Design and synthesis of the first generation of dithiolane thiazolidinedione- and phenylacetic acid-based PPARγ agonists

Article abstract of DOI:10.1021/jm0510880

A series of novel derivatives of potent antioxidant vitamin, α-lipoic acid, and related analogues were designed, synthesized, and evaluated for their PPARγ agonist activities. Compounds 9a and the water soluble analogue 11e were found to be potent PPARγ agonists. Compound 9a appeared to have a significant role in improving insulin sensitivity and reducing triglyceride levels in fa/fa rats as well as inhibited proliferation of a variety of normal and neoplastic cultured human cell types. These novel compounds may prove efficacious not only in the treatment of Type 2 diabetes, but also atherosclerosis, prevention of vascular restenosis, and inflammatory skin diseases.

Full text of DOI:10.1021/jm0510880

4072
J. Med. Chem. 2006, 49, 4072-4084
Design and Synthesis of the First Generation of Dithiolane Thiazolidinedione- and Phenylacetic
Acid-Based PPARγ Agonists
Amar G. Chittiboyina,† Meenakshi S. Venkatraman,† Cassia S. Mizuno,† Prashant V. Desai,† Akshay Patny,†
,X
Stephen C. Benson,‡ Christopher I. Ho,‡ Theodore W. Kurtz,§,X Harrihar A. Pershadsingh,|, and Mitchell A. Avery*,†
Department of Medicinal Chemistry and Laboratory for Applied Drug Design and Synthesis, School of Pharmacy, UniVersity of Mississippi,
UniVersity, Mississippi 38677, Department of Biological Sciences, California State UniVersity, Hayward, California 94542, Department of
Laboratory Medicine, UniVersity of California, San Francisco, California 94122, Department of Family Medicine, Kern Medical Center,
Bakersfield, California 93311, Department of Family Medicine, UniVersity of California, IrVine, California 92668, and Drug DiscoVery,
Bethesda Pharmaceuticals, Inc., Bakersfield, California 93311
ReceiVed October 26, 2005
A series of novel derivatives of potent antioxidant vitamin, R-lipoic acid, and related analogues were designed,
synthesized, and evaluated for their PPARγ agonist activities. Compounds 9a and the water soluble analogue
11e were found to be potent PPARγ agonists. Compound 9a appeared to have a significant role in improving
insulin sensitivity and reducing triglyceride levels in fa/fa rats as well as inhibited proliferation of a variety
of normal and neoplastic cultured human cell types. These novel compounds may prove efficacious not
only in the treatment of Type 2 diabetes, but also atherosclerosis, prevention of vascular restenosis, and
inflammatory skin diseases.
Chart 1. Structures of Representative Thiazolidinedione
PPARγ Agonists
Introduction
Type 2 diabetes, a disease which has attained epidemic
proportions in the United States and other regions of the world,
is a condition in which target tissues develop resistance to the
metabolic effects of insulin, impairment of glucose and lipid
metabolism, and long term microvascular and macrovascular
complications, resulting in potentially fatal cardiovascular events
and renal failure. The thiazolidinediones (TZDs, also known
as “glitazones”) are insulin-sensitizing pharmacological agents
that reduce insulin resistance and preserve islet â-cell function
in Type 2 diabetes. These effects are largely mediated through
the ability of these compounds to activate peroxisome prolif-
erator-activated receptor-γ (PPARγ), a nuclear transcription
factor that controls genetic programs involved in glucose and
lipid homeostasis, energy metabolism, adipocyte differentiation,
and maturation. Thus, PPARγ is the principal molecular target
in the development of insulin-sensitizing antidiabetic agents.1
Several classes of compounds are known to activate PPARγ,
which includes a putative natural ligand composed of a long
chain fatty acid, cyclopentenone prostaglandins, thiazolidinedi-
ones, phenylacetic acids, and tyrosine-based compounds.1
Troglitazone, the first member of the class to be approved
for clinical use, was removed from the market because of its
association with rare, idiosyncratic life-threatening hepatitis.2
Two later approved TZDs, pioglitazone and rosiglitazone (Chart
1), appear not to have this problem. Several TZDs and non-
TZD PPARγ agonists are under intensive clinical development
for the treatment of Type 2 diabetes and other components of
the metabolic (insulin resistance) syndrome, including hyper-
triglyceridemia, hypertension and increased cardiovascular risk.
Notwithstanding the hepatitis seen with troglitazone, the TZDs
have proven to be generally safe compounds. In addition, several
phenyl acetic and propionic acid derivatives have also been
reported to activate PPARγ both in vitro and in vivo.3-8
However, in animal and human studies, both TZD and non-
TZD full PPARγ agonists have been shown to cause significant
fluid retention, leading to an increase in intravascular volume
by approximately 15%.9 This is especially problematic in the
target population for which these drugs are used. According to
the recently published NCEP-ATP III Guidelines,10 diabetes is
designated a coronary heart disease (CHD) risk equivalent.
Therefore, TZDs further predispose diabetics to significant risk
of volume overload, systemic edema, and exacerbation of
congestive heart failure. Thus, there is a substantial need for
development of both TZD and non-TZD insulin-sensitizing
PPARγ agonists that lack the adverse effect of fluid retention.
R-Lipoic acid (1,2-dithiolane-3-pentanoic acid), a potent
antioxidant and free radical scavenger, is widely used for the
treatment of aging skin and has also been reported to have
beneficial effects on glucose metabolism11 and blood pressure.12
In eukaryotic dehydrogenases, it is covalently bound to a lysine
residue. Exogenously supplied lipoic acid is taken up readily
by a variety of cells and tissues where it is reduced rapidly to
dihydrolipoic acid. Additionally it has been reported to have
antiinflammatory and cytoprotective effects.13
* Corresponding author. Phone: 662-915-5879; Fax: 662-915-5638.
E-mail: mavery@olemiss.edu.
† University of Mississippi.
‡ California State University.
§ University of CaliforniasSan Francisco.
| Kern Medical Center.
Herein we report the design, synthesis, and biological
evaluation of a unique class of hybrid lipoic-TZD derivatives,
University of CaliforniasIrvine.
X Bethesda Pharmaceuticals.
10.1021/jm0510880 CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/20/2006

PPARγ Agonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14 4073
Scheme 1a
a Reagents and conditions: (a) Ph3P, DIAD, THF, 0 °C to room temperature, 3 h, 3a (58%), 3b (61%); (b) 1,3-thiazolidine-2,4-dione 4, benzoic acid,
piperidine, reflux, 6 h, 5a (89%), 5b (93%); (c) Mg, methanol, 0 °C to room temperature, 4 h, 6a (78%), 6b (80%); (d) 4 M HCl in dioxane, 0 °C, 30 min
5a (98%), 5b (98%).
Scheme 2a
a Reagents and conditions: (a) i-PrOCOCl, Et3N, DCM, 3 h, 9a (72%), 9b (64%), 9c (56%); (b) alane-dimethylamine complex, THF, 0 °C, 15 min; (c)
I2, NaHCO3, EtOAc (47% two steps); (d) DL-tartaric acid, THF, rt, 12 h, 92%; (e) NaBH4, THF-H2O, 0 °C, 1 h, 86%.
some of which were shown to induce transactivation of human
PPARγ in the low nanomolar range, and describe aspects of
their structure-activity relationship (SAR) with respect to their
ability to transactivate PPARγ.14-18 Results of molecular
modeling studies explaining the SAR are also presented.
