SAR Studies of Indole-5-propanoic Acid Derivatives to Develop Novel GPR40 Agonists

Article abstract of DOI:10.1021/acsmedchemlett.7b00460

G-protein coupled receptor 40 (GPR40) has been considered to be an attractive drug target for the treatment of type 2 diabetes because of its role in free fatty acids-mediated enhancement of glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. A series of indole-5-propanoic acid compounds were synthesized, and their GPR40 agonistic activities were evaluated by nuclear factor of activated T-cells reporter assay and GSIS assay in the MIN-6 insulinoma cells. Three compounds, 8h (EC₅₀ = 58.6 nM), 8i (EC₅₀ = 37.8 nM), and 8o (EC₅₀ = 9.4 nM), were identified as potent GPR40 agonists with good GSIS effects.

Full text of DOI:10.1021/acsmedchemlett.7b00460

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Letter
SAR Studies of Indole-5-propanoic acid
Derivatives to Develop Novel GPR40 Agonists
Dong-Oh Yoon, Xiaodi Zhao, Dohyun Son, Jung Tae Han, Jaesook Yun, Dongyun Shin, and Hyun-Ju Park
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00460 • Publication Date (Web): 21 Nov 2017
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SAR Studies of Indole-5-propanoic acid Derivatives to Develop
Novel GPR40 Agonists
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∥
∥
*,†
†,
†,
†
‡
‡
§
Dong-Oh Yoon, Xiaodi Zhao, Dohyun Son, Jung Tae Han, Jaesook Yun, Dongyun Shin, and Hyun-Ju Park
†School of Pharmacy, and ‡Department of Chemistry and Institute of Basic Science, Sungkyunkwan University, Suwon 16419,
South Korea
§College of Pharmacy, Gachon University, Incheon 21936, South Korea
*Corresponding author: hyunju85@skku.edu
KEYWORDS: GPR40 agonists, indole-5-propanoic acid, NFAT reporter assay, glucose-stimulated insulin secretion (GSIS).
ABSTRACT: G-protein coupled receptors 40 (GPR40) has been considered to be an attractive drug target for the treatment of type 2
diabetes because of its role in free fatty acids-mediated enhancement of glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells.
A series of indole-5-propanoic acid compounds were synthesized and their GPR40 agonistic activities were evaluated by nuclear factor of
activated T-cells (NFAT) reporter assay and GSIS assay in the MIN-6 insulinoma cells. Three compounds, 8h (EC50 = 58.6 nM), 8i (EC50
37.8 nM), and 8o (EC50 = 9.4 nM) were identified as potent GPR40 agonists with good GSIS effects.
=
18 The GPR40 agonist TUG-770 has a rigid alkyne group in the
linker part,10 which should provide a different ligand receptor
binding interaction compared to flexible benzyl oxy or amino
linker.19
Free fatty acids (FFAs) are an important source of energy for the
body and play a role in signal transduction for insulin secretion and
other cellular effects.1, 2 G-protein coupled receptors 40 (GPR40)
was identified as an orphan G-protein coupled receptors with an
unknown function.2 Recent studies revealed that GPR40 is abun-
dantly expressed in pancreas and regulates insulin secretion from
beta cells of the pancreas via long-chain FFAs.3 Takeda has devel-
oped the GPR40 agonist TAK875 (Figure 1), which activates the
glucagon-like peptide-1 (GLP-1) pathway as well as GPR40 and
increases the secretion of insulin.4 In 2011, a phase III clinical trial
of TAK875 was initiated.5, 6 The trial was the first attempt to de-
velop a GPR40 agonist as a drug for type II diabetes mellitus. How-
ever, its development was discontinued due to potential hepatotox-
icity.7 Clinical developments of some other GPR40 agonists
were also discontinued for undisclosed reasons. Recent studies
suggested that the potential liver toxicity of TAK875 and other
GPR40 agonists is associated with their analogous hydrophobic
pharmacophore. Smaller and less lipophilic compounds have im-
proved the drug-likeness properties.8, 9 As shown in Figure 1, the
common feature of most GPR40 agonists is a phenyl propanoic
acid group and a benzyl oxy or benzyl amine group in the linker
unit10-15 which are very important for GPR40 agonistic effect.16-
CO2H
F3C
CO2H
NC
F
O
AMG-837
EC50=25nM
Phase I
TUG-770
EC50=6nM
CO2H
O
O
O
N
H
MeO2S
O
CO2
H
TAK875
EC50=14nM
Phase III
GW9508
EC50=50nM
Figure 1. Reported GPR40 agonists
Figure 2. Design of indole propanoic acid
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Another GPR40 agonist includes a derivative of benzofuran
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ate for the synthesis of indole propanoic acid derivatives, as pre-
sented in Scheme 2, because it can employ various aryl or alkyl
group at the C2 position of indole ring. Among the various
methods for the synthesis of indole, we used a method that cy-
clizes the acetylenic substituent onto the amino group.
