Bioorganic & Medicinal Chemistry Letters
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
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0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.