Structure-Activity Relationship Studies of 3- or 4-Pyridine Derivatives of DS-6930

Article abstract of DOI:10.1021/acsmedchemlett.8b00645

Derivatization efforts were continued to discover backups for a potent selective PPARγ modulator, DS-6930. In this Letter, the replacement of 2-pyridine ring in DS-6930 with 3- or 4-pyridyl group is reported. As the introduction of substituents on the pyridine ring did not provide potent partial agonists, modifications of benzimidazole ring were explored to discover potent intermediate agonists. 4′-Alkoxy substituted benzimidazoles failed to show potent efficacy in vivo, whereas 7′-fluoro benzimidazole 3g (DS19161384) was found to result in robust plasma glucose reductions with excellent DMPK profiles.

Full text of DOI:10.1021/acsmedchemlett.8b00645

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Letter
SAR Studies of 3- or 4-Pyridine Derivatives of DS-6930
Tsuyoshi Shinozuka, Tomoharu Tsukada, Kunihiko Fujii, Eri Tokumaru, Yumi Matsui, Satoko Wakimoto,
Tsuneaki Ogata, Kazushi Araki, Ryoko Sawamura, Nobuaki Watanabe, Makoto Mori, and Jun Tanaka
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.8b00645 • Publication Date (Web): 26 Feb 2019
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ACS Medicinal Chemistry Letters
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SAR Studies of 3- or 4-Pyridine Derivatives of DS-6930
Tsuyoshi Shinozuka,*,† Tomoharu Tsukada,† Kunihiko Fujii,† Eri Tokumaru,† Yumi Matsui,‡
Satoko Wakimoto,† Tsuneaki Ogata,† Kazushi Araki,† Ryoko Sawamura,† Nobuaki Watanabe,†
Makoto Mori† and Jun Tanaka†
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†R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
‡R&D Division, Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan
KEYWORDS: DS-6930, benzoic acid, benzimidazole, PPARγ, partial agonist
ABSTRACT: Derivatization efforts were continued to discover backups for a potent selective PPARγ modulator, DS-6930.
In this paper, the replacement of 2-pyridine ring in DS-6930 with 3- or 4-pyridyl group is reported. As the introduction of
substituents on the pyridine ring did not provide potent partial agonists, modifications of benzimidazole ring were explored
to discover potent intermediate agonists. 4’-Alkoxy substituted benzimidazoles failed to show potent efficacy in vivo,
whereas 7’-fluoro benzimidazole 3g (DS19161384) was found to result in robust plasma glucose reductions with excellent
DMPK profiles.
Et
S
S
Thiazolidinedione (TZD)-based PPARγ full agonists,
pioglitazone hydrochloride (I, Figure 1) and rosiglitazone
maleate (II, Figure 1) demonstrated to have robust
pharmacological efficacy in clinical settings.1 However,
they attracted much attention owing to their adverse
effects. The short-term usage of TZD drugs often causes
peripheral edema.2 It has also been reported that their
long-term use is often associated with bone fracture,
carcinogenicity, and cardiovascular risks.3,4 Such adverse
effects have limited their usage because of safety concerns.
N
O
O
N
N
N
H
N
H
O
O
O
O
HCl
maleate
pioglitazone (I)
rosiglitazone (II)
N
N
CO2H
O
N
O
DS-6930 (III)
Figure 1. Chemical structures of pioglitazone
hydrochloride (I), rosiglitazone maleate (II), and DS-6930
(III).
Although it was reported that the inhibition of PPARγ
phosphorylation by Cdk5 is the underlying mechanism of
antidiabetic efficacy,5 we believe there is still scope for the
development of safer PPARγ modulators through the
selective regulation of cofactors. Such a conventional
approach led to the discovery of DS-6930 (III, Figure 1).6
DS-6930 demonstrated potent plasma glucose (PG)
reduction with fewer PPARγ-related adverse effects than
rosiglitazone in preclinical studies.6 Based on the co-
crystal structure of III bound to PPARγ ligand binding
domain (LBD), the avoidance of direct interactions with
Tyr473 on helix 12 and the additional lipophilic interactions
of dimethylpyridyl group are suggested to be related to the
intermediate agonist activity of DS-6930.6 The superior
safety profile of DS-6930 was attributable to this distinct
binding mode through the selective recruitment of
cofactors.6 We continued our exploration of structure-
activity relationship (SAR) of this series of compounds to
discover backup clinical candidates for DS-6930. Herein,
we report SAR studies of 3- or 4-pyridines to identify novel
PPARγ intermediate agonist 3g (DS19161384), which
demonstrated robust pharmacological efficacy with
excellent DMPK properties in preclinical studies.
