Design, synthesis and biological evaluation of a series of novel GPR40 agonists containing nitrogen heterocyclic rings

Article abstract of DOI:10.1016/j.bmcl.2018.07.048

A novel series of GPR40 agonists is designed by introducing nitrogen-containing heterocyclic ring at the terminal phenyl ring of TAK-875 with the aim of decreasing its lipophilicity. Three different β-substituted phenylpropionic acids were investigated as the acidic components. A total of 34 compounds have been synthesized, among which, compound 30 exhibited comparable GPR40 agonistic activity in vitro with TAK-875 and relatively lower lipophilicity through calculation (30, EC₅₀ = 1.2 μM, cLogP = 1.3; TAK-875: EC₅₀ = 5.1 μM, cLogP = 3.4). Moreover, compound 30 was able to enhance the insulin secretion of primary islets isolated from normal ICR mice and showed no obvious inhibition against cytochromes P450 in vitro. In vivo, compound 30 exhibited efficacy in oral glucose tolerance test (oGTT) in normal ICR mice.

Full text of DOI:10.1016/j.bmcl.2018.07.048

Accepted Manuscript
Design, synthesis and biological evaluation of a series of novel GPR40 agonists
containing nitrogen heterocyclic rings
Zhaozhu Sun, Tian Zhou, Xuan Pan, Ying Yang, Yi Huan, Zhiyan Xiao,
Zhufang Shen, Zhanzhu Liu
PII:
S0960-894X(18)30644-9
https://doi.org/10.1016/j.bmcl.2018.07.048
BMCL 25979
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
27 June 2018
26 July 2018
31 July 2018
Please cite this article as: Sun, Z., Zhou, T., Pan, X., Yang, Y., Huan, Y., Xiao, Z., Shen, Z., Liu, Z., Design, synthesis
and biological evaluation of a series of novel GPR40 agonists containing nitrogen heterocyclic rings, Bioorganic
& Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.07.048
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Design, synthesis and biological evaluation of
a series of novel GPR40 agonists containing
nitrogen heterocyclic rings
Leave this area blank for abstract info.
Zhaozhu Sun, Tian Zhou, Xuan Pan, Ying Yang, Yi Huan, Zhiyan Xiao, Zhufang Shen*, Zhanzhu Liu*
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica,
Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, P. R. China

Bioorganic & Medicinal Chemistry Letters
jo u r n a l h o m e p a g e : w w w . e ls e v ie r . c o m
Design, synthesis and biological evaluation of a series of novel GPR40 agonists
containing nitrogen heterocyclic rings
Zhaozhu Sun, Tian Zhou, Xuan Pan, Ying Yang, Yi Huan, Zhiyan Xiao, Zhufang Shen*, Zhanzhu Liu
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese
Academy of Medical Sciences, Beijing 100050, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A novel series of GPR40 agonists is designed by introducing nitrogen-containing heterocyclic
ring at the terminal phenyl ring of TAK-875 with the aim of decreasing its lipophilicity. Three
different β-substituded phenylpropionic acids were investigated as the acidic components. A
total of 34 compounds have been synthesized, among which, compound 30 exhibited
comparable GPR40 agonistic activity in vitro with TAK-875 and relatively lower lipophilicity
through calculation (30, EC50 = 1.2 μM, cLogP = 1.3; TAK-875: EC50 = 5.1 μM, cLogP = 3.4).
Moreover, compound 30 was able to enhance the insulin secretion of primary islets isolated
from normal ICR mice and showed no obvious inhibition against cytochromes P450 in vitro. In
vivo, compound 30 exhibited efficacy in oral glucose tolerance test (oGTT) in normal ICR mice.
Keywords:
nitrogen-containing heterocycles
GPR40 agonists
2018 Elsevier Ltd. All rights reserved.
type 2 diabetes
———
 Corresponding author. Tel.: +0-010-63165253; e-mail: liuzhanzhu@imm.ac.cn
 Corresponding author. Tel.: +0-010-83172669; e-mail: shenzhufang@imm.ac.cn

