Identification of G protein-coupled receptor 120-selective agonists derived from PPARγ agonists

Article abstract of DOI:10.1021/jm800970b

A weak, nonselective G protein-coupled receptor 120 (GPR 120) agonist 10 was found by screening a series of carboxylic acids derived from the peroxisome proliferator-activated receptor γ (PPARγ) agonist 3. Modification based on the homology model of GPR12

Full text of DOI:10.1021/jm800970b

7640
J. Med. Chem. 2008, 51, 7640–7644
Identification of G protein-coupled receptor 120-selective agonists derived from PPARγ agonists
Takayoshi Suzuki,† Sou-ichi Igari,† Akira Hirasawa,‡ Mie Hata,§ Masaji Ishiguro,| Hiroki Fujieda,† Yukihiro Itoh,†
Tatsuya Hirano,† Hidehiko Nakagawa,† Michitaka Ogura,| Makoto Makishima,| Gozoh Tsujimoto,*,‡ and Naoki Miyata*,†
Graduate School of Pharmaceutical Sciences, Nagoya City UniVersity, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan, Graduate
School of Pharmaceutical Sciences, Kyoto UniVersity, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan, JST InnoVation
Plaza Kyoto, 1-30 Goryoohhara, Nishikyo-ku, Kyoto 615-8245, Japan, Faculty of Pharmaceutical Sciences, Niigata UniVersity of Pharmacy
and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata, Japan, and Nihon UniVersity School of Medicine, 30-1 Oyaguchi-kamicho,
Itabashi-ku, Tokyo 173-8610, Japan
ReceiVed July 31, 2008
A weak, nonselective G protein-coupled receptor 120 (GPR120) agonist 10 was found by screening a series
of carboxylic acids derived from the peroxisome proliferator-activated receptor γ (PPARγ) agonist 3.
Modification based on the homology model of GPR120 led to the first GPR120-selective agonist 12. These
results provide a basis for constructing new tools for probing the biology of GPR120 and for developing
new candidate therapeutic agents.
Chart 1. Structures of R-LA (1) (Dual Agonist of GPR40 and
GPR120) and 2 (GPR40-Selective Agonist)
Introduction
G protein-coupled receptor 40 (GPR40a) and GPR120 are
members of a class of proteins known as G protein-coupled
receptors, which are activated by long-chain free fatty acids
(FFAs) such as R-linolenic acid (R-LA, 1) (Chart 1), and these
two receptors have very similar pharmacological properties.1
GPR120 is expressed in intestines and, upon stimulation by long-
chain FFAs, increases the secretion of glucagon-like peptide-1
(GLP-1) from intestinal endocrine cells,1a leading a glucose-
dependent increase of insulin secretion from pancreatic ꢀ-cells,
stimulation of insulin biosynthesis, and a decrease of glucagon
secretion.2 Moreover, GLP-1 has been reported to play a
significant role in appetite and feeding control.3 Thus, GPR120
has emerged as an attractive target for the treatment of type 2
diabetes and obesity.4
Although a number of GPR40 agonists have been identified
to date,5 including compound 2 (GW9508) (Chart 1),5a there
are only a few reports on GPR120 agonists.5a,b,6 Furthermore,
GPR120-selective agonists, which are of interest as tools for
investigating the biological functions of GPR120 and as
candidate therapeutic agents having few side effects, have not
been reported so far. We therefore initiated a search for
GPR120-selective agonists and found a carboxylic acid deriva-
tive showing agonistic activity selective for GPR120 over
GPR40. We describe here the design, synthesis, and activity of
GPR120-selective agonists.
Table 1. GPR40- and GPR120-Agonistic Activity of Compounds
3-11a
compound
R
GPR40b
GPR120b
R-LA (1)
100
121
99
104
215
125
147
58
100
0
0
31
33
57
45
0
3
n-nonyl
n-heptyl
n-hexyl
n-Bu
n-Pr
4
5
6
7
8
9
Et
Me
10
11
Ph
2-Py
98
0
56
0
a Values are means of at least three experiments. b The agonistic response
elicited by 10 µM test compound as a percentage of the response evoked
by 10 µM R-LA (1).