We reported that the high lipophilicity caused the
elevation of liver enzyme activities, and the suppression of
lipophilicity was achieved by the replacement of phenyl
ring with 2-pyridyl group, which led to the discovery of DS-
6930.6 As the derivatization of 3- or 4-pyridines has
generally been avoided owing to their poor potencies in
vitro, we have focused on them as backups.
The SAR results of 3-pyridines with in vitro ADME
profile are summarized in Table 1. Unsubstituted 3-
pyridine 1a possessed poor agonist potency. Unlike the
previous SAR of 2-pyridine series,6 the introduction of a
methyl group did not result in good potency in vitro,
despite the improvement of membrane permeability
(compounds 1b–1e). Compounds 1a–1e exhibited
comparable aqueous solubility and microsomal stability as
those of III. Accordingly, further modifications were
explored owing to the attractive in vitro ADME profile of
1a–1e. When a chloro group was incorporated in each
position of the pyridine ring, none of them had EC50 < 1 μM
(data not shown). Improved in vitro potency was observed
for 4- or 5-methoxy derivatives (1g and 1h), whereas the
introduction of 2-methoxy group did not result in high
potency (compound 1f). Although 4-methoxy analog 1g
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ACS Medicinal Chemistry Letters
exhibited the best in vitro potency among 3-pyridines, 1g
lost partial agonist activity. Full agonists were also found
in methyl analogs (1c and 1d). Further, introduction of a
substituent in 1f or 1g led full agonists 1i-1k. In contrast,
dimethyl derivative 1l exerted modest potency, with partial
agonist activity in vitro (Emax = 36%). In terms of PPARα
selectivity, only 1k showed relatively high PPARα activity.
Page 2 of 6
and 2d) exhibited EC50 = 188 and 182 nM, respectively. The
3-alkoxy group is essential for potency of 4-pyridine series,
because 3-chloro and 3,5-dimethyl analog (2e and 2f) lost
their high potency in vitro. Although 3-methoxy-5-methyl
derivative 2g showed the best potency among the 4-
pyridine series, full agonist activity was observed. The
modification of benzimidazole ring of 2g led to the
discovery of intermediate agonist 2h (Emax = 74%).
Imidazopyridine 2h exhibited adequate solubility and high
microsomal stabilities against three species, with high
PPARα selectivity.
1
2
3
4
5
6
7
8
We then focused on 4-pyridines (compounds 2 in Table
1). 3-Methyl derivative 2a lost in vitro potency, whereas 3-
ethyl analog 2b showed tenfold higher potency. Further
enhancement of potency was achieved by the introduction
of an alkoxy group. 3-Methoxy and 3-ethoxy derivatives (2c
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15
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Table 1. PPAR Transcriptional Activities and In Vitro ADME Profiles of 1 and 2
O
5
O
5
4
6
OH
N
N
OH
N
N
N
X
X
3
N
O
O
O
O
Y
2
1a-1l
2a-2h
PAMPA
Papp (10-6
cm/s)
PPARγ
EC50 (nM)a Emax (%)a
PPARγ
PPARα
EC50 (nM)a Emax (%)a
PPARα
Solubility
MS
Cmpd
X
Y
Log D
20
21
(μg/mL)
(%, h/r/mon)b
22
III
41 ± 10d
6831
>10000
543
68 ± 8.0d
66
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
NDe
13 ± 2.0d
1.4
0.5
1.0
0.8
1.0
0.9
0.8
1.3
13 ± 3.4d
<2.0
2.6
31
NTc/92/80
100/NTc/NTc
98/NTc/NTc
87/NTc/NTc
NTc
100/NTc/NTc
NTc
NTc
23
1a
H
5
23
54
71
24
1b
2-Me
77
3
25
26
1c
4-Me
110
104
45
4
5.9
27
1d
5-Me
779
5
2.4
43
13
28
