Discovery of 3-aryl-3-ethoxypropanoic acids as orally active GPR40 agonists

Article abstract of DOI:10.1016/j.bmcl.2014.04.065

The G protein-coupled receptor 40 (GPR40) mediates enhancement of glucose-stimulated insulin secretion in pancreatic β cells. The GPR40 agonist has been attracting attention as a novel insulin secretagogue with glucose dependency for the treatment of type 2 diabetes. The optimization study of compound 1 led to a potent and bioavailable GPR40 agonist 24, which showed insulin secretion and glucose lowering effects in rat OGTT. Compound 24 is a potential lead compound for a novel insulin secretagogue with a low risk of hypoglycemia.

Full text of DOI:10.1016/j.bmcl.2014.04.065

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of 3-aryl-3-ethoxypropanoic acids as orally active GPR40
agonists
Rieko Takano, Masao Yoshida, Masahiro Inoue, Takeshi Honda, Ryutaro Nakashima, Koji Matsumoto,
⇑
Tatsuya Yano, Tsuneaki Ogata, Nobuaki Watanabe, Narihiro Toda
R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The G protein-coupled receptor 40 (GPR40) mediates enhancement of glucose-stimulated insulin secre-
tion in pancreatic b cells. The GPR40 agonist has been attracting attention as a novel insulin secretagogue
with glucose dependency for the treatment of type 2 diabetes. The optimization study of compound 1 led
to a potent and bioavailable GPR40 agonist 24, which showed insulin secretion and glucose lowering
effects in rat OGTT. Compound 24 is a potential lead compound for a novel insulin secretagogue with
a low risk of hypoglycemia.
Received 6 February 2014
Revised 9 April 2014
Accepted 16 April 2014
Available online xxxx
Keywords:
GPR40
Ó 2014 Elsevier Ltd. All rights reserved.
Agonist
Diabetes
Insulin secretagogue
Glucose lowering
In recent years the number of diabetic patients has been
increasing all over the world, thus the efficient and suitable treat-
ment for each patient is in high demand.1 Insulin secretagogues
such as sulfonylureas are widely used for patients with a moderate
degree of b-cell dysfunction.2 Sulfonylureas secrete insulin inde-
pendently of glucose levels, so they may cause hypoglycemia.3
Their long term therapy also often leads to the gradual diminution
of islets activity.4–6 There are only a few choices of insulin secret-
agogues with low risk of hypoglycemia such as DPP-4 inhibitors
and GLP-1 agonists.7 Therefore, the novel orally available insulin
secretagogues with glucose dependency and strong glucose lower-
ing effects are still in demand.
The G-protein coupled receptor GPR40, highly expressed in
human and rodent pancreatic islets,8–10 is found as an attractive
target for new therapy of type 2 diabetes.8,11 This receptor is acti-
vated by medium and long-chain free fatty acids (e.g., palmitic and
linolenic acids), and sends signals to downstream pathways result-
ing in enhancement of insulin secretion by production of inositol
triphosphate and release of intracellular Ca2+ from endoplasmic
reticulum.12,13 Compared to other mechanisms, there are several
advantages of GPR40 as a target for the treatment of type 2 diabe-
tes. The most attractive point is that GPR40 induces insulin secre-
tion depending on the concentration of glucose, indicating that the
selective agonist has low risk of hypoglycemia.14 In addition, the
distribution of GPR40 has been limited (mainly in islets), in that
side effects associated with GPR40 activation in other tissues rarely
occur. Many groups reported
a variety of synthetic GPR40
agonists.15–27 Most of GPR40 agonists have the structure of
3-phenylpropanoic acid mimicking medium or long-chain free
fatty acids (Fig. 1). Among these compounds, we chose compound
1 as a starting structure to explore novel GPR40 agonists, because it
has very strong in vitro agonistic activity against GPR40 (reported
EC50 = 8.8 nM; in house data EC50 = 6.7 nM) and a simple structure
that is easy to modify.28 On the other hand, it is reported that bio-
availability of compound 1 was too poor (F = 0.9% in rats) for oral
active agents. In this article, we will show the synthetic efforts to
obtain bioavailable compounds starting from compound 1.