Chemistry. Of the 26 compounds included in this study
(Tables 1-3), compounds 3-11 had previously been synthe-
sized7 and were available in our laboratories. Compounds 12-28
have not previously been described. Thus, these compounds
were prepared as outlined in Scheme 1. 4-(4-Hydroxyphenyl-
)butyric acid methyl ester (29a)8 and 5-(4-hydroxyphenyl)pen-
tanoic acid methyl ester (29b)9 were converted to ethers 30 using
the Mitsunobu reaction. Coupling between secondary amines
and bromide 30 gave tertiary amines, and hydrolysis of the
methyl esters afforded the desired carboxylic acids 12-28.
* To whom correspondence should be addressed. Phone, fax: +81-52-
836-3407.E-mail:miyata-n@phar.nagoya-cu.ac.jp(N.M.);gtsuji@pharm.kyoto-
u.ac.jp (G.T.).
†
Graduate School of Pharmaceutical Sciences, Nagoya City University.
Graduate School of Pharmaceutical Sciences, Kyoto University.
JST Innovation Plaza Kyoto.
Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy
‡
§
Results and Discussion
|
Since it has been reported that long-chain FFAs and peroxi-
some proliferator-activated receptor γ (PPARγ) agonists, such
as ciglitazone and troglitazone, activate GPR120,1a,5b we focused
initially on carboxylic acid 3 (Table 1), which we previously
reported as a potent PPARγ agonist.7 Compound 3 and its
derivatives 4-11 (Table 1) were screened for GPR40- and
and Applied Life Sciences
|
Nihon University School of Medicine
a Abbreviations: GPR, G protein-coupled receptor; FFA, free fatty acid;
R-LA, R-linolenic acid; GLP-1, glucagon-like peptide-1; PPAR, peroxisome
proliferator-activated receptor; [Ca2+]i, intracellular Ca2+ concentration;
FLIPR, fluorometric imaging plate reader; ERK, extracellular signal-
regulated kinase.
10.1021/jm800970b CCC: $40.75
2008 American Chemical Society
Published on Web 11/13/2008

Brief Articles
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 23 7641
Table 2. GPR40- and GPR120-Agonistic Activity of Compounds 10,
12, and 13a
compound
n
GPR40b
GPR120b
R-LA (1)
100
98
26
100
56
115
58
10
12
13
2
3
4
99
a Values are means of at least three experiments. b The agonistic response
elicited by 10 µM test compound as a percentage of the response evoked
by 10 µM R-LA (1).
Table 3. GPR40- and GPR120-Agonistic Activity of compounds 12 and
14-28a
compound
R1
R2
GPR40b
GPR120b
Figure 1. Model of compound 10 docked in the GPR120 homology
model.
R-LA (1)
12
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
100
26
10
26
1
27
23
33
26
21
32
8
30
43
34
68
32
100
115
41
56
65
37
59
71
78
88
73
43
106
81
81
100
70
2-Py
2-Py
2-Py
2-Py
2-Py
2-Py
2-Py
2-Py
Ph
Ph
n-butyl
Bn
3-Py
2-Naph
4-F-Ph
3-F-Ph
4-Me-Ph
Ph
2-benzothiazolyl
2-benzoxazolyl
2-thiazolyl
4-Me-2-Py
6-Me-2-Py
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-Cl-2-Py
6-Cl-2-Py
a Values are means of at least three experiments. b The agonistic response
elicited by 10 µM test compound as a percentage of the response evoked
by 10 µM R-LA (1).
Scheme 1a
Figure 2. Model of compound 12 docked in the GPR120 homology
model.
inactive against GPR120. Among compounds 4-11, compound
7 with an n-propyl group and compound 10 with a phenyl group
showed the most potent agonistic activity toward GPR120, and
the GPR120/GPR40 selectivity of compound 10 was found to
be the highest, although it was less than that of R-LA (1).
As a basis to improve the potency and selectivity for GPR120,
we performed a binding mode study of compound 10 with the
homology model of GPR120, which was developed based on a
photointermediate model derived from the crystal structure of
bovine rhodopsin (PDB code 1F88).10 An inspection of the
simulated GPR120/compound 10 complex showed that there
appears to be an ionic interaction between the carboxylate anion
of compound 10 and the guanidinium cation of Arg99 (Figure
1). However, the distance between the oxygen of the carboxylate
and the hydrogen of the guanidine was 3.58 Å, which suggested
that there is no hydrogen bond between the two atoms.