1e
6-Me
>10000
1193
155
9
4.1
29
30
1f
2-OMe
4-OMe
5-OMe
2-Me, 4-OMe
2-OMe, 4-Me
4-OMe, 5-Me
2-Me, 4-Me
3-Me
59
8
3.0
46
1.9
58
5.1
39
11
31
1g
101
86
17
5
10.5
2.8
32
1h
231
0.9
1.7
1.4
2.0
1.3
NTc
NTc
NTc
33
34
1i
255
106
131
2
10.1
10.4
21.7
4.2
35
1j
436
12
61
-2
3
36
1k
315
125
36
100/82/98
100/100/100
100/NTc/NTc
88/NTc/NTc
98/100/100
94/NTc/NTc
NTc
37
381l
273
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
46
87
71
39
2a
CH
CH
CH
CH
CH
CH
5947
509
44
0.9
1.3
<2.0
4.2
40
2b
3-Et
99
3
41
2c
3-OMe
3-OEt
188
110
83
9
1.3
6.8
38
21
42
43
2d
182
4
1.8
1.1
12.6
4.9
44
2e
3-Cl
5947
2745
100
83
7
6.2
45
6.5
18
45
2f
3-Me, 5-Me
99
7
1.0
1.7
1.2
3.0
NTc
46
47
2g
3-OMe, 5-Me CH
3-OMe, 5-Me
112
21
20
12.2
8.5
96/96/85
91/98/100
48
2h
N
166
74
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aPPAR activity was assessed in COS-7 cells transfected with a chimeric human PPAR-Gal4 receptor expression plasmid and a
pG5luc reporter plasmid. bHuman/rat/monkey microsomal stability. cNot tested. dValues represented as mean ± S.E.M. Values
on two independent experiments. eNot determined.
As described, the introduction of substituents on 3- or 4-
pyridine ring enhanced in vitro potency to discover partial
agonist 1l and intermediate agonist 2h. As the
enhancement of in vitro potency is often associated with
full agonist activity, other modifications were required.
X-ray crystal structure of PPARγ LBD complexed with 1l
was investigated to seek other chemical modifications. The
binding mode of 1l superimposed with DS-6930 is shown
in Figure 2a. As expected, 1l displayed the same binding
mode as DS-6930.6 As no direct interaction with Tyr473 on
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helix 12 and the lipophilic interactions of dimethylpyridyl
fact, all 4’-substituted analogs 3a-3e showed full agonist
activity (Emax = 94%-116%).
1
2
3
4
5
6
7
8
group were confirmed, these interactions relates for 1l to
show partial agonist activity. A space around the 4’-
positoin of benzimidazole ring surrounded by Phe264-
Gly284-Arg288 was observed (Figure 2b). The existence of
such a space urged us to introduce 4’-substituents on
benzimidazole ring as shown in Table 2 (compounds 3).
Accordingly, we sought another solution. Several small
substituents were incorporated at 7’-position on
benzimidazole ring due to the limited space around this
position (Figure 2b). A methyl or fluoro group was
introduced into this position, and both analogs retained in
vitro potency. In particular, 7’-fluoro analog 3g
demonstrated intermediate agonist activity (Emax = 76%),
with acceptable solubility and robust microsomal stability.
The binding mode of 3g is shown in Figure 2c. 7’-Fluoro
analog 3g exhibited the same binding mode as 1l.
The introduction of 4’-methyl group in the bicyclic core
structure led to disappointing results (compound 3a),
whereas 4’-methoxy derivative 3b retained potency in vitro.
Consequently, several 4’-alkoxy groups were incorporated.
The in vitro potency was found to be correlated with the
lipophilicity of molecules (3b–3e). For example, 4’-
methoxy derivative 3b had EC50 = 249 nM, whereas 4’-
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The introduction of substituents on the benzimidazole
ring in III was then explored (compounds 4 in Table 2). 4-
Pyridine 2c was also modified (compounds 5 in Table 2).