Finally, mono and bis-Boc-glycinates 11h and 11g were
prepared from 11 by coupling with Boc-glycine. Deprotection
and HCl salt formation occurred upon exposure of 11g to
anhydrous HCl to give 11e. The mono glycinate (11h) was
acylated and then deprotected-salted to give 11f.
To study the effect of the spacer between the amide nitrogen
and the phenoxy acid group,26 derivatives with two and three
methylene spacers, 18a and 18b, respectively, were synthesized
as described in Scheme 5. These isosteres of TZD were prepared
by coupling phenol 13 with alcohol 14 using diisopropyl
azodicarboxylate (DIAD) and triphenylphosphine. Removal of
the BOC group was accomplished using HCl in dioxane to
afford the dialkylammonium chloride 16. Coupling of this amine
with lipoic acid using a mixed anhydride method in methylene
chloride provided the ester-amide 17.
Hydrolysis of the ester group of 17 employing sodium
hydroxide furnished the acid 18 (Scheme 5). To study the effect
of the spacer between the amide nitrogen and the phenoxy acetic
acid group, derivatives with two (18a)- and three (18b)-
methylene spacers were synthesized (Scheme 5) in routine
fashion as in the prior scheme.
Of related interest, the effect of removal of the ethoxy spacer
between the amide and the benzene ring could be studied by
synthesis of compound 24 in which the amide nitrogen atom
was directly attached to the phenyl ring. To achieve this goal,
the aniline derivative 2127 was prepared from 4-hydroxybenz-
aldehyde 2 as described in Scheme 6. The 4-hydroxybenzal-
dehyde 2 was alkylated with the chloroacetamide 19 to give
aryl ether 20. Treatment of the amide 20 with KOH in toluene
led to the 4-N-methylaminobenzaldehyde 21 (Mechanism
provided as Scheme A in Supporting Information). The aldehyde
21 was then condensed with 2,4-thiazolidinedione 4 to give 22,
and reduction of the double bond using Mg metal in methanol
at room temperature led to the saturated thiazolidinedione 23.
Chemistry
The thiazolidinediones 7a and 7b were prepared according
to a reported procedure19 by coupling 4-hydroxybenzaldehyde
2 with Boc-protected alcohol 1 under Mitsunobu conditions to
give aldehyde 3 (Scheme 1). Condensation of 3 with 2,4-
thiazolidinedione in the presence of piperidine20 gave the
benzylidene 5, which was reduced to the saturated 2,4-
thiazolidinedione 6 using Mg/MeOH.21 Removal of the Boc
protecting group was accomplished employing anhydrous HCl
in dioxane22 to furnish the amine hydrochloride 7. Condensing
the amine 7 with acid 8 via the mixed anhydride gave amide
9a or 9b in which R ) Me or H, respectively (Scheme 2).
Treatment of 9a with alane-N,N-dimethylethylamine [C2H5N-
(CH3)2.AlH3] complex23 led to reduction of the amide carbonyl
as well as the dithiolane ring. Reoxidation24 of the dithiol to
the disulfide (dithiolane ring) could be achieved using iodine
and sodium bicarbonate to give the amine 10. Reduction of the
dithiolane ring S-S bond alone was readily achieved using
sodium borohydride25 in THF:H2O (10:1) furnishing the dithiane
11.
To improve the pharmacokinetic profile of compound 9a (vide
infra), prodrugs were synthesized as described in Scheme 3.
Starting with the dithiol 11, treatment with succinic anhydride
led to a mixture of bis acids 11b along with the primary thioether
mono-acid 11c. The remaining free thiol moiety of 11c could
be differently reacted then to furnish mixed esters-acids such
as 11d. Alternatively, the hydrophilic diacetate 11a was readily
furnished upon exposure of 11 to acetic anhydride.

4074 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14
Chittiboyina et al.
Scheme 3a
a Reagents and conditions: (a) Ac2O (2 equiv), pyridine, rt, 2 h, 11a (88%), 11d (76%); (b) succinic anhydride (1.2 equiv), pyridine, rt, 8 h, 11c (51%)
and 11b (13%); (c) BocNHCH2CO2H, DCM, EDAC, HOBt, rt, 12 h, 11g (72%), 11h (21%); (d) 4 N HCl in dioxane, 0 °C, 30 min 11e (76%), 11f (45%,
two steps).
Scheme 4a
a Reagents and conditions: (a) MeOH, H2SO4, reflux, 6 h, 95%; (b) Ph3P, DIAD, THF, 0 °C to room temperature, 3 h, 15a (69%), 15b (63%); (c) 4 M
HCl in dioxane, 0 °C, 30 min, 16a (93%), 16b (87%).
Scheme 5a
hydrophobic and is buried mainly in the bottom half of the
ligand binding domain (Figure 1).28 In the cocrystal structure
of rosiglitazone with PPARγ LBD (PDB id: 2PRG),28 the TZD
headgroup of rosiglitazone appears to be oriented toward the
left-most part of this Y-shaped cavity and forms several primary
and secondary hydrogen bonds with critical residues of the AF-2
helix of PPARγ including His323, His449, and Tyr473 (Figure
2). It has been clearly illustrated that the presence of these
hydrogen bonds are crucial for agonist activity of PPARγ
ligands.28 It is believed that in response to these hydrogen
bonding interactions, the AF2 helix closes onto the ligand-
binding site and establishes a transcriptionally active form of
the receptor which further recruits a coactivator protein to
effectively stimulate gene transcription. Rosiglitazone appears
to occupy roughly 40% of the ligand binding domain, while
the rest of the space, largely in the downward hydrophobic arm
of the Y-shaped pocket of the PPARγ receptor, remains
unoccupied (Figure 1).28 The large size and volume (∼1300
a Reagents and conditions: (a) rac-lipoic acid, i-PrOCOCl, Et3N, DCM,
3 h, 17a (79%), 17b (69%); (b) NaOH, MeOH, H2O, rt, 3 h, 18a (97%),
18b (93%).
Coupling of the amine 23 with lipoic acid using hydroxy
benzotriazole (HOBT) and N-(3-dimethylaminopropyl)-N′-eth-
ylcarbodiimide hydrochloride (EDAC) furnished the target
amide 24.
Results and Discussion
The PPARγ ligand binding domain (LBD) is a Y-shaped
cavity extending from the C-terminal helix to the â-sheet lying
between helices H3 and H6. This latter region is mostly
Scheme 6a
a Reagents and conditions: (a) K2CO3; (b) KOH, toluene; (c) 1,3-thiazolidine-2,4-dione 4, benzoic acid, piperidine, reflux, 6 h, 89%; (d) Mg, methanol,
0 °C to room temperature, 12 h, 73%; e) rac-lipoic acid, TEA, DCM, EDAC, HOBt, rt, 12 h, 78%.