Therefore, we designed compound 12 (Table 2) in which the
number of methylene units in the linker is increased to 3. We
anticipated that extension of the carbon chain would bring the
carboxylate closer to Arg99 and allow it to interact more
a Reagents: (a) 2-bromoethanol, DEAD, PPh3, THF, rt, 19-41%; (b)
NaH or Et3N, R1R2NH, KI, DMF, 80 °C; (c) NaOH, H2O, THF, MeOH,
rt, 3-55% (two steps)
GPR120-agonistic activity by measuring the intracellular Ca2+
concentration ([Ca2+]i) using a fluorometric imaging plate reader
(FLIPR)-based assay in HEK293 cells expressing human GPR40
or human GPR120 (see the experimental procedure in the
Supporting Information). R-LA (1) was used as the standard
compound because it is a dual agonist of GPR40 and GPR120.1
Efficacy was calculated as percent agonistic response elicited
by 10 µM test compound with respect to the response evoked
by 10 µM R-LA (1) (Table 1). Although the potent PPARγ
agonist 3 showed high GPR40-agonistic activity, it was totally

7642 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 23
Brief Articles
Figure 3. Dose-dependent [Ca2+]i response induced by compounds 12 and 24 in HEK293 cells expressing GPR120 (left) or GPR40 (right).
Figure 4. ERK activation induced by R-LA (1), compound 12, and compound 24 in HEK293 cells expressing GPR120 (left) or GPR40 (right).
Table 4. GPR40- and GPR120-Agonistic Activity of Compounds 12
and 24a
(18-20) groups, but these compounds displayed weak GPR120
activity as compared with compound 12. Among compounds
14-20, compound 16 exhibited a superior selectivity toward
GPR120, although the activity of compound 16 is less than that
of compound 12. These results indicate that compound 16 may
be a lead compound suitable for further structural optimization.
Then, we changed the 2-pyridine ring of compound 12 to other
aromatic rings. Phenyl 21, 2-benzothiazole 22, and 2-benzox-
azole 23 derivatives exhibited GPR120-agonistic activity less
potent than that of compound 12, whereas the 2-thiazole 24
retained the activity and selectivity to some extent, highlighting
the importance of the nitrogen atom at the 2-position and of
the ring size. Introduction of a methyl group (25 and 26) or a
chloro group (27 and 28) into the 2-pyridine ring resulted in a
significant decrease in GPR120 activity or GPR120/GPR40
selectivity.
The dose dependency of compounds 12, 24, and R-LA (1) is
shown in Figure 3, clarifying the GPR120 selectivity of
compounds 12 and 24. The EC50 values of compound 12 for
GPR120 and GPR40 were 1.2 and 19 µM, respectively, and
the selectivity index (SI, GPR40 EC50/GPR120 EC50) was 16,
which substantially exceeded that of R-LA (1) (SI ) 2.0) (Table
4).
compound
EC50 (GPR120) (µM)
EC50 (GPR40) (µM)
SIb
R-LA (1)
12
24
2.6
1.2
1.7
5.2
19
21
2
16
12
a Values are means of at least three experiments. b SI (selectivity index)
) EC50 (GPR40)/EC50 (GPR120).
strongly with the guanidine of Arg99 via ionic and hydrogen
bonding (Figure 2), which might lead to a more potent activation
of GPR120. We also expected that compound 12 would show
increased GPR120/GPR40 activity ratio because it was reported
that extension of the methylene chain of 2 significantly decreases
the GPR40-agonistic activity.5c As expected, the GPR120-
agonistic activity and the GPR120/GPR40 selectivity of com-
pound 12 were significantly increased as compared with those
of R-LA (1) and compound 10 (Table 2). On the other hand,
further extension of the methylene chain (compound 13) resulted
in reduction of both the potency and the selectivity, which can
be explained by the steric hindrance between the carboxylate
of 13 and Arg99.
Next, we looked at the effect of replacing the phenyl or
2-pyridine ring with several substituents (Table 3). We initially
converted the phenyl group of compound 12 to alkyl (14 and
15), aromatic (16 and 17), and 3- or 4-substituted phenyl
Since it has been reported that long-chain FFAs stimulate
the extracellular signal-regulated kinase (ERK) and Akt/protein
kinase through GPR40 or GPR120,11 we examined the effects

Brief Articles
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 23 7643
and dried over Na2SO4. Filtration, concentration in vacuo, and
purification by silica gel flash column chromatography (AcOEt/n-
hexane ) 1/6) gave 150 mg (21%) of 4-{4-[2-(phenyl-2-pyridiny-
lamino)ethoxy]phenyl}
butyric acid methyl ester as a colorless oil.
