5-Aryl thiazolidine-2,4-diones: Discovery of PPAR dual α/γ agonists as antidiabetic agents

Article abstract of DOI:10.1016/S0960-894X(03)00505-5

A novel series of 5-aryl thiazolidine-2,4-diones based dual PPARα/γ agonists was identified. A number of highly potent and orally bioavailable analogues were synthesized. Efficacy study results of some of these analogues in the db/db mice model of type 2 diabetes showed them superior to rosiglitazone in correcting hyperglycemia and hypertriglyceridemia.

Full text of DOI:10.1016/S0960-894X(03)00505-5

Bioorganic & Medicinal Chemistry Letters 13 (2003) 2795–2798
5-Aryl Thiazolidine-2,4-diones: Discovery of PPAR Dual ꢀ/ꢁ
Agonists as Antidiabetic Agents
Ranjit C. Desai,a,* Wei Han,a Edward J. Metzger,a Jeffrey P. Bergman,a
Dominick F. Gratale,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, 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 13 February 2003; accepted 17 April 2003
Abstract—A novel series of 5-aryl thiazolidine-2,4-diones based dual PPARa/g agonists was identified. A number of highly potent
and orally bioavailable analogues were synthesized. Efficacy study results of some of these analogues in the db/db mice model of
type 2 diabetes showed them superior to rosiglitazone in correcting hyperglycemia and hypertriglyceridemia.
# 2003 Elsevier Ltd. All rights reserved.
Type 2 diabetes is a debilitating disease characterized by
hyperglycemia due to insulin resistance (IR) in the liver
and peripheral tissues. In the US, approximately 16
million people suffer from type 2 diabetes and an addi-
tional 14 million have impaired glucose tolerance.1 This
disease is associated with a high degree of morbidity
and mortality. Several epidemiological and clinical
studies implicate NIDDM with dyslipidemia, acceler-
ated arthrosclerosis and hypertension resulting in the
increased incidences of renal failure, heart attacks and
strokes.2 The primary therapy for NIDDM include life-
style modifications with emphasis on caloric restrictions,
exercise and oral hypoglycemic agents such as sulfonyl-
ureas and biguanides. Sulfonylureas which stimulate
insulin release from pancreatic b-cells are often only
moderately effective and can induce hypoglycemia,
weight gain and are subject to both primary and sec-
ondary failure.3,4 Therefore, an attractive approach
would be to attenuate IR without stimulating insulin
secretion.
emerged as a new class of antidiabetic agents. The
TZDs are a group of pharmacological agents that
enhance insulin action (insulin sensitizers) and promote
glucose utilization in peripheral tissues.
In the US troglitazone (Rezulin)6 was the first drug
approved in the class followed by rosiglitazone (Avandia)7
and pioglitazone (Actos).8
Following the initial report of a novel antidiabetic agent
ciglitazone5 from Takeda laboratories, the PPAR
gamma agonists (benzylthiazolidinedione, TZDs) have
Although their exact mechanism of action has not been
completely elucidated, it has been demonstrated that
TZDs elicit their pharmacological actions by binding
and activating nuclear receptor PPARg.9,10 PPARg is
mainly expressed in insulin sensitive tissues such as adi-
pocytes and to a lesser extent in muscle and liver. It is
*Corresponding author. Fax: +1-732-594-9556; e-mail: ranjit_desai@
merck.com
0960-894X/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00505-5