G-protein coupled receptor 40 (GPR40), also known as a free
fatty acid receptor, is dominantly expressed in pancreatic β cells
and intestine K, L cells [1-2]. Besides, GPR40 is also reported to
be expressed in brain, but its function is still unknown [3]. It is
well documented that GPR40 agonist is able to decrease blood
glucose level via stimulating the insulin secretion and take effect
only when patients suffer from a high blood glucose level, which
decreases the risk of hypoglycemia significantly [4,5]. Moreover,
it is reported that GPR40 agonist is able to avoid weight gain
effectively, which is a common side effect associated with clinic
drugs used for treating type 2 diabetes [5]. Given the advantages
mentioned above, GPR40 has become an excellent target for the
treatment of type 2 diabetes. To date, multiple classes of GPR40
agonists, bearing a β-substituted phenyl propionic acid in
common, have been explored [6-13] (Fig. 1).
cytochrome P450 (CYP450). Besides, compound 30 was able to
increase insulin secretion of primary islets isolated from normal
ICR mice, and in oral glucose tolerance test (oGTT) in normal
ICR mice, compound 30 also showed efficacy.
The nitrogen-containing heterocycles selected in this work
involve 1,2,3,4-tetrahydroisoquinoline and isoindoline. The
synthetic route of nitrogen-containing heterocycle components
was shown in Scheme 1. The synthesis of compounds 7a-c
containing a tetrahydroisoquinoline moiety started from bromo
substituted phenylacetonitrile. Reduction of bromo substituted
phenylacetonitrile 1a-c with BH3 in THF gave compounds 2a-c,
which were then converted to compounds 3a-c in the presence of
ethyl chloroformate and triethylamine. Cyclization of compounds
3a-c with paraformaldehyde in formic acid afforded the
intermediates 4a-c. Compounds 4a-c were treated with potassium
hydroxide, followed by protection of the amino group with
(Boc)2O to form compounds 5a-c. The coupling reaction of
compounds 5a-c with 3-(hydroxymethyl)phenylboronic acid
catalyzed by Pd(PPh3)4 resulted in the formation of
tetrahydroisoquinoline moieties 7a-c. Compound 7d bearing an
isoindoline moiety was synthesized from 4-bromophthalimide 6
through reduction by BH3 and then protection with (Boc)2O.
Compound 7d was finally obtained through Suzuki crossing
coupling
reaction
from
compound
5d
and
3-
(hydroxymethyl)phenylboronic acid.
Fig 1. Representative GPR40 agonists
Although TAK-875 was terminated in phase III clinic trial, it
is still an important lead compound for discovering novel GPR40
agonists. A great number of structural modifications based on
TAK-875 have been carried out, and a common strategy was to
introduce polar group into the structure of TAK-875 with the aim
of decreasing its lipophilicity. A variety of heterocycles, such as
thiazole, isoxazole and pyrrole, has been employed to replace the
phenyl ring of biphenyl moiety in TAK-875 and achieved
promising results [7-8, 14-16]. Inspired by these results, we
envisioned to design a novel series of GRP40 agonists by
introducing six-membered or five-membered nitrogen-containing
heterocyclic rings into the structure of TAK-875. Theoretically,
the introduction of nitrogen-containing heterocycles could
decrease lipophilicity of these newly designed compounds. The
N-H group of the heterocyclic rings could be further acylated or
alkylated to give structurally diversified derivatives. In the
meantime, the acidic component of TAK-875 could be replaced
by other β-substituted phenylpropionic acids. The structural
modification plan was depicted in Fig. 2.
Scheme 1. Synthesis of 7a-d. Reagents and conditions: (a) BH3·THF,
THF, reflux, 80.0% - 85.2%; (b) ethyl chloroformate, TEA, DCM, 0 oC to r.t.,
80.5% - 82.0%; (c) paraformaldehyde, HCOOH, reflux, 75.0% - 88.5%; (d)
KOH, MeOH, reflux; (e) (Boc)2O, DMAP, THF, r.t., 72.7% - 79.3% (for two
steps); (f) 3-(hydroxymethyl)phenyl)boronic acid, Pd(PPh3)4, 2M Cs2CO3,
DME, reflux, 81.8% - 87.2%.
The synthesis of acidic components was described in Scheme
2. Three β-substituded phenylpropionic acids including (S)-2-
(2,3-dihydrobenzofuran-3-yl)acetic acid, 2-phenoxyacetic acid
and 3-methyl-3-phenylbutanoic acid, were prepared. (S)-methyl
2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate
13
was
synthesized from resorcinol 8 via five steps. Treatment of
resorcinol 8 with ethyl 4-chloroacetoacetate in the presence of
H2SO4 generated compound 9 via Pechmann reaction. Treatment
of compound 9 in potassium hydroxide solution, followed by
esterification of -OH with acetic anhydride afforded compound
10. Reduction of 10 under hydrogen atmosphere catalyzed by
Pd/C gave key intermediate dihydrobenzofuran 11. The reaction
of the key intermediate 11 with (R)-(+)-α-phenylethylamine in
the presence of EDCI, TEA and DMAP in DCM resulted in the
Fig 2. Design of novel GPR40 agonists
Totally, 34 compounds were synthesized with three different
acidic heads and four different nitrogen-containing heterocyclic
rings. Compound 30 was discovered as the promising lead
compound for further investigation, as it exhibited comparable
GPR40 agonistic activity (EC50 = 1.2 μM) and relatively lower
lipophilicity (cLogP = 1.3) compared with TAK-875 (EC50 = 5.1
μM, cLogP = 3.4). It also showed no obvious inhibition against
formation of
a
pair of diastereoisomers. The desired
diastereoisomer 12 was purified via recrystallization from mixed
solvents of ethanol and acetone in 31.2% yield. Hydrolysis of
compound 12 in the presence of potassium hydroxide and then
esterification with methanol gave the final product (S)-methyl 2-