PPARγ Agonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14 4075
Table 1. Transactivation of PPARγ by Novel TZD and Phenyl Acetic
Acid Derivatives
compound
9a
9b
9c
R1
X
Y
m
n
R
EC50 (µM)
TZD
TZD
TZD
TZD
TZD
TZD
CO2Me
CO2Me
CO2H
CO2H
-
H
H
H
H
H
H
Cl
Cl
Cl
Cl
-
-
-
O
O
O
H2
H2
H2
O
O
O
2
2
2
2
2
2
2
3
2
3
-
-
-
3
3
1
3
3
3
3
3
3
3
-
-
-
Me
H
0.015
10
Me
Me
Me
Me
Me
Me
Me
Me
-
i.aa
10
28.00
11.05
11.05
i.a
18.49
i.a
12.30
i.a
0.076
0.55
HCl salt of 10
10a
17a
17b
18a
18b
24
O
-
rosiglitazone
pioglitazone
-
-
-
-
-
-
a i.a: inactive up to 30 µM.
Figure 1. The ligand binding domain of the PPARγ receptor with
cocrystallized rosiglitazone (colored by atom type). The receptor protein
is shown as simplified ribbons (yellow), and the binding pocket is
outlined as cyan-colored mesh. The binding pocket (mesh) was
calculated using the Binding Site Analysis module in InsightII (2000).19
binding affinity of the ligands toward the receptor. Additionally,
the presence of the lipoic acid moiety might attribute additional
antiinflammatory and cytoprotective effects and may be related
to its ability to reduce oxidative stress. On the basis of these
considerations, several TZD and phenyl acetic acid derivatives
were synthesized and tested for their ability to transactivate the
PPARγ receptor. The results of the transactivation assay are
presented in Table 1.
When compared to rosiglitazone and pioglitazone, the two
most widely prescribed drugs for the treatment of Type 2
diabetes, compound 9a was 5 and 37 times more potent,
respectively, in the transactivation assay. Surprisingly, the
replacement of a methyl group on the amide nitrogen by
hydrogen (9b) resulted in 1000-fold loss in activity (10 µM).
Reduction of the amide functionality in 9a to the amine 10
reduced the activity to the micromolar range as well. Reducing
the chain length between the amide carbonyl and [1,2]-dithiolane
ring from four methylenes as in 9a to two methylenes as in 9c
abolished activity. Modification of the 2,4-thiazolidinedione by
replacement with an isosteric acid/ester group and introduction
of chlorine on the aromatic ring gave compounds 17a and 18a
with loss of activity. Interestingly, introduction of an additional
methylene group between the nitrogen and oxygen gave
compounds 17b and 18b with activity in the range of 12-18
µM. Finally, N-acylanilide 24 was not detectably active.
To understand the reasons for this observed SAR, the
compounds were docked in the cocrystal structure with rosigli-
tazone removed, using the PPARγ ligand binding domain (PDB
id: 2PRG).28 In general, docking studies for most of the
compounds of this series revealed a binding mode very similar
to that of rosiglitazone as shown in Figure 2. In the TZD
headgroup, the phenyl ring as well as the two methylene linkers
in most of the molecules adopted a similar conformation to that
of rosiglitazone in the crystal structure. Compounds exhibiting
transactivation of PPARγ were found to retain important
hydrogen bonds with the AF-2 helix residues that are crucial
for the activity of PPARγ agonists.28 The N-methyl group, also
present in rosiglitazone, was found to have favorable hydro-
phobic interactions with residues Ile341, Val339, and Leu333
(Figure 2). The carbonyl group next to the N-methyl also
appeared to form a potentially important hydrogen bond with
the backbone amide of Ser342 (vide supra). The hydrophobic
dithiolane moiety was found to fit in the downward arm of the
Figure 2. The proposed binding mode of 9a (green) superimposed on
the cocrystal structure of rosiglitazone (magenta) in the PPARγ LBD.
The protein backbone is represented as a ribbon (cyan). Important
residues of the AF-2 helix are shown in yellow. Important hydrogen
bonds are illustrated as green dotted lines. Hydrophobic residues
surrounding the N-methyl group of 9a are shown in red.
Å3) of the LBD explains its affinity to ligands of diverse sizes
ranging from endogenous substrates such as fatty acid deriva-
tives to synthetic ligands such as fibrates and thiazolidinedione
(TZD) derivatives.28 Recently, several 5-substituted 2-benzoyl-
aminobenzoic acid (2-BABAs) PPARγ modulators have been
reported to exert their effect without direct interaction with
residues of the AF-2 helix. In fact, the X-ray crystal structures
of these compounds with PPARγ have revealed a unique binding
mode involving hydrogen bonding interactions with Ser342,29,30
an amino acid residue occupying a different arm of the Y-shaped
LBD.
On the basis of its hydrophobic nature and the ability to
activate the PPAR receptors,31 R-lipoic acid was chosen as a
fragment for coupling with a common TZD pharmacophore to
exploit the downward hydrophobic portion of the Y-pocket. The
additional hydrophobic interaction is expected to improve the

4076 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14
Chittiboyina et al.
Figure 4. The proposed binding mode of 24 (magenta) in the PPARγ
LBD superimposed on that of 9a (yellow). Only important residues
(colored by atom type) of the protein are shown. Hydrogen bonds are
denoted as green dotted lines.
Figure 3. The proposed binding mode of 9a, based on docking studies,
reveal major hydrophobic interactions with the PPARγ LBD. For
comparison, 9a is superimposed on the receptor bound conformation
of rosiglitazone (orange). Hydrophobic residues Leu270, Ile281,
Gly284, Cys285, Ile341, and Met348 located in the downward arm of
Y pocket interacting with 9a are illustrated using CPK space filling
models (magenta).
containing analogues. The increased distance between amide
carbonyl and backbone hydrogen of Ser342 also results in loss
of a hydrogen bond with this residue. These factors taken
together would appear to explain the inability of 24 to induce
transactivation of PPARγ.
Modification of the 2,4-thiazolidinedione by replacement with
isosteric acid/ester group and introduction of chlorine on the
aromatic ring gave compounds 18a and 18b. On the basis of
docking studies, the terminal carboxylate group in 18a did not
appear to form hydrogen bonds with all of the critical residues
of the AF-2 helix. Lack of a putatively crucial tripartite hydrogen
bonded group interaction might be one of the plausible reasons
for the loss of activity of this compound. Interestingly, introduc-
tion of one additional methylene group between the side chain
N and O produced the corresponding analogue 18b having value
of 12.30 µM activity. Docking of this compound revealed that
the terminal carboxylate group was pushed forward toward the
critical residues of the AF-2 helix, allowing 18b to retain the
important hydrogen bonds responsible for activation of the
PPARγ receptor.
To summarize the SAR, the optimum spacer between N and
O were found to be two methylenes for TZD derivatives and
three methylenes in the case of phenyl acetic acid derivatives.