When 4’-alkoxy group was introduced in III, 4’-ethoxy and
4’-isopropoxy derivatives 4a and 4b retained high potency
in vitro. However, the introduction of such substituents
resulted in full agonist efficacy. The enhancement of in
vitro potency was also achieved for 4-pyridines. When 4’-
methyl, 4’-ethoxy, or 4’-isopropoxy group was introduced
into benzimidazole ring, all compounds exerted high
potency in vitro (compounds 5a, 5b, and 5c). In particular,
ethoxy analog 5b demonstrated strong potency in vitro
propoxy analog 3d exhibited EC50
= 32 nM. This
modification enhanced the activity by 7.8-fold, with an
increase in Log D value by 1.0. Because the membrane
permeability progressively increased, the improvement of
membrane permeability might contribute to the high
potency in vitro. This enhancement of PPARγ potency was
not accompanied with the PPARα activation. Isopropyl
analog 3e exhibited high potency in vitro with enhanced
aqueous solubility compared with that of 1l. The
improvement in solubility achieved was over tenfold, even
though 3e was more lipophilic than 1l. Compound 3e
maintained robust stability against human liver
microsomes. However, 3e showed full agonist activity. In
with an intermediate agonist activity (EC50 = 58 nM, Emax
=
71%). Compound 5b also exhibited improved aqueous
solubility. The introduction of 7’-fluoro group resulted in
full agonist 5d.
Table 2. PPAR Transcriptional Activities and In Vitro ADME Profiles of 3, 4 and 5
4'
4'
4'
O
O
O
X
X
X
OH
OH
N
N
OH
N
N
N
N
N
N
O
O
O
O
O
O
N
O
7'
7'
7'
3a-3g
4a, 4b
5a-5d
PAMPA
PPARγ
EC50 (nM)a Emax (%)a
PPARγ
PPARα
EC50 (nM)a Emax (%)a
PPARα
Solubility
MS
Cmpd
X
Log D
Papp (10-6
(μg/mL)
(%, h/r/mon)b
cm/s)
3a
3b
3c
3d
3e
3f
4’-Me
811
249
104
32
116
99
103
94
103
92
76
84
88
83
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
4
1
1.7
1.2
1.6
2.2
1.9
1.8
1.6
1.7
2.0
1.7
1.7
2.0
1.7
6.0
2.7
3.2
50
130
34
100/NTc/NTc
NTc
100/NTc/NTc
NTc
4’-OMe
4’-OEt
4’-OPr
5
4.8
11.8
9.1
1
4’-Oi-Pr 31
4
10
3
630
14
91/65/81
NTc
7’-Me
7’-F
244
7.0
3g
4a
4b
5a
5b
5c
5d
246
58
9.2
28
12
100/100/100
100/NTc/NTc
96/13/84
4’-OEt
2
18.6
24.5
12.6
15.5
17.3
14.0
4’-Oi-Pr 57
9
13
5
7.6
36
4’-Me
57
58
100/NTc/NTc
100/NTc/NTc
97/91/94
97/NTc/NTc
4’-OEt
71
120
53
4’-Oi-Pr 32
7’-F 60
100
95
14
18
2.1
aPPAR activity was assessed in COS-7 cells transfected with a chimeric human PPAR-Gal4 receptor expression plasmid and a
pG5luc reporter plasmid. bHuman/rat/monkey microsomal stability. cNot tested.
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b)
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a)
c)
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Figure 2. X-ray crystal structures of 1l (PDB 6IZM) and 3g (PDB 6IZN) bound to PPARγ-LBD. (a) Details of the binding
mode of 1l (blue) superimposed with DS-6930 (magenta). Hydrogen bonds are marked as red dotted lines. (b) Compound 1l in
PPARγ-LBD. PPARγ-LBD is shown in surface representation, and residues F264, G284, R288 and 1l are shown in stick
presentation. (c) Details of the binding structure of 3g to PPARγ-LBD. Hydrogen bonds are marked as red dotted lines.