(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate 13. Ethyl 2-(4-
hydroxyphenoxy)acetate 16 was prepared from hydroquinone 14
and ethyl bromoacetate 15 through alkylation. The synthesis of
the third acidic component 20 started from isopropylidene
malonate 17. Condensation of isopropylidene malonate 17 with
acetone furnished compound 18, which subsequently underwent
Michael addition reaction to generate compound 19. Treatment of
19 with hydrochloric acid in DMF triggered hydrolyzation and
decarboxylation, followed by debenzylation and esterification to
give the target compound 20.
Scheme 3. Synthesis of final products. Reagents and conditions: (a) 13,
16 or 20, ADDP, tributylphosphane, toluene, r.t., 78.2% - 93.0%; (b) TFA,
DCM, r.t., 72.5% - 91.6%; (c) NaOH, MeOH, r.t.; (d) acetaldehyde,
NaCNBH3, AcOH, THF, 0 oC; (e) alkyl halide, K2CO3, KI, DMF, 100 oC; (f)
acyl chloride, TEA, DCM, 0 oC to r.t..
Scheme 2. Synthesis of the acidic components 13, 16 and 20. Reagents
and conditions: (a) ethyl 4-chloroacetoacetate, H2SO4, 0 oC to r.t., 80.4%; (b)
KOH, reflux; (c) Ac2O, 0 oC to r.t., 89.1% (for two steps); (d) Pd/C, H2,
30psi, MeOH, r.t., 79.7%; (e) (R)-(+)-α- phenylethylamine, EDCI, DMAP,
TEA, DCM, r.t., 31.2%; (f) 8M KOH, MeOH, reflux; (g) SOCl2, MeOH, 0
oC, 56.0% (for two steps). (h) EtONa, EtOH, r.t., 56.5%; (i) Acetone, AcOH,
morpholine, r.t., 75.6%; (j) Mg, 1-benzyloxy-4-iodobenzene, THF, reflux to 0
oC, 65.9%; (k) 8M HCl, DMF, reflux; (l) Pd/C, H2, 30 psi, MeOH, r.t.; (m)
SOCl2, MeOH, 0 oC, 68.9% (for three steps).
With the nitrogen-containing heterocycle components and the
acidic components in hand, the final products were synthesized
according to the procedure as depicted in Scheme 3. Reaction of
7a-d with various β-substituded phenylpropionic acid (13, 16 and
20), followed by deprotection by TFA, smoothly provided the
corresponding intermediates 22a-d, 54-61, respectively.
Hydrolysis of 22a-d resulted in the formation of products 23a-d.
Alternatively, compounds 22a-d were reacted with alkyl halides
or acyl halides, which were then hydrolyzed with sodium
hydroxide to yield target products 24-45. The synthesis of
compounds 62-69 was realized according to the method
established above.
All compounds were initially evaluated for their GPR40
agonistic activity by detecting luciferase activity in HEK293E
cells expressed hGPR40 at a concentration of 10 μM [17]. TAK-
875 was employed as the positive compound. The results are
summarized in Table 1.
As can be seen from Table 1, the substituents on the nitrogen
atom had a remarkable influence on the GPR40 agonistic
activity. Compounds 23a-d without any substituents on N atom
did not show any activity on GPR40 cell. Compounds 24, 29 and
35 bearing an ethyl group on the N atom only exhibited slight
agonistic activities on GPR40. In contrast, introduction of benzyl
group led to a dramatic increase of GPR40 agonistic activity in
vitro. The activities of compounds 25 and 41 were approximately
90% of that of TAK-875, while compounds 30 and 36 exhibited
better activities than TAK-875. Compounds (28, 33, 39 and 44)
possessing a benzoyl group showed moderate activity on GPR40.
Increasing the distance between the distal phenyl and N atom as
exemplified in compounds 26, 31, 37 and 42 resulted in a loss of
GPR40 agonistic activity. The position of the six-membered
nitrogen-containing heterocycles had little if any effect on the
GPR40 agonistic activity, but generally the activity of 1,2,3,4-
tetrahydroisoquinoline derivatives was superior to that of
isoindoline derivatives. Replacing the acidic component with
phenoxyacetic acid and 3-methyl-3-phenyl-butanoic acid led to a
reduced GPR40 activity, except compound 66, which maintained
comparable activity with TAK-875. The result was outlined in
Table 2.
Table 1. In vitro GPR40 agonistic activity of compounds 23a-d and 24-45
Compd.
R
Act%
Compd.
R
Act%
23aa
24a
25a
26a
27
R=H
n/a
7.8
89.4
54.8
43.6
23ca
35a
36a
37a
38
R=H
n/a
n/a
107.7
n/a
n/a
R=Ethyl
R=Benzyl
R=Phenethyl
R=Acetyl
R=Ethyl
R=Benzyl
R=Phenethyl
R=Acetyl