High lipophilicity of 1 seems to cause poor PK profiles. First we
replaced the phenyl ring of compound 1 with various hetero aro-
matic rings to reduce lipophilicity29,30 (Table 1). The synthesis of
pyridine derivative 2 was shown in Scheme 1. (20,60-Dimethylbi-
phenyl-3-yl)methanol (12) was reacted with 2,5-dibromopyridine
in the presence of NaH. The corresponding bromopyridine 13 and
ethyl acrylate were coupled under the microwave-assisted Heck
coupling condition.31 Olefin moiety of compound 14 was reduced
with NaBH4 using NiCl2 as a catalyst. Saponification of ethyl ester
in compound 15 gave pyridine derivative 2. Other compounds in
Table 1 were synthesized in the similar manner as in Scheme 1.
Pyridine derivative 2 showed similar GPR40 agonistic activity to
compound 1. In contrast, pyridine derivative 3 was found to be a
weaker agonist than compound 1. Five-membered hetero aromatic
⇑
Corresponding author. Tel.: +81 3 3492 3131; fax: +81 3 5740 3643.
E-mail address: toda.narihiro.jw@daiichisankyo.co.jp (N. Toda).
http://dx.doi.org/10.1016/j.bmcl.2014.04.065
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Takano, R.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.04.065

2
R. Takano et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
CO H
2
CO H
2
Me
CO H
2
CN
Me
O
F
N
H
O
Me
TUG-770
GW9508
1
Me
O
F C
3
CO H
2
O
MeO S
O
Me
TAK-875
Figure 1. Representative GPR40 agonists.19–23
O
2
CO H
2
AMG-837
Table 1
rings were not tolerant (compound 4, 5). Next we introduced
another nitrogen atom to compound 2 to lower its hydrophobicity
(compound 6–8). Only a pyrazine derivative 6 kept strong activity
with a lowered logD value, while its solubility became worse.
Methyl scanning of compound 2 (compound 9–11) resulted in less
potent agonists. We assessed PK profiles of compound 2 in rats.
Bioavailability of compound 2 (F = 24%) was improved compared
to compound 1 (F = 0.9%) probably due to lower lipophilicity of 2
(Table 3).
These results encouraged us to take further optimization of
compound 2 in order to adjust the PK profiles better. It is well
known that fatty acids are metabolized via b-oxidation in the mito-
chondria,32 hence compound 2 which contains propanoic acid moi-
ety could be metabolized. Therefore we introduced substituents on
the carbon chain of the propanoic acid to block the oxidation
(Table 2). The fluoro, methyl and alkoxy substituents were intro-
GPR40 agonistic activities of heteroaryl derivatives
Me CO2H
Me
CO2H
A
O
O
Me
Me
1
2-11
Compound
A
Human EC50 (nM)a
6.7
Rat EC50 (nM)a
LogDb
1
18
>3.3
3.0
N
2
3
4
3.5
71
38
210
840
N
2.4
S
duced on the a-position (compound 16–18). Only the fluoro group
52
>2.4
kept activity. The acidity of carboxylic acid has changed by the
electronic effect of these substituents. Electron donating substitu-
ent (compound 17, 18) could decrease the ionic interaction of the
carboxylic acid. On the other hand, these substituents on the
b-position were tolerant (compound 19–21). Among them, the alk-
oxy substituent (compound 21) was promising in terms of strong
agonistic activity and preserved lipophilicity. Conformationally
restricted derivative 22 did not increase its agonistic activity.
To determine cytotoxicity of a series of compounds, we evalu-
ated the inhibition of mitochondrial respiratory chain complex 1,
which blocks electron transportation and leads to the cell toxic-
ity.33–35 Unfortunately these derivatives including compound 21
have strong inhibition of complex 1. It was reported that the
number of aromatic rings correlated with successful transition of
compounds from discovery through clinical trials.36,37 We hypoth-
esized that the biphenyl moiety which was the common structure
of these compounds was crucial for cytotoxicity. Compound 23
was synthesized to remove the biphenyl structure. As we expected,
the function of the respiratory chain could keep working normally.