a)
vitro, whereas better results were observed with full
agonist 2c (37% PG reduction, p < 0.05). Further
enhancement of the efficacy was achieved in 4-pyridines 2g
and 2h with statistical significance (p < 0.01). Compound
2g exerted 61% reduction of PG, whereas 66% PG reduction
was observed in imidazopyridine 2h. Note that 2g is a full
agonist. Owing to the excellent plasma exposure, 7’-F
substituted analog 3g exhibited excellent efficacy (73% PG
reduction, p < 0.01). Of 2-pyridines, 4’-ethoxy derivative 4a
showed modest efficacy, whereas 4’-isopropoxy analog 4b
lost the potent efficacy in vivo. As both compounds showed
the same range of strong potency in vitro, the difference in
the plasma exposure of the compounds resulted in such a
pharmacological gap. 4’-Alkoxy substituted 4-pyridines, 5a
and 5b, lost potent efficacy in vivo. The reasons for this
poor efficacy are unclear, because 5a showed sufficient
plasma exposure with high potency in vitro. Overall, 4’-
alkoxy substituted benzimidazoles tended to show lower
efficacy in vivo. 4’-Alkoxy analog 3e resulted in lower PG
reduction than 7’-F analog 3g, owing to the lower plasma
exposure of the compound. Unsubstituted benzimidazole
III exerted higher efficacy than 4’-alkoxy analogs 4a and 4b,
and the same relationship was observed between
unsubstituted analog 2c and 4’-alkoxy derivatives (5a and
5b).
b)
Figure 3. Pharmacological effects and PK parameters of
PPARγ modulators. (a) PG reduction (% change in PG level
vs vehicle control) in ZDF rats after the oral administration
of 3 mg/kg of the test compounds in 0.5% methylcellulose
on day 14 (n = 5). Data are represented as mean ± S.E.M.
Statistical significance compared to vehicle treatment is
denoted by *p < 0.05 and **p < 0.01. (b) AUC0-24 h (h*μg/mL)
was acquired by the administration of compounds to ZDF
rats on Day 15 (n = 5). Each value is the mean ± S.D.
Based on pharmacological results combined with ADME
profile, 2h and 3g were selected as candidates for further
evaluations. PK study of these compounds was performed
by oral administration to male cynomolgus monkeys at 3
mg/kg as shown in Table 3. The compounds (1 mg/kg) were
intravenously administered to the same monkey to
calculate the total body clearance (CL), distribution
volume at steady state (Vss) and F value. 4-Pyridine 2h
retained excellent CL comparable to III. Further
improvement of CL was achieved in 7’-fluoro derivative 3g.
7’-Fluoro analog 3g demonstrated excellent PK parameters,
including the lowest CL as well as the highest AUC and F
even compared to III. The PK parameters of 3g in rodents
at the same dose (3 mg/kg p.o., 1 mg/kg i.v.) are
summarized (Table 3). 7’-Fluoro analog 3g showed lower
AUC and higher CL in rodents than in monkeys. Although
Several potent compounds were advanced to in vivo
pharmacological profiling. These compounds were
assessed for their ability to reduce PG in Zucker diabetic
fatty (ZDF) rats at 3 mg/kg p.o. for 14 days as shown in
Figure 3a. Plasma exposures of the test compounds (AUC)
are shown in Figure 3b. DS-6930 exerted a statistically
significant reduction in PG (57%, p < 0.05). 3-Pyridine 1l
exhibited poor efficacy in vivo owing to low potency in
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3g exerted the highest CL and the lowest bioavailability in candidate selection.
1
2
3
4
5
6
mice, these PK parameters were acceptable for clinical
Table 3. Pharmacokinetic Parameters and Bioavailability of Compounds III, 2h and 3g at 3 mg/kga
CL
Cmax
AUClast
Cmpd
Species
Tmax (h)
T1/2 (h)
F (%)
Vss (L/kg)
(mL/min/kg
)
(μg/mL)
(h*μg/mL)
7
8
9
0.36
±
III
Monkey
2.25 ± 0.72b
5.00 ± 4.2b
13.5 ± 0.42b
23.5 ± 5.9b
89 ± 15b
2.06 ± 0.21b
0.0071b
2h
3g
3g
3g
Monkey
Monkey
Rat
0.50 ± 0.37b
28.8 ± 10b
3.49 ± 0.93c
1.29 ± 0.43c
4.50 ± 4.9b
0.50 ± 0.0b
2.25 ± 1.75c
0.50 ± 0.0c
7.30 ± 2.8b
9.34 ± 3.3 b
3.45 ± 0.70c
4.35 ± 2.49c
5.12 ± 2.4b
128 ± 73b
28.0 ± 6.65c
2.07 ± 0.26c
18 ± 8.7b
76 ± 34b
74 ± 18c
21 ± 2.6c
2.08 ± 1.1b
0.35 ± 0.049b
0.15 ± 0.042b
0.27 ± 0.035b
0.62 ± 0.22b
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0.40 ± 0.23b
1.29 ± 0.18b
4.91 ± 0.66b
Mouse
aThe test compounds in 0.5% methylcellulose were administered to male cynomolgus monkeys at 3 mg/kg (p.o.). Total body
clearance (CL), distribution volume at steady state (Vss), and F value were calculated after intravenous administration of the
test compounds (1 mg/kg). Each value represents the mean ± S.D. bn = 2. cn = 3.
