongation. In animal models,
compounds 21 and 22 reduced phencyclidine-induced hyperactivity with a high threshold for
catalepsy induction. It thus provides potential candidates for further preclinical studies.
Keywords:
D2
5-HT1A
5-HT2A
2016 Elsevier Ltd. All rights reserved.
PCP-inducedhyperactivity
Catalepsy
Schizophrenia is among the most serious mental illness
characterized by the coexistence of positive (e.g., hallucinations
and delusions), negative (e.g., social withdrawal, anhedonia and
poverty of thought and content of speech), and cognitive (e.g.,
impaired attention and learning) symptoms.1 It affects
approximately 1% of the world’s population and has a
considerable social and economic impact.2
The first-generation antipsychotics (e.g., chlorpromazine, 1
and haloperidol, 2, Figure 1) are dopamine D2 receptor (D2R)
antagonists. However, their application is limited by the wide
range of side effects (e.g., Parkinson-like extrapyramidal
symptoms (EPS), prolactin release, weight gain, or even fatal
cardiovascular events).3 The second-generation antipsychotics
(e.g., risperidone, 3 and ziprasidone, 4, Figure 1) have a
broadened receptor-binding profile which results in their unique
therapeutic properties for pharmacological treatment of
neuropsychiatric disorders4,5 and they are classified as “atypical
antipsychotics”.
The third-generation antipsychotics (e.g., cariprazine, 5,
aripiprazole, 6 and brexpiprazole, 7, Figure 1) are dopaminergic
and serotoninergic modulators. Aripiprazole is characterized as a
D2R partial agonist with weak intrinsic activity (IA, 30%) , 5-
HT2AR antagonist and 5-HT1AR partial agonist according to the
literature.6 Besides, aripiprazole is also a -arrestin-biased D2R
partial agonist which is well tolerated and does not significantly
induce EPS, weight gain, QT prolongation or increase plasma
prolactin
levels.6
Brexpiprazole,
exhibiting
similar
Figure 1. Representative typical and atypical antipsychotics.
———
Corresponding author. Tel.: +86 21 20231000-2409; e-mail: heyang@simm.ac.cn.
Corresponding author. E-mail: wangzhen@simm.ac.cn.

Scheme 2. Reagents and conditions: (a) 1-bromo-4-chlorobutane, K2CO3,
DMF, rt, 5 h; (b) 1-(2,3-dichlorophenyl)piperazine hydrochloride, K2CO3,
DMF/H2O , 95 °C, 5 h.
pharmacological mechanism to aripiprazole, was also developed
by Otsuka and is considered to be a successor of aripiprazole.7
Blockade of post-synaptic serotonin receptor subtype 2A (5-
HT2A) by atypical antipsychotics in substantia nigra neurons may
elevate dopamine’s level in axonal terminals. These
antipsychotics are therefore able to compensate for the
hypoactivity of dopamine in the nigrostriatal dopamine pathways
to counteract D2R-mediated EPS.8 Likewise, the antagonism of
serotonin 5-HT2A receptors (5-HT2AR) by atypical antipsychotics
in the mesocortical dopamine pathway is responsible for
balancing the dopamine activity deficiency and leading to an
improvement of negative and cognitive symptoms of
schizophrenia.9,10
SAR of the Benzamide Moiety. To investigate the effects of
substituents (R1 and R2) in the benzamide region, we designed a
series of compounds outlined in Figure 2. Compounds 9a−9d
with R1 of different length were prepared to see if the group size
or liposolubility had an influence on the activity. Compounds
9e−9o with R2 of various groups were meant to investigate the
effect of substitute positions and electrical factors.
Furthermore, the serotoninergic system plays an important
role in the regulation of emotion, cognitive behavior, and
working memory. Serotonin 5-HT1A receptors (5-HT1AR) are
particularly dense in prefrontal cortex, hippocampus, and
amygdala region.11,12 Agonism of the 5-HT1AR increases
dopamine release in the frontal cortex, which may reduce
negative symptoms and cognitive deficits in patients with
schizophrenia.13 5-HT1AR agonists and partial agonists have also
demonstrated clinical effectiveness in the treatment of anxiety14
and depression.15,16 Recent preclinical and clinical studies also
suggest that 5-HT1AR agonists may be useful in treating
dementia,17 Parkinson’s disease,13,18 pain associated with spinal
cord injuries,19 ischemia,20 and ADHD.21 Thus, the aim of our
work was to develop novel antipsychotics that act on
dopaminergic and serotoninergic receptors with potent and
balanced activities as well as with low activities for receptors
associated with side effects. Our goal was to develop a
pharmacological agent that could effectively address the positive
symptoms, negative symptoms and cognitive deficits in
schizophrenia with minimal side effects.