We also found that a tetramethylene moiety was the optimal
spacer between the amide carbonyl and the 1,2-dithiolane
moiety. In the present series, compounds having a TZD as a
headgroup were more potent than the corresponding carboxylate
derivatives. The N-methylamide moiety seems to be important
but not absolutely essential for potent agonist activity. On the
basis of docking comparisons with this PPAR-γ activity, it
appears for this class that an L-shaped bend is enforced by the
amide group. Optimal lengths for the arms of this “L” appear
to be approximately 10 Å. More detailed SARs at this position
are in progress.
The prodrug approach is commonly used to improve phys-
icochemical, biopharmaceutical, and drug delivery properties
of therapeutic agents. Ideally, an inactive pro-moiety is co-
valently attached to the parent molecule, and the resulting
prodrug is converted to the parent drug in the body before it
exhibits its pharmacological effect.35,36 Compound 9a has very
low solubility in water (39 µg/mL). To overcome this problem,
the S-S bond was reduced to the dithiol derivative 11 which
showed considerable activity. Derivatization to give mono and
dithio-amides gave more soluble derivatives (11a-f) that in
many cases could be safely assumed to be more soluble and
therefore more bioavailable candidates than the aqueously
Y pocket and was involved in hydrophobic interactions with
surrounding residues such as Cys285, Gly284, Ile281, Leu270,
Met348, and Ile341. These hydrophobic interactions appear to
improve the binding free energy of the ligand receptor complex.
Such interactions have been proposed to contribute toward
PPARγ binding affinity for a series of propionic acid deriva-
tives.32 However, it should be mentioned here that the most
active compound of this series was as potent as rosiglitazone
while compound 9a in the present series is 5 times more potent
than rosiglitazone.
Compound 9a appears to meet all these requirements and is
the most potent compound of the series. All the crucial hydrogen
bonds with the AF-2 helix residues were found to be conserved
(Figure 2). Additionally, hydrophobic interactions of the ap-
pended dithiolane moiety (Figure 3) and the presence of a
Ser342 hydrogen bond (Figure 2) appear to be significant
contributors toward its high potency. Compound 9b, which lacks
the N-methyl group, appears to lose some of the important
hydrophobic interactions with surrounding residues such as I341,
V339, and L333. The N-methyl group in rosiglitazone as well
as 9a was found to be similarly pointing upward, and its
presence seemed essential for retaining the activity of the amide
series. Similar behavior has also been observed for certain oxime
analogues containing a 5-benzyl-2,4-thiazolidinedione moi-
ety,33,34 where removal of the N-methyl group from the
compound was found to retard binding to the PPARγ receptor
compared to the bioactive methyl analogue. Therefore, it might
be hypothesized that the lower activity of 9b could be due to
the loss of hydrophobic interactions of the N-methyl group with
complementary residues in the portion of the receptor. An
additional explanation could include the probable metabolic
differences between [N(H)CdO vs N(CH3)CdO], the former
amide being more readily cleaved by peptidases and thereby
deactivated (7 has low potency).
Removing the linker between the nitrogen and the phenyl
ring in 9a furnished compound 24, which is three atoms shorter
than the prototype compounds of the series. In the binding mode
proposed by the docking studies, the TZD ring of 24 was not
able to interact with the residues of the AF-2 helix as clearly
seen in Figure 4. This leads to loss of the critical hydrogen
bonds paramount for the PPARγ receptor activity of the TZD

PPARγ Agonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14 4077
Table 2. Transactivation of PPARγ by TZD-lipoate Derivatives
max. fold
EC50,
activation
compd
R1
R2
µM
at 10 µM
11
H
H
0.075
0.039
0.080
0.02
0.15
0.06
129.0
149.9
60.0
177.2
168.4
71.0
11a
11b
11c
11d
11e
11f
COCH3
COCH3
CO(CH2)2CO2Na
H
COCH3
COCH2NH3Cl
COCH3
CO(CH2)2CO2Na
CO(CH2)2CO2Na
CO(CH2)2CO2Na
COCH2NH3Cl
COCH2NH3Cl
Figure 5. Induction of adipogenesis by rosiglitazone and compounds
9a and 11e.
0.195
138.1
Table 4. Antiproliferative Effects of Rosiglitazone, 9a, and 11e
IC50 (µM)
Table 3. Inhibition of PHA/PMA-Induced Interleukin-2 Secretion in
Human T Lymphocytes by Rosiglitazone and Compounds 9a, 11, and
11e
human cell type
rosiglitazone
9a
11e
keratinocytes (primary culture)
HT-29 colon cancer cells
MCF-7 breast cancer cells
8
45
>50
0.6
10
15
1
8
25
percent inhibition
T lymphocytes + PHA/PMA
IL-2 released
(pg/mL supernatant)
control (no drug)
456 + 28
112 + 7
37 + 7
- -
75
92
80
92
10 µM rosiglitazone
10 µM compound 9a
10 µM compound 11
10 µM compound 11e
differentiation and lipid accumulation shown by staining the
lipid-laden maturing adipocytes with Oil Red O (Figure 5).
Effect on Growth of Human Keratinocytes. Inflammatory,
proliferative skin diseases such as psoriasis are associated with
inappropriate hyperproliferation of keratinocytes and production
of inflammatory cytokines, particularly IL-2, by T lymphocytes
which invade the epidermis and contribute to the pathophysi-
ology of the disease.45 Table 4 shows the inhibitory effects of
compounds 9a and 11e on proliferating human keratinocytes
in culture. Both compounds 9a and 11e were approximately an
order of magnitude more effective than rosiglitazone at inhibiting
keratinocyte proliferation.46 PPARγ activation has been shown
to inhibit IL-2 production in T lymphocytes.39
Effect on MCF-7 Breast Cancer Cells. It has been suggested
that the PPARγ transcriptional pathway could induce terminal
differentiation of malignant breast epithelial cells and offers a
nontoxic therapy for human breast cancer.47 It has also been
observed that treatment of MCF-7 breast cancer cell line with
troglitazone, a thiazolidinedione, for 4 days reversibly inhibited
cancer cell growth. This is mediated by inhibition of cellular
proliferation by blocking certain critical events for G1/S phase
progression. Compounds 9a and 11e were more effective than
rosiglitazone at inhibiting the proliferation of MCF-7 human
breast cancer cells (Table 4).
91 + 6
37 + 6
(biologically) intractable dithiolane 9. Because 11 could be
oxidized chemically to 9, it was assumed that 11 would revert
to 9 by oxidation in vivo. The acyl derivatives of 11 should
also serve after enzymatic hydrolysis, as precursors to 11 and
hence 9. The prodrugs of 11 had comparable activity in the
nanomolar range but were more easily dissolved for bioassay.
Careful pharmacodynamic studies to obtain exact bioavailability
figures seemed premature at this point of the research but may
be worthy of more detailed exploration at a later time.
Since compound 9a was considered the primary drug from
its prodrugs and because it had potent PPARγ activity, it was
selected as a representative member for further biological
activities.