activity relationship; PAMPA, parallel artificial membrane
permeation assay; ZDF rat, Zucker diabetic fatty rat.
In summary, the 2-pyridine ring of DS-6930 was replaced
with a 3- or 4-pyridyl group to identify backup clinical
candidates for DS-6930. Although the introduction of
substituents on 3- or 4-pyridine ring resulted in
improvements of the in vitro potency, potent agonists
showed full agonist activity. The introductions of 4’-
substituent on benzimidazole ring also enhanced potency
in vitro, while these compounds exhibited modest in vivo
efficacy in ZDF rats. Most of 4’-substituted compounds
including 3e exerted full PPARγ agonist activity. Other
modifications of the benzimidazole ring led to the
discovery of 7’-fluoro analog 3g and imidazopyridine 2h,
which demonstrated potent PG reduction in vivo with an
intermediate agonist activity in vitro. Among them, 7’-
fluoro analog 3g (DS19161384) exhibited excellent DMPK
profile.
REFERENCES
(1) Yki-Järvinen, H. Thiazolidinedions. N. Engl. J. Med.
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(2) Mudaliar, S.; Chang, A. R.; Henry, R. R.
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Implications. Endocr Pract 2003, 9, 406–416.
(3) Loke, Y. K.; Singh, S.; Furberg, C. D. Long-Term Use
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M.; McMurray, J. J.; RECORD Study Team.
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ASSOCIATED CONTENT
Supporting Information
General synthetic procedure of all compounds; experimental
procedures and characterization data of selected compounds;
procedures for pharmacological activities. This material is
available free of charge via the Internet at http://pubs.acs.org.
Type
2 Diabetes (RECORD): A Multicentre,
Randomised, Open-Label Trial. Lancet 2009, 373,
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(5) Choi, J. H.; Banks, A. S.; Estall, J. L.; Kajimura, S.;
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AUTHOR INFORMATION
Corresponding Author
*Tel: +81-3-3492-3131. Fax: +81-3-5436-8563. E-mail:
sinozu.xf6@gmail.com;
shinozuka.tsuyoshi.s5@daiichisankyo.co.jp.
(6) Shinozuka, T.; Tsukada, T.; Fujii, K.; Tokumaru, E.;
Shimada, K.; Onishi, Y.; Matsui, Y.; Wakimoto, S.;
Kuroha, M.; Ogata, T.; Araki, K.; Ohsumi, J.;
Sawamura, R.; Watanabe, N.; Yamamoto, H.;
Fujimoto, K.; Tani, Y.; Mori, M.; Tanaka J. Discovery
of DS-6930, A Potent Selective PPARγ Modulator.
Part II: Lead Optimization. Bioorg. Med. Chem. 2018,
26, 5099-5117.
ORCID ID
Tsuyoshi Shinozuka: 0000-0002-7785-6080
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
PPAR, peroxisome proliferator-activated receptor; TZD,
thiazolidinedione; Cdk5, cyclin-dependent kinase 5; PG,
Plasma glucose; LBD, ligand binding domain; SAR, structure
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SAR Studies of 3- or 4-Pyridine Derivatives of DS-6930
Tsuyoshi Shinozuka,*,† Tomoharu Tsukada,† Kunihiko Fujii,† Eri Tokumaru,† Yumi Matsui,‡ Satoko Wakimoto,†
Tsuneaki Ogata,† Kazushi Araki,† Ryoko Sawamura,† Nobuaki Watanabe,† Makoto Mori† and Jun Tanaka†
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F
3g (DS19161384)
PPAR EC50: 246 nM

PPAR
Emax: 76%

73% PG reduction in ZDF rats (3 mg/kg)
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