28
R=Benzoyl
84.2
39
40
R=Benzoyl
R=Phenylacetyl
46.0
20.4
23ba
29a
30a
31a
32
R=H
R=Ethyl
n/a
n/a
23da
41a
R=H
n/a
R=Benzyl
R=Phenethyl
R=Acetyl
R=Benzoyl
R=Phenylacetyl
89.8
77.0
36.8
60.8
34.8
100
R=Benzyl
R=Phenethyl
R=Acetyl
R=Benzoyl
R=Phenylacetyl
136.3
85.0
5.0
39.8
31.6
42a
43
44
45
TAK-875
33
34
a Compounds was prepared as hydrochloride.
Table 2. In vitro GPR40 agonistic activity of compounds 62-69
Compd.
X
Act%
Compd.
X
Act%
62
66
O
28.8
90.0
64
68
O
4.6
22.8
C(CH3)2
C(CH3)2
63
67
TAK-875
O
17.8
58.6
100
65
69
O
18.9
23.8
C(CH3)2
C(CH3)2
As listed in Table 1 and Table 2, several compounds exhibited
excellent GPR40 agonistic activity at a concentration of 10 μM,
which was similar to or even better than the positive compound
TAK-875. To further investigate the activity of these compounds,
EC50 was evaluated and listed in Table 3. All tested compounds
exhibited comparable activity with TAK-875. The highest
activity was observed with compounds 30, 36 and 66 with the
EC50 value of 1.2 μM, 0.8 μM and 0.8 μM, respectively.
Table 4 The effect of stimulating insulin secretion of
compounds 30 and 36
Compd.
DMSO (G-2.8 mM)
DMSO (G-16.8 mM)
TAK-875
Insulin (ng/mL/protein)
0.1±0.2***
1.8±0.6
2.1±0.1
30
2.9±0.8*
36
2.8±0.7*
*P<0.05; ***P<0.001, versus DMSO (G-16.8 mM)
The cLogP values of these compounds were also calculated
using Molinspiration cheminformatics, which was used to predict
their lipophilicity premilinarily (Table 3) [18]. The result
demonstrated that cLogP values of these compounds were
generally lower than TAK-875, which suggested this novel series
of GPR40 agonists could show a relatively low lipophilicity
compared with TAK-875.
Table 3 EC50 and cLogP values of representative compounds
Compd.
25
EC50 (μM)
5.4
cLogP
1.3
28
30
2.2
1.2
3.2
1.3
31
4.0
1.5
36
41
66
0.8
3.0
0.8
5.1
1.3
1.1
4.4
3.4
Fig 3. Glucose-stimulated insulin secretion in primary islets isolated from
ICR mice in the presence of glucose (2.8 mM and 16.8 mM, respectively) and
testing compounds as indicated. The insulin concentraion was quantified by
ELISA and was presented as a ratio to the total protein concentration of islets.
Data are presented as mean ± SD (n = 5), *P<0.05, versus DMSO (2.8 mM
glucose).
TAK-875
The direct effect of stimulating insulin secretion of
compounds 30 and 36 was evaluated on primary islets isolated
from normal ICR mice at a concentration of 10 μM [19]. The
result indicated that compounds 30 and 36 could increase insulin
secretion in a high concentration of glucose (16.8 mM) (Table 4
and Figure 3).
The cytochrome P450 inhibition of compounds 30 and 36 was
then tested at a concentration of 5 μM (Table 5). The results
showed that compounds 30 and 36 exhibited no significant
inhibition against CYP2D6, CYP2C9, CYP3A4 and CYP1A2.
Table 5 CYP450 inhibitory activity (%) of compounds 30, 36
and TAK-875
CYP
30
36
TAK-875