Effect on Inflammatory Interleukin Production. TZDs
have been shown to inhibit the activation of human peripheral
blood lymphocytes and their production of inflammatory
interleukins, such as interleukin (IL)-1â, IL-2, IL-6, interferon-γ
(INFγ), and tumor necrosis factor-R (TNF-R).37,38 The effects
of compounds 9a, etc. (9a, 11, 11e) compared to rosiglitazone
on T lymphocte activation are shown in Table 3. The assay
measured as the ability of the compounds to inhibit IL-2
production by mitogen-stimulated peripheral blood mononuclear
cells, enriched in T lymphocytes.31 At a concentration of 10
µM, compounds 9a, 11e, and 11 were more effective inhibitors
of T lymphocyte IL-2 production than rosiglitazone. PPARγ
activation has been shown to inhibit IL-2 production in T
lymphocytes.39
Effect on H29 Colon Cancer Cells. Rosiglitazone has been
shown to induce differentiation in HT-29 cells, resulting in the
inhibition of G1/S mitotic growth transition, resulting in
48
inhibition of cell proliferation.
Our newly synthesized
compounds 9a and 11e similarly inhibited the proliferation of
HT-29 human colon cancer cells but were more potent than
rosiglitazone in this regard. The IC50 values are shown in Table
4. The IC50 values shown in Table 4 are unlikely to be
physiologically relevant, although other members of this class
may be designed to improve the inhibitory potency in certain
cancer cell lines.
Toxicity Studies. At all concentrations of rosiglitazone and
synthetic compounds used in these studies, there was no
evidence of cytotoxicity.
Effect on Adipocyte Differentiation and Adipogenesis.
Differentiation of preadipocytes into adipocytes is part of a
metabolic response to nutritional and hormonal signaling and
requires a cascade of changes in gene expression. Studies have
suggested the importance of PPARγ in mediating such changes
during terminal adipocyte differentiation. It is known that
40-42
adipocyte differentiation depends on PPARγ
and forced
expression of PPARγ and/or administering potent PPARγ
agonists promotes adipose conversion of fibroblasts and myo-
blasts.43,44 Compounds 9a and 11e and rosiglitazone similarly
promoted the differentiation of murine 3T3-L1 preadipocyte
fibroblasts (IC50 ∼ 0.6 µM) in culture by inducing terminal
Insulin-Sensitizing and Antidyslipidemic Effects in the
Insulin-Resistant Zucker Fatty (fa/fa) Rat. The first potent
PPARγ agonist prototype synthesized, compound 9a, was tested
to determine its antidiabetic and triglyceride-lowering activities.
The insulin resistant, genetically obese fa/fa Zucker rat is a

4078 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14
Chittiboyina et al.
Table 5. Insulin Sensitizing and Triglyceride Lowering Effects of 9a in
type-2 diabetes, but also in atherosclerosis, prevention of
vascular restenosis, inflammatory bowel disease, inflammatory
skin diseases such as psoriasis and atopic dermatitis, neurode-
generative diseases such as multiple sclerosis and Alzheimer’s
disease, and neoplasms.54
Zucker Ratsa
insulin
(ng/mL)
glucose
(mg/dL)
triglycerides
(mg/dL)
control (n ) 8)
9a (n ) 8)
6.3 + 1.6
1.4 + 0.2*
182 + 8
180 + 19**
320 + 39
54 + 4*
a *p < 0.025; **N.S.
Experimental Section
General Methods. All reactions were carried out under an argon
atmosphere with dry, appropriately distilled solvents stored over
dried 4 Å molecular sieves (at least 24 h) using anhydrous
techniques and conditions, unless otherwise stated.1 To monitor
reaction progress and chromatography fractions, thin-layer chro-
matography (TLC) was performed on precoated silica gel G or GP
Uniplates from Analtech. The plates were visualized with a 254-
nm UV light, iodine chamber, or charring with dilute sulfuric acid.
Flash chromatography was carried out on silica gel 60 [Scientific
Adsorbents Incorporated (SAI), particle size 32-63 µm, pore size
60 Å]. IUPAC names were generated using ACD/Name software,
version 9.04 (ACD/Labs 9.00 release). Melting points were
determined on an OptiMelt V.1.061 (Stanford Research Sysems,
2005) apparatus and are uncorrected. 1H NMR and 13C NMR spectra
were recorded on Bruker 300, 400, and 500 MHz NMR machines.
The chemical shifts are reported in parts per million (ppm)
downfield from tetramethylsilane, and J-values are in Hz. IR spectra
were recorded using a Thermo-Nicolet IR 300 FT/IR spectrometer
on a germanium crystal plate as neat solids or liquids. The high-
resolution mass spectra (HRMS) were recorded on a Micromass
Q-Tof Micro mass spectrometer with lock spray source.
Procedure for the Preparation of Ether 3a or 3b. To a solution
of N-methyl-N-Boc alcohol (2.86 mmol), phenol (3.42 mmol) and
triphenylphosphine (1.12 g, 4.3 mmol) in dry THF (20 mL) was
added diisopropyl azodicarboxylate (0.85 mL, 0.87 g, 4.3 mmol)
dropwise at 0 °C, and the mixture was allowed to stir for 3 h at
room temperature. THF was removed under reduced pressure, and
the resulting residue was dissolved in EtOAc (50 mL), washed with
1 N NaOH (10 mL), water (10 mL), and brine (10 mL), dried over
anhydrous MgSO4, and concentrated. The crude product was
purified by column chromatography with ethyl acetate and hexanes
to yield the coupled product.
tert-Butyl [2-(4-formylphenoxy)ethyl]methylcarbamate (3a):
White crystalline solid, 58%; mp:63.5-65.6 °C; 1H NMR (CDCl3,
500 MHz): 1.47 (s, 9H), 2.99 (s, 3H), 3.64 (s, 2H), 4.20 (bs, 2H),
7.01 (d, J ) 8.5 Hz, 2H), 7.84 (d, J ) 8.5 Hz, 2H), 9.89 (s, 1H);
13C NMR (CDCl3, 125 MHz): 28.8, 35.8, 36.5, 48.4, 66.7, 67.2,
80.0, 114.7, 130.0, 131.9, 155.6, 163.5, 190.4; HRMS calcd for
C15H22NO4 [M + H]+ 280.1549, found 280.1544.
tert-Butyl [2-(4-formylphenoxy)ethyl]carbamate (3b): White
crystalline solid, 61%; mp: 87.9-89.8 °C;; 1H NMR (CDCl3, 500
MHz): 1.46 (s, 9H), 3.58 (d, J ) 4.5 Hz, 2H), 4.12 (t, J ) 5 Hz,
2H), 5.10 (bs, 1H), 7.01 (d, J ) 8.5 Hz, 2H), 7.84 (d, J ) 9 Hz,
2H), 9.89 (s, 1H); 13C NMR (CDCl3, 125 MHz): 28.7, 40.2, 67.7,
79.8, 114.7, 130.1, 131.9, 155.7, 163.3, 190.4; HRMS calcd for
C14H20NO4 [M + H]+ 266.1392, found 266.1385.
widely used animal model of Type 2 diabetes for the develop-
ment of insulin-sensitizing and antidiabetic pharmaceutical
agents, including the thiazolidinediones. The test group of insulin
resistant, Zucker rats were given a dose of 100 mg/kg body
weight of compound 9a, or vehicle only (see Methods). The
results are shown in Table 5. Although there was no effect on
blood glucose over the period of time studied (4 weeks),
compound 9a produced a marked (78%) reduction in serum
insulin levels. The body weight within both groups were similar.