1
2
3
4
5
6
7
8
that was designed as a constrained planar derivative of benzyl
oxy linker. Its agonistic activity is weaker than other derivatives
having benzyl oxy or alkyne moieties in the linker part.20 In a
similar way to develop TAK875, various bicyclic acid moieties
including 2-(1H-indol-1-yl)acetic acid or 3-(1H-indol-1-yl)ace-
tic acid, are adopted in the acid tail part of GPR40 agonists with
benzyl oxy linker. However, their activity are weaker than those
with a phenyl propanoic acid tail (EC50 values ranging between
1 and 10 μM).21 Based on these reports, we designed novel
GPR40 agonists by employing an indole moiety in which a phe-
nyl ring is fused to a pyrrole ring as a bioisostere of two-atom
linker unit,22 and a small-size aryl group to reduce the hydro-
phobicity (Figure 2). A series of 3-(2-aryl-1H-indol-5-yl) pro-
panoic acid derivatives were prepared for the present structure-
activity relationship study. We expected binding modes of these
molecules would be similar to that of TAK875 to give an ago-
nistic effect on GPR40,23 although their indole linker unit is
more rigid than the benzyloxy linker.
Synthesis of indole propanoic acid derivative was accom-
plished as summarized in Scheme 2. Various phenyl groups
were introduced to the key intermediate 5 by the Sonogashira
reaction. In this reaction, the bulkiness of the ortho-substituent
of aryl halide affected the yield, and the diyne compound was
obtained as a main side product. For the synthesis of indole,
gold chloride (AuCl3) was used and the indole compound 7 was
easily obtained under the mild reaction condition.24 Finally, the
resulting indole compounds were hydrolyzed to give the final
products, 8a - 8r.
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Table 1. 2–Aryl substituted indole propanoic acid
O
OH
R
N
H
Scheme 1a

M
PPAR
Compd
TAK875
R
EC50 (nM, hFFA1)a
14
ALog Pb
5.06
c

at 10
8a
8b
N.A.
447
14%
4%
3.65
4.14
N.A.
8c
8d
4.14
4.14
3.63
8%
N.A.
N.A.
N.A.
N.A.
54.6
37.8
4%
0%
O
8e
O
O
8f
3.63
3.63
5%
5%
1%
8g
8h
Scheme 2a
Cl
O
O
4.31
4.31
O
O
a
b
H2
N
H2
N
101%d
1%
8i
8j
R
R
6
5
Cl
O
O
4.31
4.39
778
OH
O
c
Cl
R
N
N
H
H
56%
8k
1800
8a-8r
7
aReagents and Conditions
: (a) Aryl halide, PdCl2(PPh3)2, CuI, TEA,
Br
,
DMF, 80oC; (b) AuCl3, EtOH, 60oC; (c) NaOH, MeOH, 40oC
a Luciferase reporter assay, b AlogP 25 was predicted by schrödinger maes-
tro, c % activity compared to 1μM rosiglitazone, d PPARγ EC50=2.4μM, N.A.
no activity (> 25 μM).
The synthesis of key intermediate 5 was achieved as shown
in Scheme 1. The esterification of commercially available 3-(4-
aminophenyl) propanoic acid 1 under sulfuric acid, provided
compound 2. To prepare 2-ethynylaniline 5, the iodination of
compound 2 was carried out first. The Sonogashira coupling re-
action was conducted to replace iodo group with ethynyl group
(compound 4), and then following TMS (trimethylsilyl ether)
deprotection using TBAF (tetrabutylammonium fluoride) directly
to afford compound 5. Compound 5 is an important intermedi-
We conducted a nuclear factor of activated T-cells (NFAT)-
luciferase reporter assay26 in Chinese hamster ovary (CHO)
cells to evaluate the GPR40 agonistic activities of the com-
pounds in comparison with TAK875 respectively (Figure S1a
in the Supporting Information). Our reporter assay system was
validated using the reference molecule TAK875, giving the
EC50 value of 14 nM (Table 1) which is similar to that from the
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calcium influx assay.11 In terms of lipophilicity, the calculated
logP (ALogP) values for all of compounds, except 8m, were
less than that of TAK875 (5.06) indicating that hydrophobicity
is reduced in indole propanoic acid derivatives as expected.
