5-Aryl thiazolidine-2,4-diones as selective PPARγ agonists

Article abstract of DOI:10.1016/S0960-894X(03)00257-9

A series of 5-aryl thiazolidine-2,4-diones containing 4-phenoxyphenyl side chains was designed, synthesized, and evaluated for PPAR agonist activities. One such compound 28 exhibited comparable levels of glucose correction to rosiglitazone in the db/db mouse type 2 diabetes animal model.

Full text of DOI:10.1016/S0960-894X(03)00257-9

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1801–1804
5-Aryl Thiazolidine-2,4-diones as Selective PPARꢀ Agonists
Hiroo Koyama,a,* Julia K. Boueres,a Wei Han,a Edward J. Metzger,a
Jeffrey P. Bergman,a Dominick F. Gratale,a Daniel J. Miller,a Richard L. Tolman,a
Karen L. MacNaul,b Joel P. Berger,b Thomas W. Doebber,b Kwan Leung,c
David E. Moller,b James V. Hecka and Soumya P. Sahooa,*
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
bDepartment of Metabolic Disorders—Diabetes, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
cDepartment of Drug Metabolism, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
Received 9 December 2002; accepted 30 January 2003
Abstract—A series of 5-aryl thiazolidine-2,4-diones containing 4-phenoxyphenyl side chains was designed, synthesized, and eval-
uated for PPAR agonist activities. One such compound 28 exhibited comparable levels of glucose correction to rosiglitazone in the
db/db mouse type 2 diabetes animal model.
# 2003 Elsevier Science Ltd. All rights reserved.
Type 2 diabetes is a chronic disease characterized by
insulin resistance in the liver and peripheral tissues
accompanied by a defect in pancreatic b-cells.1,2
Between 1997 and 1999, a new class of drugs called
‘glitazones’3 was approved by the FDA for the treat-
ment of type 2 diabetes (Fig. 1). These agents share a
common partial chemical structure: thiazolidine-2,4-
diones (TZD). Glitazones correct hyperglycemia by
enhancing tissues’ sensitivity to insulin. Because of this
mechanism of action, glitazone treatment is not asso-
ciated with dangerous hypoglycemic incidents that have
been observed with conventional sulfonylurea agents
and insulin therapy. In the mid-1990s, the molecular
target of glitazones was reported to be the peroxisome
proliferator-activated receptor-g (PPARg).4À7 The
PPARs are a group of nuclear receptors that act as
transcriptional factors which play a major role in the
regulation of lipid metabolism and storage.8À10
To date, a large number of compounds containing TZD
moiety have been synthesized and tested for PPAR
agonist activities.11 Several of these have reportedly
entered clinical studies. While the vast majority of TZD-
containing antidiabetic agents reported in the literature
have a methylene group bridging the TZD and the
phenyl group (5-benzyl TZDs), we and others have
independently found that compounds with a TZD
directly connected to the phenyl group (5-aryl TZDs)
can be potent and selective PPAR agonists.12,13 Herein,
we would like to report the results of our SAR studies
on 5-aryl-thiazoline-2,4-diones.14
The design of 5-aryl TZD structure came from the
phenylacetic acid series that had been studied earlier in
our laboratories:15 a TZD was introduced as a carb-
oxylic acid surrogate (Fig. 2). Some of the partial
structures of 5-aryl-TZDs 11–30 (Scheme 1) and our
SAR interests were derived from our previous work in
the phenylacetic acid series.16,17
Figure 1. Currently marketed glitazone antidiabetic drugs.
*Corresponding author. Fax: +1-732-594-9556; e-mail: hiroo_koyama@
merck.com
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00257-9