To a solution of 4-{4-[2-(phenyl-2-pyridinylamino)ethoxy]
phenyl}butyric acid methyl ester (149 mg, 0.382 mmol) obtained
above in 2 mL of MeOH and 2 mL of THF was added aqueous 2
N NaOH (0.6 mL), and the solution was stirred overnight at room
temperature. The mixture was neutralized with 0.6 mL of 2 N HCl
and concentrated in vacuo. The residue was purified by silica gel
flash column chromatography (CHCl3/MeOH ) 19/1) to give 115
mg (80%) of 12 as a colorless solid: mp 98-99 °C. 1H NMR
(CDCl3, 500 MHz, δ; ppm) 8.21 (1H, d, J ) 4.0 Hz), 7.41 (2H, t,
J ) 7.3 Hz), 7.33 (2H, d, J ) 7.4 Hz), 7.30-7.20 (2H, m), 7.04
(2H, d, J ) 8.6 Hz), 6.79 (2H, d, J ) 8.6 Hz), 6.60 (1H, t, J ) 7.0
Hz), 6.41 (1H, d, J ) 8.9 Hz), 4.32 (2H, t, J ) 5.2 Hz), 4.26 (2H,
t, J ) 5.8 Hz), 2.59 (2H, t, J ) 7.4 Hz), 2.34 (2H, t, J ) 7.4 Hz),
1.91 (2H, quintet, J ) 7.4 Hz). MS (EI) m/z: 376 (M+). HRMS
calcd for C23H24N2O3 376.179, found 376.178. Anal. (C23H24N2O3)
C, H, N.
Figure 5. PPAR transactivation activity of compound 12. [4-Chloro-
6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid 31 (WY14643) (PPARR
agonist),12 {2-methyl-4-[4-methyl-2-(4-trifluoromethylphenyl)thiazol-
5-ylmethylsulfanyl]phenoxy}acetic acid 32 (GW501516) (PPARδ
agonist),13 and rosiglitazone (PPARγ agonist) were used as positive
controls.
of compounds 12 and 24 on the accumulation of phosphorylated
ERK (p44/42) in HEK293 cells expressing human GPR40 or
human GPR120 by means of Western blotting analysis (see the
experimental procedure in the Supporting Information). Con-
sistent with the results obtained in the FLIPR-based assay,
compounds 12 and 24 did not activate ERK compared with
R-LA (1) in HEK293 cells expressing GPR40 but increased the
amount of phosphorylated ERK more than did R-LA (1) in
HEK293 cells expressing GPR120 (Figure 4).
We also examined the agonistic activity of compound 12,
the most potent and selective GPR120 agonist among these
compounds, toward PPARs (other long-chain FFA receptors).
As a result, compound 12 proved to be totally inactive toward
PPARs (Figure 5).
Synthesis
of
4-{4-[2-(n-Butyl-2-pyridinylamino)ethoxy]
phenyl}butyric Acid (14). A solution of 4-[4-(2-bromoethoxy)phe-
nyl]butyric acid methyl ester (30a) (956 mg, 3.17 mmol), N-n-
butylpyridin-2-amine7 (1.4 g, 9.32 mmol), Et3N (0.88 mL, 6.33
mmol), and KI (530 mg, 3.19 mmol) in THF (3 mL) was stirred
overnight at reflux temperature. After cooling to room temperature,
the reaction mixture was diluted with AcOEt, washed with water
and brine, and dried over Na2SO4. Filtration, concentration in vacuo,
and purification by silica gel flash column chromatography (AcOEt/
n-hexane ) 1/6) gave 272 mg (23%) of 4-{4-[2-(n-butyl-2-
pyridinylamino)ethoxy]phenyl}butyric acid methyl ester as a color-
less oil.
To
a
solution of 4-{4-[2-(n-butyl-2-pyridinylamino)
ethoxy]phenyl}butyric acid methyl ester methyl ester (272 mg,
0.734 mmol) obtained above in 4 mL of MeOH and 4 mL of THF
was added aqueous 2 N NaOH (1.1 mL), and the solution was
stirred overnight at room temperature. The mixture was neutralized
with 1.1 mL of 2 N HCl and concentrated in vacuo. The residue
was purified by silica gel flash column chromatography (CHCl3/
Conclusion
In conclusion, we have identified a GPR120-selective agonist
12, which was derived from PPARγ agonist 3. To our
knowledge, compound 12 is the first GPR120-selective agonist
and therefore represents a lead compound from which it should
be possible to develop more potent and selective GPR120
agonists, which are expected to be useful as tools for probing
the biology of GPR120 and as candidate therapeutic agents with
potentially fewer side effects.