2D6
2C9
3A4
1A2
23.60
16.25
30.69
20.92
39.47
3.94
27.62
25.73
23.22
21.02
33.96
28.00
mice [20]. Compound 30 effectively reduced the area under the
curve of blood glucose (AUC low 13.8%, P<0.01) after oral
glucose administration at 50 mg/kg, however 36 did not have an
obvious effect on the blood glucose compared with control group
(Table 6 and Figure 4).
Furthermore, we evaluated the efficacy of compounds 30 and
36 in vivo by oral glucose tolerance test (oGTT) in normal ICR
Table 6 The oGTT of compounds 30 and 36
blood glucose (mg/dL)
dose
Group
AUC
(mg*h/dL)
(mg/kg)
0 min
30 min
60 min
120 min
53.7±9.9
49.0±7.4
49.9±8.2
58.0±9.4
Control
TAK-875
30
67.0±13.4
58.1±9.2
60.3±12.6
61.2±13.0
227.6±18.7
175.8±25.0
120.0±21.2***
150.2±26.3*
172.7±34.3
290.0±23.5
206.6±22.8***
250.8±32.2**
280.9±46.7
50
50
50
155.2±19.4***
196.2±27.9**
214.1±39.9
36
n = 10, *P<0.05; **P<0.01; ***P<0.001 versus control group
3 0 0
A
C O N
C o m p o u d -36
C o m p o u n d -30
2 0 0
T A K -875
1 0 0
0
0
3 0
6 0
9 0
1 2 0
B
4 0 0
3 0 0
2 0 0
1 0 0
0
*
* * *
5
7
6
0
N
3
3
-
d
O
-
8
-
d
C
n
u
n
K
A
u
o
Fig 5. Molecular simulation of compound 30 and GPR40
o
T
p
p
m
m
o
o
In conclusion, a novel series of GPR40 agonists containing
nitrogen heterocyclic rings derived from TAK-875 were designed
and synthesized. The structural activity relationship studies
indicated that the substituents on the nitrogen atom had a
remarkable effect on the GPR40 agonistic activity. Compounds
bearing benzyl group on N atom exhibited excellent activity.
Among all compounds, compound 30 showed excellent GPR40
agonistic activity in vitro. It was able to increase insulin secretion
and did not have obvious inhibition on cytochrome P450 in vitro.
Premilinary study indicated that compound 30 could regulate
blood glucose level of normal ICR mice effectively. Moreover,
the cLogP value of compound 30 was lower than that of TAK-
875. Further investigation of compound 30 is still in progress in
our laboratory and the result will be reported in due course.
C
C
Fig 4. Blood glucose curves (A) and AUC (B) of oGTT in ICR mice. To
perform oGTT, 12h-fasted mice were orally administered with compound 30,
36 and TAK-875 (at the indicated doses) 1 hour prior to oral glucose load (2
g/kg). Blood glucose levels were determined at 0 min and 30, 60, 120 minutes
after glucose load. Data are presented as mean ± SD (n = 10), *P<0.05,
***P<0.001, versus control.
To further understand the interaction of this series of GPR40
agonists with GPR40, the molecular simulation between
compound 30 and GPR40 protein (the complex structure of
GPR40 was obtained from the Protein Data Bank, PDB code:
4PHU) was conducted using CDocker protocol with default
settings in Discovery Studio 2017 software package (BIOVIA,
San Diego: Dassault Systemes). The molecular simulation result
indicated compound 30 bound to GPR40 predominantly through
a strong hydrogen bond between the carboxyl group with
ARG183 and two salt bridges with ARG183 and ARG 2258.
Besides, benzene rings were interacted with a number of amino
acid residues via Pi-Pi interaction (-CDocker interaction energy =
37.76 kcal/mol, Figure 5).
Acknowledgments
This work was financially supported by CAMS Innovation
Fund for Medical Sciences (CIFMS, 2016-I2M-3-009) and
Beijing Key Laboratory of Active Substance Discovery and
Druggability Evaluation.
Supplementary data
Supplementary datd associated with this article can be found,
in the online version, at http://dx.doi.org/

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Highlights
·
·
A series of novel GPR 40 agonists was prepared.
The compounds feature the nitrogen-containing
heterocycles.
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Compound 30 exhibited efficacy both in vitro and in
vivo.