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H. Koyama et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1801–1804
of substituted phenoxyphenols 9 and 10 was conducted
in the similar fashion as described in Scheme 2.
Table 1 summarizes the in vitro activities of compounds
11–30. By and large, compounds are chronologically
arranged in the table as the SAR evolved. The initial set of
compounds 11–14 were synthesized to investigate into the
effects of R1 group and the tether length. Although based
on the data of a small number of examples, compounds
with a three methylene tether appeared to give superior
PPARg activities than corresponding four methylene
tethered ones. The SAR of R1 group seemed to be fairly
restricted. Based on these findings, we decided to continue
our SAR studies while keeping these structural features
constant: (three methylene tether and R1=nPr). We have
revisited the issues of tether length and R1 group from time
to time as we continued SAR studies and we observed
these structural features generally gave the best results.19
Figure 2. 5-Aryl TZD as a phenylacetic acid replacement.
General synthesis of 5-aryl thiazolidine-2,4-diones is
depicted in Scheme 1. Thus, appropriately substituted
mandelates were treated with 1,3-dibromopropane or
1,4-dibromobutane and cesium carbonate in DMFat
65 ꢀC to form an ether linkage yielding 2. Compound 2
was coupled with para-substituted 4-phenyoxyphenols
such as 8, 9, or 10 giving rise to 3. A standard TZD for-
mation protocol was applied to these mandelate deriva-
tives to give the final compounds 11–30.18 Synthesis of
substituted 4-phenoxyphenols is shown in Scheme 2. A
variety of para-substituted phenols 4 underwent an addi-
tion–elimination reaction with 4-fluorobenzadehyde in
refluxing N,N-dimethylacetamide to give 5. Subsequent
Baeyer–Villiger oxidation of the aldehydes yielded phe-
nols 6. From compound 6, allyl ether formation fol-
lowed by Claisen rearrangement and hydrogenation of
the resulting 2-allyl-4-phenoxyphenols gave 8. Synthesis
In general, we used the binding assay as a tool to identify
inactive compounds and viewed the results of trans-
activation assays as more meaningful estimation of func-
tional activity because of the nature of nuclear receptors.
Next, we became interested in studying the effects of R2
and R3 groups. In addition to improving the potency,
ꢀ
ꢀ
Scheme 1. (a) Br(CH2)3-4Br, Cs2CO3, DMF , 65 C, 74–80%; (b) 8, 9, 10, 4-phenoxyphenol, or 2-isobutyl-4-phenoxyphenol, Cs2CO3, DMF , 65 C,
71–82%; (c) SOCl2, Py rt 85–90%; (d) thiourea, NaOAc, EtOH refl. 70–79%; (e) aq–HCl, EtOH, refl. 75–83%.
Scheme 2. (a) K2CO3, N,N-dimethylacetamide, refl. 56–76%; (b) mCPBA 62–75%; (c) allylbromide, K2CO3, acetone 95%; (d) o-dichlorobenzene,
refl.; (e) H2, Pd/C 56–70% (two steps); (f) (i) TBS-Cl, imidazole, DMF; (ii) R4SO2Cl, Et3N, CH2Cl2; (iii) TBAF70% (three steps).

H. Koyama et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1801–1804
Table 1. In vitro human PPAR activities of compounds 11–30
1803
Compd
n
R1
R2
R3
Binding IC50 (mM)a
Transactivation EC50 (mM)b
a
d
g
a
d
g
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
1
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
nPr
nPr
iBu
H
H
H
H
H
H
H
H
50
>50
0.34
>50
2.0
>10
>10
0.16
>50
0.18
3.0
0.48
>15
>3
>3
>3
>3
0.3
1.0
H
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
FH
Cl
Me
OMe
nPr
H
H
H
H
H
H
H
H
H
H
H
>3
>3
>3
>3
>3
>3
>3
>3
>3
3
0.3
0.7
0.1
0.4
0.2
H
H
H
H
Me
CF3
iBu
c-Pentyl
Ph
F
Cl
OMe
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
0.88
6.0
>10
1.0
0.43
6.7
1.0
0.12
2.6
1.8
0.13
0.18
0.13
0.82
2.0
0.46
0.25
2.0
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>3
>3
0.03
>3
>50
3
>10
>3
>3
>50
>3
>3
>3
0.02
0.06
0.08
0.03
0.12
27
28
29
30
SO2Me
NHSO2Me
NHSO2-4-tolyl
5.7
0.25
>3
>3
>3
>3
0.5
0.02
Rosiglitazone
All data SDÆ15% (n=3).
aBinding affinities were measured using radioligands following published procedure.20
bAgonist activities were measured in PPAR-GAL4 chimeric COS-1 cells following published procedure.20 The EC50 refers to the concentration
yielding a 50% response relative to the standard. All compounds were full agonists.
we were interested in finding out if these positions are
metabolically labile, being ortho or para to the phenol
ethers. In light of the potency and selectivity, when the
data of compounds 11 and 15–19 are compared, introduc-
tion of substituents at R2 position increases binding affinity
to undesired PPARd, albeit not the functional activity. The
SAR studies of R3 group proved to be more fruitful.
Introduction of a hydrophobic group of an intermediate
size (22–28) improved the functional activity toward
PPARg up to 10-fold from the original compound 11.
compounds 11 and 15, it appears that the introduction of
a fluorine group at R2 position did not alter the clearance
in rats. The R2 position of 11 may not be a major meta-
bolic site. Compound 24 suffered from poor absorption
presumably due to the lipophilic phenyl group at R3
position. Compounds 25–28 generally had modest clear-
ance and fair to good oral bioavailability.
Finally, compounds with good functional activity and
desirable pharmacokinetic profiles were tested for efficacy
in db/db mouse: an obese animal model characterized by
severe insulin resistance and marked hyperglycemia.
The results are summarized in Table 3.
Table 2 summarizes the results of pharmacokinetic stud-
ies of selected compounds in rat. Comparing the data of
Table 3. In vivo efficacy of compounds 11, 15, and 25–28 in db/db
mice
Table 2. Pharmacokinetic profiles of compounds 11, 15, and 24–28 in
rat
Compd
Dose
(mpk)
Glucosea
correction
(%)
Triglycerideb
correction
(%)
Compd
iv (0.5 mg/kg)
Clpa
po (2 mg/kg)
nAUCc Fd
b
t1/2
(h)
(mL/min/kg)
(mM h)
(%)
11
15
25
26
27
28
10
10
10
10
10
10
5
77
43
78
86
67
86
62
67
46
74
50
71
80
67
78
55
74
52
11
15
24
25
26
27
2.3Æ0.2
2.9Æ0.3
2.8Æ0.1
3.6Æ0.4
2.9Æ0.3
1.1Æ0.2
2.1Æ0.2
2.7Æ0.5
2.3Æ0.6
1.7Æ0.3
2.2Æ0.2
2.1Æ0.3
5.4Æ0.9
2.8Æ0.5
2.8Æ0.2
1.2Æ0.3
13.8Æ1.7
7.43Æ2.5
0.70Æ0.2
5.97Æ0.8
6.70Æ1.0
11.7Æ0.5
11.8Æ2.4
16.4Æ6.9
89
63
6
63
58
39
84
85
28
Rosiglitazone
Rosiglitazone
28
Rosiglitazone
10
5
Fasted male Sprague–Dawley rats (n=3), which have been surgically
cannulated in the femoral artery and vein, received an intravenous
dose by bolus injection into the femoral vein, or an oral gavage dose.
Blood samples were taken serially at selected time points from the
Male db/db mice (12–13 weeks of age, n=7) and non-diabetic mice
(lean control, n=7) were provided ad libitum access to rodent chow
and water and received once-a-day oral dosing of the sodium-salts of
tested compounds by gavage with vehicle (0.25% methylcellulose) for
11 days. Blood was collected from the tail for measurement of plasma
levels of glucose and triglyceride. For further experimental details, see
ref 20.
femoral arterial cannula.
aClearance.
bHalf life.
cDose-normalized AUC.
dBioavailability.
aSDÆ15%.
bSDÆ20%.