almost lost the activities with EC50 >10μΜ (8s, 8t, and 8u in the
Supporting Information Table S1).
1
2
3
4
5
6
7
8
We also identified the unique Br•••π interaction30, 31 between
the Br substituent of drug and Phe142 in the binding site, as a
possible key factor for GPR40 agonistic activity (Figure 3A). In
the binding pose of 8o, the distance from o-Br to the centroid of
phenyl ring in Phe142 is 3.71Å and that to the nearest carbon of
phenyl ring is 3.33Å, giving a difference of 0.38Å. Since this
difference is bigger than 0.3Å, the Br•••π interaction can be
formed with an “edge-on” geometry. However, for the m-Br an-
alogue (8k), the distance from m-Br atom to the centroid of phe-
nyl ring in Phe142 is 5.25Å (Figure 3B), and that to the nearest
carbon of phenyl ring is 4.46Å. It means the Br•••π interaction
cannot be formed, because both distances are longer than 4.2Å.
Thus, the Br•••π interaction might contribute to provide higher
binding affinity toward GPR40 for 8o.
Since another antidiabetic target PPARɣ is also activated by
fatty acids, it is plausible that GPR40 agonists may have PPARɣ
agonistic activity.27 Several indole-5-acetic acid and α- alkoxy-
indole-5-propionic acid derivatives, which are structurally sim-
ilar to our compounds, were also reported as PPAR agonists.28,
29 Thus, we examined the PPARɣ transactivation activity of our
compounds at 10 μM (Tables, 1 and 2) and most of them did not
show significant PPARɣ agonist activity, except 8i. The EC50
values for PPARɣ were determined for 8i, 8k, and 8r, and they
were 2.4 μM, 236.4 μM, and 56.9 μM, respectively (Figure S2
in the Supporting Information). Although 8i showed some
PPARɣ agonist activity, it is about 60 times more selective for
GPR40.
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To examine the effects of substituents on phenyl ring, the al-
kyl- (methyl, methoxyl, ethyl, or isopropyl) substituted deriva-
tives did not show good GPR40 agonistic activity while the hal-
ogen substitution resulted in significant agonistic activity (Ta-
bles, 1 and 2). Chloro substitution (8h - 8j) provided good ac-
tivity in the order meta-  ortho- > para-position. At first, we
examined if the meta substitution is important for activity, meta-
bromophenyl analogue 8k was synthesized, but its activity was
about 50-fold lower than the meta-chloro derivative 8i. There-
fore, we focused on the ortho substitution assuming that the ste-
ric effect of ortho substituent may adjust the dihedral angle be-
tween the indole ring and the phenyl ring optimal for ligand
binding (Table 2). Various ortho- substituted derivatives were
prepared and their agonistic effects were evaluated. Among the
alkyl substituted analogues, only o-methyl phenyl attached
compound 8b, showed submicromolar activity. Derivatives
with o-CF3 (8l), o-OCF3 (8m), and o-F (8n) exhibited moderate
micromolar potency. The compound having o-Br substituent
(8o), showed the highest agonistic activity (EC50 = 9.4 nM)
while the m-Br derivative showed almost 200 times lower ac-
tivity (Table 1). These results suggest that a substituent at the
ortho position of aryl group may not only be a simple steric
blocker to adjust the conformation of the ligand, but may also
be involved in interaction with the receptor. The halogen atom
is preferred at the ortho position and the agonistic activity de-
creases in the order Br > Cl > F > H.
Table 2. Effect of ortho-substiuted aryl 2-indole propanoic acid
a Luciferase reporter assay, b AlogP 25 was predicted by schrödinger maes-
tro, c % activity compared to 1μM rosiglitazone, N.A. no activity (> 25μM).