Food intake was not measured.
The genetically obese Zucker (fa/fa) fatty rat has been widely
used as an animal model of type 2 diabetes in the development
of antidiabetic drugs, particularly thiazolidinediones, for the
identification and development of potential antidiabetic phar-
maceutical agents.49 However, this (fa/fa) rat, has been shown
to have a missense point mutation (AfC) which results in an
amino acid substitution at position 269 (GlnfPro) in the
extracellular ligand binding domain of the leptin receptor.50 This
mutation, which leads to severe insulin resistance and the
development of type 2 diabetes, is exceedingly rare in humans
and is not the determinant for common place type 2 diabetes
seen in humans. Of interest is the fact that, unlike other
thiazolidinediones which have demonstrable glucose-lowering
effects, these lipoic acid derivatives, represented by compound
9a, may be less effective in the Zucker genetic model and should
therefore be tested in a dietary (high-fat, high-carbohydrate fed)
model of insulin resistance, which more closely reflects obesity-
related, insulin-resistant diabetes seen in humans. It should be
noted that different PPARγ ligands can have variable effects
in different in vivo animal models.51,52
Of considerable interest was the 83% reduction in triglycer-
ides by compound 9a. In comparison, rosiglitazone reduced
triglycerides by approximately 40% in Zucker rats.53 The ability
for compound 9a to activate PPARR in the mouse construct
was tested and determined to be 40 µM, which is similar to the
well-known antidyslipidemic fibrates, known PPARR agonists.
This could account for the triglyceride-lowering effect shown
in Table 5. These data indicate that 9a and likely other related
compounds in this class would be efficacious in improving
insulin sensitivity and reducing triglycerides in insulin resistant,
Type 2 diabetic patients and patients with primary (familial) or
secondary hypertriglyceridemia (Table 5).
Procedure for the Preparation of 5. A mixture of benzaldehyde
(3, 10 mmol), thiazolidine-2,4-dione (1.17 g, 10 mmol), benzoic
acid (0.160 g, 1.3 mmol), and piperidine (0.128 g, 150µL, 1.5 mmol)
in toluene (25 mL) was refluxed for 6 h with continuous removal
of water using a Dean-Stark apparatus. The reaction mixture was
cooled to room temperature, and the resulting solid was collected
by filtration, washed with water, and dried to afford 5.
Conclusion
In conclusion, we have discovered potent antidiabetic activity
in a series of [1,2]-dithiolane pentamide thiazolidinediones.
Comparisons of SAR with the docked structures revealed that
the members of this subclass of PPARγ agonists have an
enforced L-shape with an approximate 90° bend that fits into
the Y-shaped or perhaps more aptly T-shaped LBD of the
PPARγ agonist crystal structure. Each span of the “L” is
optimally 9-12 Å with one acidic end and another lipophilic
end. Compound 9a is one of the most potent of such compounds
and additionally has an effect on the growth of normal
keratinocytes and neoplastic cells. Therefore, these novel
compounds may prove efficacious not only in the treatment of
tert-Butyl (2-{4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)-
methyl]phenoxy}ethyl)methylcarbamate (5a): Bright yellow
1
solid, 89%; mp: 157.2-160 °C; H NMR (CD3OD, 500 MHz):
1.46 (s, 9H), 2.98 (s, 3H), 3.67 (bs, 2H), 4.26 (bs, 2H), 7.14 (d,
J ) 8.5 Hz, 2H), 7.59 (d, J ) 8.5 Hz, 2H), 7.73 (s, 1H); 13C NMR
(CD3OD, 125 MHz): 28.0, 34.6, 44.3, 48.0, 66.4, 78.9, 115.2,
122.5, 126.2, 131.0, 131.9, 160.2, 167.9, 168.3; HRMS calcd for
C18H23N2O5S [M + H]+ 379.1328, found 379.1325.

PPARγ Agonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14 4079
tert-Butyl (2-{4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)-
methyl]phenoxy}ethyl)carbamate (5b): Yellow solid, 93%; mp:
165.2-166.5 °C; H NMR (DMSO-d6, 500 MHz): 1.40 (s, 9H),
The combined mixture was stirred at 0 °C for 1 h. Upon completion,
water was added, and the aqueous layer was extracted with
dichloromethane (2 × 50 mL). The combined organic layers were
washed with 10% sodium bicarbonate (20 mL) and brine (20 mL)
and dried over anhydrous MgSO4. The solvent was removed under
vacuum, and the residue was chromatographed over silica gel
(MeOH:CHCl3, 1:99).
1
3.32 (t, J ) 5.5 Hz, 2H), 4.05 (t, J ) 5.5 Hz 2H), 7.05 (t, J ) 1.5
Hz, 1H), 7.11 (d, J ) 8.5 Hz, 2H), 7.56 (d, J ) 8.5 Hz, 2H), 7.76
(s, 1H); 13C NMR (DMSO-d6, 125 MHz): 29.0, 40.0, 67.3, 78.4,
115.8, 121.0, 126.0, 132.0, 132.4, 160.4, 167.9, 168.3; HRMS calcd
for C17H21N2O5S [M + H]+ 365.1171, found 365.1154.
Procedure for the Preparation of 6. A solution of thiazolidine-
2,4-dione (5, 2 mmol) and magnesium turnings (1.0 g, 40 mmol)
in dry MeOH (25 mL) was stirred at room temperature for 4 h.
The reaction mixture was acidified with 6 N HCl to pH 6.5 and
extracted with dichloromethane (2 × 15 mL). The combined organic
layers were washed with water (10 mL) and brine (5 mL), dried
over MgSO4, and evaporated under reduced pressure. The residue
was chromatographed over silica gel using ethyl acetate and hexanes
(4:6) to afford 6 as a colorless solid.
tert-Butyl (2-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phen-
oxy}ethyl)methylcarbamate (6a): White solid, 78%; mp: 148.5-
149.4 °C; 1H NMR (CDCl3, 500 MHz): 1.47 (s, 9H), 2.98 (s, 3H),
3.09 (dd, J ) 9.5, 14.0 Hz, 1H), 3.47 (dd, J ) 3.5, 14.0 Hz, 1H),
3.60 (bs, 2H), 4.08 (bs, 2H), 4.49 (dd, J ) 3.5, 9.5 Hz, 1H), 6.85
(d, J ) 8.5 Hz, 2H), 7.15 (d, J ) 8.5 Hz, 2H), 9.30 (bs, 1H); 13C
NMR (CDCl3, 125 MHz): 28.8, 35.6, 38.1, 48.4, 54.0, 66.9, 80.2,
114.7, 115.2, 130.2, 156.4, 157.5, 170.6, 174.3; HRMS calcd for
C18H25N2O5S [M + H]+ 381.1484, found 381.1492.
tert-Butyl (2-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phen-
oxy}ethyl)carbamate (6b): White solid, 80%; mp: 121.2-122.7
°C; 1H NMR (CDCl3, 500 MHz): 1.48 (s, 9H), 3.12 (dd, J ) 9.5,
14.0 Hz, 1H), 3.47 (dd, J ) 3.5, 14.0 Hz, 1H), 3.55 (bd, J ) 4
Hz,2H), 4.03 (t, J ) 5 Hz, 2H), 4.51 (dd, J ) 3.5, 9.5 Hz, 1H),
5.06 (bs, 1H), 6.87 (d, J ) 8.0 Hz, 2H), 7.17 (d, J ) 8.0 Hz, 2H),
8.96 (bs, 1H); 13C NMR (CDCl3, 125 MHz): 28.7, 38.1, 40.4, 53.9,
67.4, 79.8, 114.7, 128.0, 130.3, 156.2, 157.8, 170.3, 174.1; HRMS
calcd for C17H22N2O5S [M + Na]+ 389.1147, found 389.1141.
