Discovery of DS-1558: A potent and orally bioavailable GPR40 agonist

Article abstract of DOI:10.1021/ml500391n

GPR40 is a G protein-coupled receptor that is predominantly expressed in pancreatic β-cells. GPR40 agonists stimulate insulin secretion in the presence of high glucose concentration. On the basis of this mechanism, GPR40 agonists are possible novel insuli

Full text of DOI:10.1021/ml500391n

Letter
pubs.acs.org/acsmedchemlett
Discovery of DS-1558: A Potent and Orally Bioavailable GPR40
Agonist
Rieko Takano,† Masao Yoshida,† Masahiro Inoue,† Takeshi Honda,† Ryutaro Nakashima,†
Koji Matsumoto,† Tatsuya Yano,† Tsuneaki Ogata,† Nobuaki Watanabe,† Masakazu Hirouchi,†
Tomoko Yoneyama,‡ Shuichiro Ito,‡ and Narihiro Toda*,†
†R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
‡Drug Discovery and Biomedical Technology Unit, Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo
134-8630, Japan
S
* Supporting Information
ABSTRACT: GPR40 is a G protein-coupled receptor that is predominantly expressed in
pancreatic β-cells. GPR40 agonists stimulate insulin secretion in the presence of high glucose
concentration. On the basis of this mechanism, GPR40 agonists are possible novel insulin
secretagogues with reduced or no risk of hypoglycemia. The improvement of in vitro activity
and metabolic stability of compound 1 led to the discovery of 13, (3S)-3-ethoxy-3-(4-{[(1R)-
4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid, as a potent and
orally available GPR40 agonist. Compound 13 (DS-1558) was found to have potent glucose
lowering effects during an oral glucose tolerance test in ZDF rats.
KEYWORDS: GPR40, agonist, insulin secretagogue, diabetes, glucose lowering
ype 2 diabetes is a metabolic disorder characterized by
Timpaired glucose homeostasis caused by insufficient
insulin secretion or insulin resistance. The number of diabetics
has been increasing all over the world and has reached nearly
350 million.1,2 Current common therapies include the use of
insulin injections, sulfonylureas, metformin, and glinides.3,4
Most of them are associated with problems such as weight gain,
risk of hypoglycemia, and lack of sustained efficacy.5−9 Lately,
glucose-dependent insulin secretagogues, such as GPR11910
Figure 1. Reported GPR40 agonists.20−28
and GPR14211 agonists, have attracted attention as alternative
treatments for diabetes. Among them, DPP-IV inhibitors
enhancing the activity of GLP-1 have already been widely
used. Most recently, SGLT2 inhibitors that inhibit the reuptake
of urinal sugar have been developed as hypoglycemic agents
with low risk of weight gain.
GPR40 is primarily expressed in pancreatic β-cells and
activated by long-chain free fatty acids, resulting in enhance-
ment of glucose-stimulated insulin secretion (GSIS) dependent
on elevated glucose levels.12−17 On the basis of this GSIS
mechanism, GPR40 has also received considerable attention as
a novel therapeutic target for type 2 diabetes because of its low
risk of hypoglycemia.18,19 Recently, several groups have
reported GPR40 agonists that contain acidic moieties such as
a carboxylic acid or thiazolidinedione (Figure 1).20−28 We have
also identified 3-ethoxypropanoic acid 1 as a promising lead
compound (Figure 2).29
Figure 2. Optimization of lead compound 1.
Although compound 1 showed a glucose lowering effect in
rats after oral administration, its half-life was very short (Table
2). High in vivo clearance of 1 was probably due to metabolic
oxidation at the benzyl position because we detected a
glutathione (GSH) adduct of 2-methylbenzaldehyde, a putative
metabolite of 1, from a GSH trapping assay in human liver
microsomes. Therefore, we designed the cyclized compounds
Herein we describe the lead optimization of 1 to discover
(3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-
inden-1-yl]oxy}phenyl)propanoic acid (13), a potent and orally
available GPR40 agonist.