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R. C. Desai et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2795–2798
hypothesized that their activation by TZDs affect the
expression of a number of genes involved in lipid and
glucose metabolism and preadipocyte differentia-
tion.11,12 Both rosiglitazone and pioglitazone are potent
agonists of PPARg. Recently, a group of Japanese sci-
entists at Kyorin Pharmaceutical Co. have disclosed
KRP-297, a novel antidiabeic agent.13 Unlike rosiglita-
zone and pioglitazone, KRP-297 is the first published
example of PPARg and PPARa dual agonist. In a
comparative study in ob/ob mice, KRP-297 demon-
strated superior efficacy to pioglitazone in reducing
glucose, insulin and triglyceride levels.13
The results of the in vitro activities of compounds 12–26
are summarized in Table 1. In contrast to the para
linked analogue 11, the very first synthesized meta
linked analogue 12 displayed potent activity at both the
PPARa and PPARg receptors in the binding and trans-
activation assays. Encouraged by this initial result, we
decided to further pursue this series. However, before
undertaking further work in this series, it was essential
that, as in the case of the para linked series, we establish
the need for the three carbon methylene tether and
n-propyl group at R1 for the selectivity and potency.16
As seen for the data for compound 13, the absence of
propyl group furnished a potent but a non-selective
PPAR agonist, while extending the tether with an addi-
tional methylene group as in the case of analogue 14
gave PPARg selective agonist. With these requirements
satisfied, a series of R2 substituted analogues 15–23 were
synthesized with a dual objective of probing SAR and
also to block a site of potential metabolic oxidation. In
general, lipophilic substituents at R2 showed 3- to 10-
fold reduced affinity for PPARg receptor and weak
activity at the PPARa receptor. With the introduction
of chloro and fluoro substituents, as in the case of
compounds 20 and 21, a trend towards dual PPARa/g
activity was restored though there was a some loss
PPARa is found primarily in the liver and is the molec-
ular target for the fibrate class of lipid-modulating
drugs.14 Considering the potential benefits of fibrates in
the treatment of coronary disease in diabetic patients,15
the combined profile of dual PPARa/g agonist(s) would
offer an attractive option for the management of
hyperglycemia and hypertriglyceridemia. We have
recently reported a novel series of 5-aryl thaizolidene-
2,4-diones as selective PPARg agonists as represented
with 1116 (Fig. 1). Unlike the classical PPAR gamma
agonists, 11 has thiazolidene-2,4-dione ring directly
attached to the phenyl ring. Also, a common feature in
this series is the para relationship between the thiazoli-
dene-2,4-dione ring and the 3-carbon methylene linker.
With the objective of further probing the SAR, we
decided to explore the corresponding meta-linked TZD
analogues typified by 12 (Fig. 1). Described below are
the results of this investigation.
The general synthesis of 5-aryl thaizolidene-2,4-diones is
described in Scheme 1. Thus, mandelate 1 was alkylated
with 1,3-dibromoropropane to give 2. Coupling of 2
with appropriate phenol 8 furnished 3. Application of
the standard TZD-forming protocol to 3 provided final
compounds 12–26.17 The synthesis of substituted 4-
phenoxy phenols 8 is shown in Scheme 2. A variety of
phenols (4) underwent an addition–elimination reaction
with 4-fluorobenzaldehyde in DMA to give 5. Bayer-
Villager oxidation followed by allyl ether formation,
Claisen rearrangement and finally hydrogenation of the
olefin transformed 5 to 8.
Scheme 1. (a) Br(CH2)3À4Br, Cs2CO3, DMF, 65 ꢀC; (b) 8, Cs2CO3,
DMF, 65 ꢀC; (c) SOCl2, Py, rt; (d) thiourea, NaOAc, EtOH, refl; (e)
aqHCl, EtOH, refl.
Scheme 2. (a) K2CO3, N,N-dimethylacetamide, refl; (b) mCPBA;
(c) allylbromide, K2CO3, acetone; (d) o-dichlorobenzene, refl; (e) H2,
Pd/C.
Figure 1. p-Aryl TZD versus m-aryl TZD.