Procedure for the Preparation of 7. A solution of 4 N HCl in
dioxane (10 mL) was added at once to a suspension of carbamates
(6, 10 mmol) in anhydrous ether (25 mL) under a N2 atmosphere
at 0 °C, and the resulting mixture was allowed to stir for 30 min.
The solvents were removed under vacuum to yield 7 as white
amorphous solid.
N-(2-{4-[(2,4-Dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}ethyl)-
5-(1,2-dithiolan-3-yl)-N-methylpentanamide (9a): Viscous liquid,
1
yield 72%; H NMR (CDCl3, 300 MHz): 1.45 (m, 2H), 1.65 (m,
4H), 1.89 (m, 2H), 2.3 (t, J ) 7.4 Hz, 1H), 2.44 (m, 2H), 3.1 (m,
3H), 3.42 (dd, J ) 5 Hz, 18 Hz, 1H), 3.56 (m, 1H), 3.47 (t, J )
6.7 Hz, 2H), 4.1 (t, J ) 6.7 Hz, 2H), 4.49 (dd, J ) 5, 12.3 Hz,
1H), 6.82 (d, J ) 8 Hz, 2H), 6.83 (d, J ) 8.6 Hz), 7.15 (d, J ) 8
Hz, 2H), 8.19 (bs, 1H); 13C NMR (CDCl3, 75 MHz): 24.3, 24.7,
28.7, 28.8, 32.4, 32.9, 33.9, 34.6, 37.5, 37.6, 38.3, 39.9, 47.7, 48.9,
53.3, 65, 66.3, 114.5, 128.1, 130.2, 130.4, 157.5, 157.9, 170.7,
173.3, 174.5. HRMS calcd for C21H29N2O4S3 [M + H]+ 469.1284,
found 469.1263; IR (cm-1): 3030, 2926, 1752, 1696, 1609, 1512,
1303, 1244, 1154, 1052. HPLC (Method 1): 100% pure (1.65 min)
at 241 nm; HPLC (Method 2): 99% pure (1.56 min) at 229.1 nm.
N-(2-{4-[(2,4-Dioxa-1,3-thiazolidine-5-yl)methyl]phenoxy}-
ethyl)-5-(1,2-dithiolan-3-yl)pentanamide (9b): Viscous liquid,
1
64%; H NMR (CDCl3, 300 MHz): 1.5-1.45 (m, 2H), 1.75-1.5
(m, 6H), 1.8 (m, 2H), 2.2 (t, J ) 7.4 Hz, 1H), 2.3 (m, 2H), 3.2-
3.0 (m, 3H), 3.4 (dd, J ) 4, 16 Hz, 1H), 3.5 (m, 1H), 3.6 (dd, 2H),
4.02 (t, J ) 5 Hz, 2H), 4.5 (dd, J ) 4, 9.3 Hz, 1H), 5.9 (bs, 1H),
6.83 (d, J ) 8.4 Hz), 7.14 (d, J ) 8.4 Hz, 2H), 8.3 (bs, 1H); 13C
NMR (CDCl3, 75 MHz): 25.7, 29.2, 30.3, 34.9, 36.7, 38, 38.8,
39.3, 40.6, 54, 56.7, 67.2, 115.1, 128.0, 130.9, 157.0, 170.0, 173.0,
174.0; HRMS calcd for C20H27N2O4S3 [M + H]+ 455.1127, found
455.1096; IR (cm-1): 3021, 2926, 1752, 1698, 1609, 1516, 1303,
1234, 1159, 1052. HPLC (Method 1): 96% pure (1.89 min) at 241
nm; HPLC (Method 2): 94% pure (1.76 min) at 229.1 nm.
N-(2-{4-[(2,4-Dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}-
ethyl)-3-(1,2-dithiolan-3-yl)-N-methylpropanamide (9c): Viscous
liquid, 56%; 1H NMR (CDCl3): 2.0 (m, 1H), 2.65-2.80 (m, 3H),
3.0 (dd, J ) 4, 16 Hz, 1H), 3.1(m, 3H), 3.6 (m, 2H), 3.75 (t, 2H),
4.12 (t, J ) 5 Hz, 2H), 4.48 (dd, J ) 4, 9 Hz, 1H), 6.83 (d, J ) 8.6
Hz, 2H), 7.14 (d, J ) 8.4 Hz, 2H), 8.6 (bs, 1H); 13C NMR
(CDCl3): 34.4, 37.9, 38.1, 39.7, 40.0, 40.3, 48.5, 50.8, 51.2, 54.0,
65.4, 66.8, 115, 128.6, 130.8, 130.9, 157.9, 158.3, 171.5, 171.7,
171.9, 175.2; HRMS calcd for C18H23N2O4S3 [M + H]+ 427.0814,
found 427.0807; IR (cm-1): 3025, 2924, 2850, 1749, 1695, 1634,
1611, 1510, 1405, 1302, 1243, 1154. HPLC (Method 1): 95% pure
(1.53 min) at 241 nm; HPLC (Method 2): 99% pure (1.43 min) at
229.1 nm.
5-{4-[2-(Methylamino)ethoxy]benzyl}-1,3-thiazolidine-2,4-di-
one hydrochloride (7a): White solid, 98%; mp: 220.5-221.3 °C;
1H NMR (CD3OD, 500 MHz): 2.81 (s, 3H), 3.17 (dd, J ) 9.0,
14.0 Hz, 1H), 3.38 (dd, J ) 4.0, 14.0 Hz, 1H), 3.46 (bs, 2H), 4.27
(bs, 2H), 4.73 (dd, J ) 4.0, 9.0 Hz, 1H), 6.98 (d, J ) 8.0 Hz, 2H),
7.24 (d, J ) 8.0 Hz, 2H); 13C NMR (CD3OD, 125 MHz): 32.7,
37.1, 48.4, 53.5, 63.1, 114.3, 119.1, 129.5, 130.4, 157.0, 175.2;
HRMS calcd for C13H16N2O3S [M + Na]+ 303.0779, found
303.0773.