Received: September 26, 2014
Accepted: January 13, 2015
© XXXX American Chemical Society
A
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ACS Medicinal Chemistry Letters
Letter
between the benzylic position and the ortho position of the
phenyl ring to avoid benzyl oxidation (Figure 2).
First we investigated the stereoconfiguration of the ethoxy
moiety (Table 1). Chiral separation of the Cl-substituted
derivative revealed that (S)-stereochemistry was preferred for
GPR40 agonistic activity (2−4).
Next we synthesized cyclized derivatives with 5- or 6-
membered rings. Among indane derivatives (6−8), compound
6 was the most potent agonist. Tetralin derivative 9 with the
same stereochemistry at the benzyl position was weaker than 6.
Accordingly, we focused our investigation to the substituents
on the indane ring. The methyl (10) and ethoxy (11)
derivatives showed similar potency to compound 6. The Cl
(12) and CF3 (13) substituents provided a significant leap in
agonistic activity. We synthesized possible diastereomers (14−
16) of 13 and confirmed that compound 13 was the most
potent agonist. The stereoconfiguration at both indane and
ethoxy moieties significantly impacted the GPR40 agonistic
activity. Furthermore, compound 13 had no PPARγ agonistic
activity up to 100 μM, whereas noncyclic compound 5 had
partial PPARγ agonistic activity (EC50 = 10.4 μM, Emax =11.3%
relative to rosiglitazone). This indicated that the fixed
conformation improved the GPR40 selectivity over PPARγ.
In addition, 13 had no activity for GPR120 and exhibited >100-
fold selectivity over 68 other diverse receptors, ion channels,
and transporters.30 Thus, potent and selective GPR40 agonist
13, named DS-1558, was selected for further investigations.
Compound 13 (DS-1558) was synthesized as shown in
Scheme 1. This route was considered to be able to synthesize
Table 1. Structures and in Vitro Activities of the
Phenylpropanoic Acid Series
a
Scheme 1
a
Reagents and conditions: (i) HCO2H, NEt3, RuCl[(R,R)-Tsdpen]-
(mesitylene), r.t., 85%, 99% ee; (ii) 4-fluorobenzonitrile, NaH, THF/
DMF, r.t., quant.; (iii) 5 N NaOH aq., 2-methoxyethanol, 120 °C,
84%; (iv) methyl potassium malonate, CDI, MgCl2, NEt3, THF/
EtOAc, r.t. to 45 °C, 84%; (v) HCO2H, NEt3, RuCl[(S,S)-
Tsdpen](mesitylene), 38 °C, 91%, 96% de; (vi) EtI, Ag2O, toluene,
110 °C, 84%; (vii) LiAlH4, THF, 0 °C, quant.; (viii) TEMPO,
NaClO2, NaClO, pH 6.86 phosphate buffer, acetonitrile, 0 to 10 °C,
85%, 98% de.
this compound on a large scale using mild reactions, which
were arranged to suppress the production of diastereomers
minimally. In actual fact, we obtained 80 g of 13 (DS-1558)
starting from about 90 g of 17 with high optical purity (98%
de).
Starting from a commercially available indanone 17, chiral
alcohol 18 was obtained by Ru-catalyzed asymmetric transfer
hydrogenation with good enantioselectivity (99% ee).31 A SNAr
reaction was used to obtain aryl ether 19. After yielding benzoic
acid 20 on hydrolysis in an alkali solution, β-ketoester 21 was
synthesized by the condensation of magnesium methylmalo-
nate with acid imidazolide preformed from 20 and CDI.32 The
chiral Ru-catalyst with opposite chirality was utilized again for
a
A calcium flux assay in transfected-GPR40 CHO cells. Assay results
are the average of triplicates. Standard deviation was 20%.