Figure 2. Compounds designedto explore the SAR of benzamide moiety.
We selected the arylpiperazine systemas a flexible scaffold for
achieving a fine balancing of D2R/5-HT2AR antagonism and 5-
HT1AR agonism activities. Taking aripiprazole as a lead, we
designed and synthesized compound 8 and 9a. Compound 8
exhibited a dramatic decrease in the activity of 5-HT1AR agonism
(Scheme 1), while compound 9a had comparable activity to that
of aripiprazole. Therefore, 9a was selected for further structural
optimizations to look for more favorable antipsychotics and also
exploit the structural-activity relationships (SAR) especially in
the benzamide and base regions.
Scheme 3. Reagents and conditions: (a) 1,4−dibromobutane, K2CO3, acetone,
reflux, 150 min; (b) 1-(2,3-dichlorophenyl)piperazine hydrochloride, K2CO3,
1
NaI, CH3CN, reflux, 7 h; (c) R NH2, EtOH, sealedtube, 50-100 °C, overnight.
A representative synthesis route of compounds 9a−9o is shown
in Scheme 3. Methyl 3-hydroxybenzoate (10a) and methyl 3-
hydroxy-4-methoxybenzoate (10e) are commercially available.
The other substituted benzoates (10b−10d, 10f−10l) were
obtained by methyl esterification of corresponding benzoic acids
heated with methanol in the presence of concentrated sulfuric
acid or thionyl chloride. Mono-substitution of 1,4-dibromobutane
with 10a−10l gave the methyl bromobutoxybenzoate 11a−11l,
which subsequently reacted with commercially available 1-(2,3-
dichlorophenyl)piperazine hydrochloride to afford intermediates
12a−12l. Compounds 9a−9o were prepared by aminolysis of
12a−12l in a sealed tube with corresponding amines in alcohol.
The D2R, 5-HT2AR antagonism and 5-HT1AR agonism of
compounds 9a−9o were displayed in Table 1. It could be found
that larger groups (Et, n-Pentyl) of R1 had little influence on the
D2R and 5-HT2AR antagonism, but obviously decreased the 5-
HT1AR agonism. Although compounds 9a and 9b exhibited
similar activity, we chose 9a for further investigation on account
of the polarity and lipophicity.
Scheme 1. Discovery of benzamide derivatives as potential multireceptor
antipsychotics
Several representative substituents, including electron
donating or withdrawing groups were introduced to the
benzamide ring at different positions to derive eleven compounds
(9e−9o). Compounds bearing R2 substituents at 2-position of the
benzamide displayed better potency for the three receptors than

those with substituents at 3, 4 or 6-positions. Compound 9f with
a 2-F substituent exhibited excellent 5-HT1AR agonism activity
especially. Introducing substituents at 6-position (9g, 9n, 9o)
significantly weakened the D2R antagonism and 5-HT1AR
agonism. Similarly, 3-substitution led to a decrease in the activity
to some extent, and compounds 9j and 9k were only moderate
D2R antagonists/5-HT1AR agonists. It was noticeable that
compound 9h with 4-OCH3 group was about 1-fold more potent
than the lead, but the 4-Cl substituted derivative 9l was much less
active, especially for the agonism of 5-HT1AR. Comparing
compounds 9f and 9o with 9a, we found that fluoro-substitution
at ortho-position of CONHMe group could enhance antagonism
activity for 5-HT2AR by 3-fold. It suggests that conformation
constrain by potential H-F hydrogen bond may prefer 5-HT2AR
antagonismactivity.22
Scheme 4. Reagents and conditions: (a) 1,4-dibromobutane, K2CO3, acetone,
reflux, 4h; (b) 1-(2,3-dichlorophenyl)piperazine hydrochloride, K2CO3, NaI,
CH3CN, reflux, overnight; (c)methylamine in ethanol, 50 °C, overnight.