However its GPR40 agonistic activity has significantly diminished.
According to its logD value of 0.7, hydrophobic interaction
between the receptor and the ligand might be too weak. In order
to restore the binding affinity, the central pyridine ring was
S
N
5
65
540
NTc
N
6
7
8
9
3.8
420
130
9.3
16
310
2.5
NT
2.0
NT
N
N
N
N
N
N
1400
130
Me
Me
N
N
10
81
1100
NT
11
2500
13
9100
99
NT
NT
Me
GW 9508
—
a
Calcium flux assay in GPR40-transfected CHO cells. Means of two or three
experiments.
b
LogD values were determined at pH 7.4.
c
NT = Not tested.
Me
Me
Br
CO2Et
Me
N
N
i
ii
O H
O
O
Me
Me
Me
12
14
13
CO2Et
Me
Me
CO2H
iii
iv
N
N
O
O
Me
Me
2
15
Scheme 1. Synthesis of compound 2. Reagents and conditions: (i) NaH, 2,5-dibromopyridine, DMF, 70 °C, 93%; (ii) ethyl acrylate, Pd(OAc)2, P(o-tol)3, Et3N, MeCN, microwave,
80 °C, 88%; (iii) NaBH4, NiCl2, MeOH, 0 °C, 88%; (iv) NaOH aq, EtOH, 50 °C, 84%.
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R. Takano et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
Table 2
GPR40 agonistic activities of substituted propanoic acid derivatives
a
a
Compound
R
Human EC50 (nM)
Rat EC50 (nM)
LogDb
Complex 1c (% inhibition)
58
Me
Me
Me
Me
CO H
2
1
6.7
8.6
18
>3.3
O
O
O
O
Me
Me
Me
Me
CO2H
CO2H
N
N
N
NTd
NT
58
NT
NT
F
16
17
18
250
Me
65
2100
>10,000
CO2H
OMe
120
NT
F
Me
Me
Me
Me
CO H
2
N
N
N
19
20
21
22
23
24
25
18
10
96
NT
3.3
2.8
NT
0.7
1.2
NT
91
39
66
NT
1.0
6.0
NT
O
O
O
O
Me
Me
Me
Me
OEt
CO H
2
320
130
190
760
79
CO2H
14
CO H
2
N
O
49
Me
Me
OEt
CO2H
N
230
20
O
OEt
CO2H
OEt
Me
O
CO H
2
35
78
Me
O
O
OEt
CO2H
26
370
290
NT
NT
Me
a
b
c
Calcium flux assay in GPR40-transfected CHO cells. Means of two or three experiments.
LogD values were determined at pH 7.4.
%Inhibition of the mitochondrial respiratory chain complex 1 at 100
NT = Not tested.
l
M of compound.39
d
changed back to the phenyl ring. As a result, compound 24 recov-
ered strong GPR40 agonistic activity (EC50 = 20 nM) and moreover
the inhibition of mitochondrial function by 24 was found to be
weak. It is reported that small nonpolar substituents at meta-
position were favored over ortho- or para-position on the benzyl
moiety of propanoic acid series.38 In contrast, the methyl substitu-
ent introduced at ortho- or meta-position was acceptable in the
b-ethoxy-propanoic acid series (compound 24–26).
Compound 24 was synthesized via Scheme 2. Benzyl moiety was
introduced by the reaction of 4-hydroxybenzaldehyde (27) and 2-
methylbenzyl bromide in the presence of Cs2CO3. b-Hydroxyl ester
29 was obtained by aldol reaction of aldehyde 28 and ethyl acetate
with the base of LHMDS. The alkylation of hydroxyl substituent at
b-position of 29 by iodoethane with excess amount of Ag2O in tol-
uene reflux gave the ethoxy product 30 in moderate yield. Hydroly-
sis of ethyl ester 30 in methanol at room temperature gave 24.