B
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the asymmetric hydrogenation of β-ketoester to give β-
hydroxyester 22 in a good diastereo ratio (96% de). The β-
hydroxy group in 22 was alkylated in the neutral conditions of
EtI and Ag2O without the retro-aldol reaction. The ester group
of 23 was reduced into primary alcohol and subsequently
oxidized to carboxylic acid 13 (DS-1558) by TEMPO. This
multistep procedure was adopted in order to avoid β-
elimination.
The absolute stereochemistry of 13 (DS-1558) was
determined by X-ray crystal structural analysis in the form
with (S)-arginine and methanol solvate. On the basis of
absolute configuration of the (S)-arginine, the absolute
configurations of the ethoxy and the indane moieties were
determined as (S) and (R), respectively (Figure 3).
Figure 3. ORTEP representation of 13 (DS-1558).
Pharmacokinetic (PK) parameters were summarized in Table
2. Compound 13 (DS-1558) showed higher plasma exposure
Table 2. Comparison of Pharmacokinetic Properties of 1
a
and 13 (DS-1558) in Rats, Dogs, and Monkeys
compd
species
1
13 (DS-1558)
Figure 4. Effects of 13 (DS-1558) during an OGTT in male ZDF rats.
Time-dependent changes of plasma glucose (A) and plasma insulin
(B). The results are represented as the mean standard error (n = 6,
9-weeks old).
rat
rat
dog
monkey
i.v.
dose (mg/kg)
Cl (L/h/kg)
Vdss (L/kg)
T1/2 (h)
2
1
0.5
1
0.37
0.16
0.37
0.020
0.19
6.0
0.042
0.23
4.0
0.032
0.62
17
p.o.
potency of 13 (DS-1558) at 0.1 mg/kg was similar to that of
sitagliptin at 10 mg/kg. Simultaneously, the augmentation of
plasma insulin levels by 13 (DS-1558) at 0.1 mg/kg and
sitagliptin at 10 mg/kg was observed (Figure 4B).
dose (mg/kg)
Cmax (μg/mL)
AUC (μg·h/mL)
F (%)
3
1
1
1
3.3
5.3
64
3.1
40
80
1.7
14
66
2.3
30
100
In conclusion, we have shown the lead optimization of 3-
ethoxypropanoic acid 1 to identify the promising compound 13
(DS-1558). The cyclization of benzyl carbon improved not
only the half-life but also GPR40 selectivity. We developed the
chiral synthesis of 13 (DS-1558) on a large scale with Ru-
catalyzed asymmetric transfer hydrogenation as a key reaction.
The potent in vivo glucose lowering effect of 13 (DS-1558) was
demonstrated in ZDF rats, type 2 diabetic model rats. Further
details of 13 (DS-1558) will be reported in due course.
a
The data is the mean value. The statistics are shown in the
Supporting Information.
and longer half-life than compound 1 in rats. The improved PK
profiles were also observed in monkeys and dogs. As we
expected, the cyclization approach was efficient at improving
the PK profiles.
The GPR40-mediated effects of 13 (DS-1558) on glucose-
stimulated insulin secretion were confirmed in isolated islets
from GPR40 KO and wild-type mice. Improvement of glucose
tolerance and insulin secretion were also recognized during the
in vivo studies of these mice and ZF rats.33 Furthermore, we
evaluated in vivo efficacy of this compound by an oral glucose
tolerance test (OGTT) in Zucker diabetic fatty (ZDF) rats,
which exhibit obesity with diabetes and are widely used for
therapeutic research on type 2 diabetes. The compound was
orally administrated 30 min prior to a glucose challenge (2 g/
kg). Even at the minimum dosing, 0.03 mg/kg, the 13 (DS-
1558) treatment markedly reduced the glucose excursion
compared to the control (Figure 4A). The glucose-lowering
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and analytical data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: toda.narihiro.jw@daiichisankyo.co.jp.
■
Notes
The authors declare no competing financial interest.
C
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ABBREVIATIONS
■
CDI, 1,1′-carbonyldiimidazole; TEMPO, 2,2,6,6-tetramethylpi-
peridine N-oxyl; PPAR, peroxisome proliferator-activated
receptor
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