Table 2. Functional activities for the D2, 5-HT1A and 5-HT2A
receptors of compounds 13 and 14
Cmpd
D2R
5-HT1A
R
5-HT2AR
IC50 (nM) EC50 (nM) IC50 (nM)
13
14
9a
6
167
70
32
309
122
24
2200
820
1100
2790
17.2
285
SAR of the Base Moiety. As we can see in Table 1, compound
9f with a 2-F substituent exhibited more potent activities for 5-
HT1AR and 5-HT2AR than compound 9a, and maintained
favourable activity for D2R. Shown in Table 3, we designed eight
compounds bearing F or H at 2-position but with different base
moieties. Their synthesis route was presented in Scheme 5,
following a similar procedure to that previously described for
compounds 9a−9o. Compounds containing the same base moiety
showed almost comparable activities for D2R and 5-HT1AR,
while 2-F substitution evidently increase antagonism activities
for 5-HT2AR. That is consistent with SAR of the benzamide
moiety discussed above. Compounds 21−26 containing the base
moiety of launched drugs (risperidone, ziprasidone,
brexpiprazole, respectively) possess excellent functional
activities for all three receptors while compounds 27 and 28
bearing the base of 1-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-
piperazine exhibited fairly weak activities for 5-HT2AR.
To investigate the effect of relative position of butoxy and
CONHMe group, we designed and synthesized compounds 13
and 14. As shown in Table 2, compound 13 possessed much
Table 1. Functional activities for the D2, 5-HT1A and 5-HT2A
receptors of compounds 6, 9a-9o
Cmpd
R1
R2
D2R
5-HT1A
R
5-HT2AR
IC50 (nM)
EC50 (nM) IC50(nM)
6
9a
9b
9c
9d
9e
9f
-
-
17.2
32
285
24
2790
1100
1100
670
CH3
H
H
H
55
26
Et
H
116
16.8
9.8
101
464
74
n-Pentyl
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
1100
460
2-CH3
2-F
39.4
3600
12
7.2
360
9g
9h
9i
6-CH3
4-OCH3
2-Cl
3-CH3
3-Ac
4-Cl
3-F
122
26
860
Table 3. Functional activities for the D2, 5-HT1A and 5-HT2A
receptors of compounds 21-28
840
34.9
89.8
37.7
58.5
1580
202
171
34.4
97.2
137
>10000
361
120
301
340
9j
1400
494
9k
9l
1380
1320
720
9m
9n
9o
Cmpd
R2NH
R'
D2R
5-HT1A
R
5-HT2AR
6-OCH3
6-F
30.3
IC50 (nM) EC50 (nM) IC50 (nM)
weaker activities while slightly reduced activities of compound
14 was observed for all three receptors compared to compound
9a, suggesting that introducing CONHMe group at the meta-
position of butoxy moiety may afford compounds with the best
pharmacological profiles.
21
22
H
F
8.5
23
13
13
46
15
23
24
25
H
F
10
12
91
4.3
2.7
5.1
180
35
H
216
26
27
F
43
6
80
H
4.1
12
>10000

Figure 3. Effect of test compounds on PCP-induced hyperactivity in mice
(8/group). PCP was administered ip at a dose of 7 mg/kg immediately before
test start.Test compounds includingaripiprazole were administered ig45 min
before test start. Locomotor activity was evaluated in automated activity
chambers for 60 min. Results are expressed as the means ± SEM of distance
traveled. Statistical evaluation was performed by two-way ANOVA followed
by student’s t test for multiple comparisons. *p < 0.05 versus vehicle
treatment; ##p < 0.01 versus PCP treatment.
28
F
30
8.2
1900
9a
6
H
-
32
24
1100
2790
-
17.2
285
Table 4. In vitro human liver microsome assessment of
compounds 21 , 22, 24 and 26a
Cmpd
21
22
24
26
Loss (0.5 h) 3% 14% 47% 51%
a
The test compound was dissolved and diluted to the desired concentration
with DMSO. Liver microsomes were incubated in a 96-well plate containing
100 mM PBS buffer (pH 7.4), 0.5 mg/mL microsomal protein, 2 M test
compound and 1.0 mM NADPH. Incubations were conducted at 37 °C. The
enzymatic reaction was stopped by protein precipitation in acetonitrile after
30 min.The loss ofthe test compound was determined by LC-MS/MS.
Scheme 5. Reagents and conditions: (a) R2NH, K2CO3, NaI, CH3CN, reflux,
overnight; (b) methylamine in ethanol, 50 °C, overnight.