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H. Koyama et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1801–1804
The glucose and triglyceride levels correction of the
tested compounds was generally in good accordance
with PPARg agonist activities and PK profiles of the
compounds. For example, compounds 11 and 15 have
the same level of PPARg transactivation activity but
compound 15 showed slightly weaker efficacy because
of its lower exposure (nAUC). Compounds 11 and 28
have essentially the same PK profiles but compound 28
is more efficacious because of its superior PPARg agonist
activity. Compound 28 exhibited higher levels of glucose
and triglyceride correction to rosiglitazone despite its
weaker functional activity in vitro. This might be perhaps
caused by the longer half life (t1/2) of 28.
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In conclusion, we have identified a series of novel 5-aryl-
thiazolidine-2,4-diones as potent and selective PPARg
agonists. In the SAR studies, this class of compounds
generally maintained a high level of receptor subtype
(PPARg) selectivity and exhibited good oral efficacy in
db/db mice. One such compound 28 exhibited compar-
able levels of glucose and triglyceride correction to
rosiglitazone in the db/db mouse studies.
15. Santini, C.; Berger, G. D.; Han, W.; Mosley, R.; MacNaul,
K.; Berger, J.; Doebber, T.; Wu, M.; Moller, D. E.; Tolman,
R. L.; Sahoo, S. P. Bioorg. Med. Chem. Lett. 2003, 13, 1277.
16. Adams, A. D.; Von Langen, D.; Tolman, R. L.; Koyama,
H. US Patent 6,090,839, July 18, 2000.
Acknowledgements
The authors would like thank Margaret Wu, John
Venture, Chhabi Biswas, and Neelam Sharma for their
support in biological evaluation of compounds.
17. Adams, A. D.; Von Langen, D.; Koyama, H.; Tolman, R.
L. US Patent 6,160,000, Dec. 12, 2000.
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19. A small number of closely related compounds with ethylene-
1,2-bis-ether linkages (n=0) were also synthesized and eval-
uated. However, they generally showed significantly reduced
binding affinity to PPARg as well as other receptor subtypes.
20. Berger, J.; Leibowitz, M. D.; Doebber, T. W.; Elbrecht,
A.; Zhang, B.; Zhou, G.; Biswas, C.; Cullinan, C. A.; Hayes,
N. S.; Li, Y.; Tanem, M.; Venture, J.; Wu, S. M.; Berger,
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