Please cite this article in press as: Takano, R.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.04.065

4
R. Takano et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Table 3
PK parameters of compound 2 and 24 in ratsa
Compound
Cl (L/h/kg)
Vdss (L/kg)
T1/2 (h)
Cmax
(l
g/ml)
AUC (
lg h/ml)
F (%)
2
24
1.2b
0.22b
0.16d
0.24b
0.37d
3.5c
3.3e
2.0c
5.3e
24c
64e
0.37d
a
b
c
This experiment was carried out with F344 rats.
The compound was dosed iv at 10 mg/kg.
The compound was dosed po at 10 mg/kg.
The compound was dosed iv at 2 mg/kg.
The compound was dosed po at 3 mg/kg.
d
e
OH
CHO
CO2Et
i
ii
Me
Me
CHO
O
O
HO
27
28
29
OEt
OEt
iii
iv
CO2Et
CO2H
Me
Me
O
O
30
24
Scheme 2. Synthesis of b-ethoxy substituted compound 24. Reagents and conditions: (i) 2-methylbenzyl bromide, Cs2CO3, DMF, rt, quant.; (ii) ethyl acetate, LHMDS, THF,
ꢀ78 °C, 84%; (iii) Ag2O, iodoethane, toluene, 100 °C, 38%; (iv) NaOH aq, MeOH, rt, 64%.
PK profiles of 24 were evaluated and found to be improved
compared to compound 2 presumably due to interruption of
b-oxidation. Low clearance and high plasma exposure were consid-
ered to be suitable profiles as an oral agent (Table 3).
We first examined in vitro insulinotropic effects of compound
24 from MIN6 cells.40,41 The significant increases of insulin were
observed as dose dependently from 0.001 to 10 lM compound
24 in the presence of 25 mM glucose (Fig. 2).
Next, the glucose lowering effect of compound 24 was evalu-
ated by an oral glucose tolerant test (OGTT) in diabetic Zucker fatty
rats (Fig. 3).42 Compounds were administrated orally in 9-week-old
Zucker fatty rats 30 min prior to the glucose challenge. Compound
24 significantly reduced blood glucose excursion in a dose depen-
dent manner with doses ranging from 1 to 10 mg/kg. Sitagliptin, a
marketed DPP-4 inhibitor, was included as a positive control in this
study. Compound 24 at a dose of 3 mg/kg showed similar efficacy
to sitagliptin at a dose of 10 mg/kg, therefore the potency of com-
pound 24 was seemed to be as 3-fold strong as sitagliptin. As
Figure 3. Effects of compound 24 and Sitagliptin on plasma glucose levels during
OGTT.42 Values are expressed as the mean S.E. (n = 6). The compound was
administrated before 30 min of glucose administration (2 g/kg).
shown in Figure 4, robust increase of insulin secretion was also
observed. During this test, exposure of compound 24 was sufficient
to exhibit potent in vivo efficacy (Table 4).
Finally, We confirmed that compound 24 was inactive up to
10
the fatty acids as their ligands.
lM on GPR120 and PPAR a,c
,d receptors,10,43 which have also
In conclusion, we discovered a series of propanoic acid deriva-
tives as a lead structure for potent and orally bioavailable GPR40
agonists. Starting from compound 1, introduction of substituents
on propanoic acid moiety improved the PK profiles, and removal
of the biphenyl structure lowered the toxicity risks. Among them,
compound 24 was found to be a promising lead compound. Com-
pound 24 increased insulin secretion from MIN6 cells and lowered
plasma glucose level in rat OGTT. Further optimization on this ser-
ies is ongoing and will be reported in due course.
Figure 2. Effects of compound 24 on insulin secretions from MIN6 cells.40,41 Values
are expressed as the mean S.E. (4 wells).
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R. Takano et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
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Table 4
PK parameters of compound 24 during OGTT
Compound 24
Cmax
(l
g/ml)
AUC (lg h/ml)
1 mg/kg
3 mg/kg
10 mg/kg
4.1
14
51
4.8
19
78
Acknowledgments
MIN6 cells were licensed in from Prof. Jun-ichi Miyazaki at
Osaka University. We thank Prof. Miyazaki and the staffs at his
laboratory for their assistance in the use of MIN6 cells and useful
advice.
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Please cite this article in press as: Takano, R.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.04.065