1
MeOH ) 19/1) to give 128 mg (49%) of 14 as colorless oil. H
NMR (CDCl3, 500 MHz, δ; ppm) 8.14 (1H, d, J ) 4.0 Hz), 7.41
(1H, dt, J ) 1.9, 7.1 Hz), 7.06 (2H, d, J ) 8.6 Hz), 6.82 (2H, d,
J ) 8.5 Hz), 6.51 (1H, t, J ) 4.9 Hz), 6.50 (1H, d, J ) 7.4 Hz),
4.14 (2H, t, J ) 6.1 Hz), 3.91 (2H, t, J ) 5.8 Hz), 3.49 (2H, t, J
) 7.7 Hz), 2.60 (2H, t, J ) 7.3 Hz), 2.34 (2H, t, J ) 7.3 Hz), 1.92
(2H, quintet, J ) 7.7 Hz), 1.62 (2H, quintet, J ) 7.7 Hz), 1.37
(2H, sextet, J ) 7.7 Hz), 0.96 (3H, t, J ) 7.3 Hz). MS (EI) m/z:
356 (M+). HRMS calcd for C21H28N2O3 356.210, found 356.211.
Compounds 13 and 16-28 were prepared from 30 and an
appropriate amine using the procedure described for 12, and
compound 15 was prepared from 30a and N-benzylpyridin-2-amine
using the procedure described for 14.
Experimental Section
Synthesis of 4-[4-(2-Bromoethoxy)phenyl]butyric Acid
Methyl Ester (30a). To a solution of 4-(4-hydroxyphenyl)butyric
acid methyl ester (29a) (5.0 g, 25.7 mmol), 2-bromoethanol (3.5
g, 28.0 mmol), and 2.2 M diethyl azodicarboxylate solution in
toluene (15.3 mL, 33.7 mmol) in THF (65 mL) was slowly added
triphenylphosphine (8.8 g, 33.6 mmol) at 0 °C and the solution
was stirred at room temperature for 4 h. After that, the reaction
mixture was concentrated in vacuo and purification by silica gel
flash column chromatography (AcOEt/n-hexane ) 1/8) gave 1.50 g
(19%) of 30a as a pale-yellow oil. 1H NMR (CDCl3, 500 MHz, δ;
ppm) 7.10 (2H, d, J ) 8.9 Hz), 6.84 (2H, d, J ) 8.9 Hz), 4.27
(2H, t, J ) 6.4 Hz), 3.66 (3H, s), 3.63 (2H, t, J ) 6.4 Hz), 2.59
(2H, t, J ) 7.6 Hz), 2.32 (2H, t, J ) 7.6 Hz), 1.92 (2H, quintet, J
) 7.6 Hz).
Compounds 3-11 were available in our laboratories and have
been previously described.7
Acknowledgment. We thank Dr. Yoshiyuki Takahara (Phar-
maFrontier) and Dr. Itsuo Uchida (JST Innovation Plaza Kyoto)
for their valuable comments.
Supporting Information Available: Experimental details for
the synthesis of compounds 12-28, spectroscopic data, elemental
analysis results, experimental procedures for the biological testing,
and a brief description of the molecular modeling. This material is
available free of charge via the Internet at http://pubs.acs.org.
Synthesis
of
4-{4-[2-(Phenyl-2-pyridinylamino)ethoxy]
phenyl}butyric Acid (12). To a solution of N-phenylpyridin-2-amine
(305 mg, 1.79 mmol) in 3 mL of DMF was added NaH (60%, 86
mg, 2.15 mmol), and the mixture was stirred at 60 °C for 30 min.
Then, to the reaction mixture were added KI (150 mg, 0.90 mmol)
and 4-[4-(2-bromoethoxy)phenyl]butanoic acid methyl ester (30a)
(539 mg, 1.79 mmol) obtained above, and the mixture was stirred
at 80 °C for 2 h. After cooling to room temperature, the reaction
mixture was diluted with AcOEt, washed with water and brine,
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