R. C. Desai et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2795–2798
Table 1. In vitro human PPAR activities of compounds 11–26
2797
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
1
1
2
1
1
1
1
1
1
1
1
1
1
1
1
nPr
nPr
H
H
H
H
>50
>10
>10
0.19
0.18
>3
0.026
ND
ND
>3
ND
ND
>3
>3
0.3
0.014
ND
ND
0.167
ND
ND
0.123
0.353
0.165
0.085
0.069
0.023
0.047
0.027
0.106
0.02
0.028
0.047
0.057
0.076
0.195
0.17
0.335
0.291
0.33
0.226
0.073
0.077
0.3
>3
ND
ND
>3
ND
ND
>3
>3
>3
>3
>3
>3
>3
>3
>50
>3
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
H
iPr
tBu
iBu
c-Pentyl
Ph
Cl
F0.028
OMe
OH
Cl
>5
2.1
>10
>10
2.0
>10
0.1
3
>50
>50
>50
>50
>50
>50
>5
>3
0.18
0.066
>3
>3
0.082
0.156
0.085
>3
2.55
0.95
0.068
0.162
>10
3.8
0.03
Cl
Me
>50
>50
>50
>50
0.064
0.056
0.078
0.25
Cl
FMe
0.112
Rosiglitazone
>50
aBinding affinities were measured using radioligands following published procedure.19
bAgonist activities were measured in PPAR-GAL4 chimeric COS-1 cells following published procedure.18 The EC50 refers to the concentration
yielding a 50% response relative to the standard. ND, not run.
Table 2. Pharmacokinetic profiles of compounds 12, 15, 20, 21, 24,
and 26 in SD rats
Table 3. In vivo efficacy of selected dual agonists in db/db mice
Compd
Dose
(mpk)
Glucose
correction (%)
Triglyceride
correction (%)
Compd
iv (0.5 mg/kg)
po (2 mg/kg)
Clpa (mL/min/kg) t1/2b (h) nAUCc (mMh) Fd (%)
12
20
21
24
10
10
10
10
10
10
91Æ4.7
86Æ7.5
90Æ4.6
79Æ5.9
78Æ8.5
67Æ6.2
67Æ3.9
68Æ1.4
76Æ6.0
77Æ3.5
69Æ5.5
74Æ3.3
12
15
20
21
24
26
9.5Æ0.3
6.1Æ0.8
1.5Æ0.3
3.3Æ2.0
2.9Æ0.1
1.3Æ0.2
2.2Æ1.4
3.3Æ0.2
1.2Æ0.3
21.78Æ0.9
0.3Æ0.04
1.5Æ0.22
3.3Æ0.14
0.8Æ0.24
0.6Æ0.15
16.4Æ6.9
62
6
9.7Æ1.7
44
66
19
20
85
26
Rosiglitazone
10.2Æ0.42
7.9Æ1.1
10.5Æ0.37
2.7Æ0.5
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.18
Rosiglitazone
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
femoral arterial cannula.
aClearance.
bHalf life.
glucose and triglycerides correction correlated well with
the functional activity and PK profile of the compound.
For example, compounds 12 and 21 are essentially
identical in their efficacy, whereas analogues 24 and 26
are comparatively slightly less efficacious, potentially
due to lower exposure and short half life. It is interest-
ing to note that despite much lower exposure (>25-fold)
and around 4-fold lower bioavailability, both 24 and 26
demonstrated comparable blood glucose correction with
respect to rosiglitazone.
cDose-normalized AUC.
dBioavailability.
(10-fold) in functional activity. Finally, adding sub-
stituents at R3 as in examples 24–26 did not alter the
PPARa/g selectivity.
The pharmacokinetic study data on selected analogues
is recorded in Table 2. Compound 12 has an overall
superior PK parameters with 62% bioavailability and
dose normalized AUC of 21.78 mM h in rats. The cor-
responding fluoro substituted analogue 21 did not show
any decrease in the clearance possibly indicating that R2
position may not be a major site for metabolic oxida-
tion in rats. Surprisingly, the normalized AUC for this
analogue was about 7-fold less when compared to 12.
Based on the functional activity and desirable PK
parameters, compounds 12, 20, 21, 24, and 26 were
selected for efficacy studies in highly insulin resistant,
obese and hyperglycemic db/db mice as described by
Berger et al.18 As seen from the data in Table 3, the
In summary, we have identified a potent series of 5-aryl
thaizolidene-2,4-diones class of dual PPARa/g agonists.
Changing the point of attachment of thaizolidene-2,4-
dione ring onto the phenyl ring from the para to meta
orientation with respect to the three carbon methylene
tether transformed PPARg selective agonists to dual
PPARa/g agonists. A number of highly potent and
orally active analogues were synthesized. In the db/db
mice model of diabetes, these compounds displayed
superior efficacy when compared to the benchmark
rosiglitazone.

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10. Willson, T. M.; Cobb, J. E.; Cowan, D. J.; Wiethe, R. W.;
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