To understand the dramatic difference in GPR40 agonistic ac-
tivity between o-Br (8o) and m-Br (8k) based on their binding
modes, docking simulations were carried out using the X-ray
structure of TAK875-GPR40 complex (pdb id = 4PHU).23 Most
GPR40 agonists have a carboxylic acid moiety as a key phar-
macophore. The analysis of X-ray structure revealed a polar in-
teraction network between the carboxylate group of TAK875
and Arg183, Arg258, Tyr91, and Tyr240, which is crucial for
GPR40 agonistic activity. Likewise, in the docked models of
GPR40 with 8o and 8k within the TAK875-binding pocket (Fig-
ure 3), the carboxylate moiety also forms hydrogen bonds with
Arg183 and Arg258. In addition, indole N-H interacts with
backbone amide carbonyl oxygen of Leu138 by forming a H-
bond, suggesting that indole NH group may affect the receptor
binding affinity. To verify the significance of indole NH for
GPR40 agonistic effect, we prepared and tested several N-meth-
ylated indole derivatives of 8i, 8j, and 8o, and found that they
In most of the reported GPR40 agonists with a propanoic acid
functional group, some substituents on its beta position were
employed to improve the metabolic stability by avoiding β-ox-
idation. Therefore, we inspected a liver microsomal stability of
compound 8h, 8i and 8o, and they exhibited good metabolic
stability (Table 3).
Table 3. Metabolic stability of compound 8h, 8i, and 8o
a microsomal stability: Clearance intrinsic (μL/min/mg)
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To detect insulin secretion effects of derivatives having
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GPR40 agonistic activity in the NFAT luciferase assay, we per-
formed a glucose stimulated insulin secretion (GSIS) assay in
MIN6 cells.1 The insulin secretion effect was verified at a glu-
cose concentration of 17mM. For compounds, 8h, 8i and 8o,
insulin secretion was elevated by 1.4-, 1.7-, and 1.6-fold com-
pared to 17mM glucose, respectively (Figure 4). Compounds,
8i and 8o yielded GSIS effects similar to that of the reference
compound TAK875 (1.7 fold). In contrast, the compound 8a
with low GPR40 agonist activity (EC50 > 25 μM), did not induce
insulin secretion. The result suggests that the GSIS effect of 8h,
8i and 8o is related with selective GPR40 activation.
**
**
***
*
# # #
60
40
20
9
DMSO3mM 17mM 1µM 10µM 1µM 10µM 1µM 10µM 1µM 10µM 1µM 10µM
Glucose
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TAK875
8a
8h
8i
8o
17mM Glucose
Figure 4. Glucose-stimulated insulin secretion test of derivative 8a, 8h, 8i,
and 8o in MIN6 cells. The data represented as the mean ± standard error
(n=2). ###p ≤ 0.01 by Student’s test; *p ≤ 0.05, **p ≤ 0.025, ***p ≤ 0.01 vs
17mM glucose alone by Student’s test.
In conclusion, for development of novel GPR40 agonists, we
utilized indole propanoic acid moiety as a simplified novel scaf-
fold for a potent GPR40 agonists. Various derivatives were pre-
pared and their GPR40 agonistic activities were evaluated by an
NFAT luciferase assay. Among these derivatives, potent GPR40
agonists were identified. These agonist, 8h, 8i, and 8o showed
good microsomal stability as well as an excellent insulin secre-
tion effect in MIN6 cells. Based on these results, we continue
to perform further in vivo efficacy study in due course for the
development of more potent GPR40 agonists as anti-diabetic
candidates.
Supporting Information
Syntheses and characterization data for the compound 8a-
8u, assay protocols, and computational modeling
AUTHOR INFORMATION
Corresponding Author
* Tel: +82-31-290-7719. E-mail: hyunju85@skku.edu.
Author Contributions
∥Theses authors contributed equally.
Notes
Figure 3. Computational analysis of the binding mode of 8o (A) and 8k (B)
into GPR40. The carboxylate moiety is highly coordinated by several key
res dues. Hydrogen bond interactions (<3Å) are depicted as dashed cylin-
ders. Grey capped sticks represent key amino acid residues with in the bind-
ing site and ribbon is backbone of hGPR40. The binding site is rendered in
MOLCAD lipophilic potential surface, and colored from blue (hydrophilic)
to dark brown (hydrophobic).
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Science, ICT and future Planning (NRF-
2014R1A2A1A11050892).
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