Behavioral in Vivo Evaluation. Based on the above result of in
vitro pharmacological evaluation, we selected several compounds
(21, 22, 24, 26) which had good IC50 and EC50 values (<100 nM)
for testing in vivo in several mice models sensitive to mesolimbic
mediated antipsychotic-like activity
Compared with aripiprazole and risperidone (with ED50 values
of 2.93 and 0.03 mg/kg, respectively, Table 5), compounds 21
and 22 exhibited significant dose-dependent responses in PCP-
induced hyperactivity model (Figure 4), with ED50 values of 0.06
and 0.11 mg/kg, respectively (Table 5). This result suggested that
they were more potent than aripiprazole.
Phencyclidine (PCP)-induced hyperactivity model is usually
used for assessing antipsychotic efficacy.23,24 PCP and ketamine,
uncompetitive NMDA receptor antagonists, could induce
schizophrenic symptoms in healthy subjects and aggravate
existing psychoses in schizophrenic patients. It revealed that
endogenous dysfunction of NMDA receptor-mediated
neurotransmission might be involved in the pathogenesis of
schizophrenia.24,25
Table 5. Behavioral effects of compounds 21 and 22
Cmpd
PCPa CATb CAT/PCP
21
22
0.06
0.11
6.76
7.04
7.13
0.30
112.67
64.09
2.43
Aripiprazole 2.93
Risperidone 0.03
10
aPCP: phencyclidine-induced hyperactivity (ED50, mg/kg, ig). bCAT:
catalepsy (ED50, mg/kg, ig).
As shown in Figure 3, compounds 24 and 26 with the base
moiety of ziprasidone and brexpiprazole respectively did not
exhibit the expected activity even though at a dose of 10 mg/kg,
probably due to their poor metabolic stability assessed by in vitro
human liver microsome (HLM) test (Table 4). Compounds 21
and 22 containing the base moiety of risperidone remarkably
decreased the PCP-induced hyperactivity at the same dose (10
mg/kg), but meanwhile a sedative effect was observed. When the
dose was reduced to 1 mg/kg, compounds 21 and 22 also
significantly reduced the PCP-induced hyperactivity, but did not
cause sedation in mice.
Figure 4. Effect of compounds 21 and 22 (0.1, 0.3, 1 mg/kg, ig) on PCP-
induced hyperactivity in mice (7 mg/kg, ip, 8/group). Results are expressed as
the means ± SEM of distance traveled. Statistical evaluation was performed
by two-way ANOVA followed by student’s t test for multiple comparisons.
**p < 0.01 versus vehicle treatment; ##p < 0.01 versus PCP treatment.
Catalepsy is frequently used to predict the propensity of
antipsychotic to induce EPS.26 The side-effect liability of tested
compounds was evaluated applying the horizontal bar
experiment, a very sensitive measure of catalepsy induced by
D2R blockade.27 As presented in Table 5, risperidone had the
highest tendency to induce catalepsy with an ED50 value of 0.30
mg/kg. Aripiprazole, compounds 21 and 22 were found to have
low cataleptogenic potential with ED50 values of 7.13, 6.76, and
7.04 mg/kg, respectively. The therapeutic indices (ratio between
efficacy (PCP-induced hyperactivity model) and side effects
(catalepsy)) of compounds 21 and 22 were 113 and 64,
respectively, while the indices of aripiprazole and risperidone are

below 10. These results suggested that compounds 21 and 22
were devoid of cataleptogenic effects.
The authors gratefully acknowledge Topharman Shanghai Co.,
Ltd for providing intermediates.
Further in Vitro Binding Profiles of 21 and 22. Many atypical
antipsychotics are associated with numerous side effects,
including substantial weight gain, orthostatic hypotension and
QT interval prolongation.28-30 Therefore, further characterization
of binding profiles of compounds 21 and 22 is essential.
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22
35
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2560
972
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hERG (Ether-a-Gogo-Related Gene) potassium channel
blockade is a crucial indicator of potential pro-arrhythmic
tendency. Drug-induced blockade of hERG channel is commonly
associated with prolongation of the electrocardiographic QT
interval, resulting in long QT syndrome.37,38 Therefore,
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In summary, a series of benzamide derivatives derived from
aripiprazole was prepared and proved to be potential
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PCP-induced hyperactivity with a high threshold for catalepsy
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5-HT2C receptors and low affinity for hERG channels. The
characteristics of high therapeutic potential and low side-effect
risk have promoted 21 and 22 into further preclinical studies for
the treatment ofschizophrenia.
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Acknowledgments
This work was supported by Chinese Ministry of National
Science and Technology create significant new drugs, special
major science and technology (2013ZX09507001).
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