5-[(4-{2-[5-(1,2-Dithiolan-3-yl)pentylmethylamino]ethoxy}-
phenyl)methyl]-1,3-thiazolidine-2,4-dione (10). To a solution of
amide 9a (4.68 g, 10 mmol) in dry tetrahydrofuran (100 mL) at 0
°C was added alane-N,N-dimethylethylamine complex (40 mL,
20 mmol) dropwise over 30 min. After stirring for an additional
90 min at the same temperature, water (20 mL) was added, and
the mixture was stirred at 0 °C for an additional 10 min. The
precipitated aluminum hydroxide was filtered and washed with ethyl
acetate. The filtrate was concentrated under vacuum, and the residue
was diluted with water (50 mL) and extracted with ethyl acetate
(2 × 50 mL). The combined organic layers were washed with brine,
dried over anhydrous MgSO4, and concentrated to a clear oil. The
residue was dissolved in ethyl acetate (40 mL) and cooled to 0 °C.
To this solution, chilled aqueous sodium bicarbonate solution (10%
w/v, 100 mL) was added followed by a solution of iodine (2.54 g,
10 mmol) in ethyl acetate (50 mL) dropwise until a brown color
persisted. After 15 min the reaction mixture was quenched with
aqueous sodium thiosulfate solution (10% w/v 15 mL). The organic
layer was separated and washed with brine, dried over anhydrous
MgSO4, and concentrated. The residue was chromatographed over
silica gel (MeOH:CHCl3, 2:98) to yield amine 10 (2.13 g, 47%)
along with recovered starting material 9a (0.87 g): 1H NMR
(CDCl3, 300 MHz): 1.34 (m, 2H)., 1.45 (m, 2H), 1.5 (m, 2H), 1.6
(m, 2H), 1.89 (dddd, J ) 6.7, 7.2, 18 Hz, 1H), 2.4 (s, 3H), 2.44
5-[4-(2-Aminoethoxy)benzyl]-1,3-thiazolidine-2,4-dione hy-
1
drochloride (7b): White solid, mp: 214.0-214.7 °C; 98%; H
NMR (CD3OD, 500 MHz): 3.16 (dd, J ) 9.0, 14.0 Hz, 1H), 3.38
(bs, 2H), 3.41 (dd, J ) 4.0, 14.0 Hz, 1H), 4.23 (bs, 2H), 4.73 (dd,
J ) 4.0, 9.5 Hz, 1H), 6.98 (d, J ) 8.0 Hz, 2H), 7.23 (d, J ) 8.0
Hz, 2H); 13C NMR (CD3OD, 125 MHz): 37.1, 39.2, 53.5, 64.0,
114.3, 129.4, 130.3, 157.1, 175.5; HRMS calcd for C12H15N2O3S
[M + H]+ 267.0803, found 267.0795.
General Procedure for the Preparation of Amides (9a-c).
To a 100 mL round-bottomed flask was added amine/amine
hydrochloride (2.6 mmol) in anhydrous dichloromethane (30 mL).
To this suspension triethylamine (0.37 mL, 2.7 mmol) was added
at 0 °C, and the mixture was stirred at this temperature for an
additional 10 min. Racemic lipoic/bisnorlipoic acid (2.7 mmol) was
dissolved in anhydrous dichloromethane (20 mL) in a separate
round-bottomed flask and was cooled to 0 °C. To this was added
triethylamine (0.37 mL, 2.7 mmol) followed by the dropwise
addition of isopropyl chloroformate (2.7 mL, 2.7 mmol, 1 M in
toluene) over 10 min. The mixture was stirred for an additional 10
min at this temperature, and the resulting mixed anhydride was
then transferred via cannula to the flask containing the free amine.

4080 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14
Chittiboyina et al.
(dddd, J ) 6.7, 7.2 18 Hz, 1H), 2.58 (dd, J ) 9, 18 Hz, 1H), 2.90
(t, J ) 5.3 Hz, 2H), 3.2-3.0 (m, 3H), 3.40 (dd, J ) 3.6, 18 Hz,
1H), 3.5 (m, 1H), 4.06 (t, J ) 5.4 Hz, 2H), 4.34 (dd, J ) 3.7, 9
Hz, 1H), 6.77 (d, J ) 8.5 Hz, 2H), 7.2 (d, J ) 8.5 Hz, 2H); 13C
NMR (CDCl3, 75 MHz): 25.4, 27.4, 29.4, 35.1, 38.4, 38.8, 40.6,
41.7, 55.0, 55.5, 56.9, 57.4, 65.0, 114.9, 129.7, 130.8, 157.7, 175.5,
180.0; HRMS calcd for C21H30N2O3S3 [M + H]+ 455.1491, found
455.1507; IR (cm-1): 2925, 2851, 1749, 1697, 1607, 1586, 1462,
1301, 1243. HPLC (Method 1): 95% pure (1.67 min) at 241 nm;
HPLC (Method 2): 99% pure (1.62 min) at 229.1 nm.
Tartrate Salt of 5-[(4-{2-[5-(1,2-Dithiolan-3-ylpentyl)meth-
ylamino]ethoxy}phenyl) methyl]-1,3-thiazolidine-2,4-dione (10).
To a stirred solution of amine 10 (1.30 g, 2.86 mmol) in dry
tetrahydrofuran (50 mL) at 0 °C was added a solution of DL-tartaric
acid (0.40 g, 2.7 mmol) in THF (40 mL). After the addition was
complete, the mixture was stirred at the same temperature for 12
h. The solvent was removed under vacuum, and the residue was
washed with chloroform to remove unreacted amine. The product
was recrystallized with ether-pentane (1:1 v/v) to yield the tartrate
salt as a white crystalline powder (1.60 g, 92%): 1H NMR (DMSO-
d6, 300 MHz): 1.14-1.20 (m, 4H), 1.40-1.70 (m, 4H), 2.38 (m,
1H), 2.57 (s, 3H), 2.80 (m, 2H), 2.90-3.10 (m, 3H), 3.16 (t, 2H),
3.30 (dd, J ) 4, 16 Hz, 1H), 3.50 (m, 1H), 4.13 (s, 2H), 4.19 (t,
2H), 4.82 (dd, J ) 4.2, 9 Hz, 1H), 6.88 (d, J ) 8.4 Hz, 2H), 7.15
(d, J ) 8.4 Hz, 2H); 13C NMR (DMSO-d6, 75 MHz): 25.1, 26.0,
29.2, 35.0, 37.2, 38.9, 40.7, 41.6, 54.0, 55.0, 56.7, 57.0, 64.3, 72.9,
115.2, 130.0, 131.2, 157.7, 172.8, 174.8, 174.9, 177.0.
N-(2-{4-[(2,4-Dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}-
ethyl)-6,8-dimercapto-N-methyloctanamide (11). To a solution
of 9a (1.0 g, 2.13 mmol) in tetrahydrofuran (20 mL) at 0 °C was
added a solution of sodium borohydride (0.16 g, 4 mmol in 2 mL
of water). The mixture was allowed to stir at the same temperature
for an additional 1 h. After completion of the reaction, aqueous 1
N HCl (5 mL) was added, and the solvent was removed under
vacuum. The residue was diluted with water (20 mL) and extracted
with chloroform (2 × 25 mL). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, and concentrated
under vacuum. The residue was chromatographed over silica gel
(1% methanol in chloroform) to yield dithiol 11 as a viscous liquid
(0.87 g, 86%): 1H NMR (CDCl3, 300 MHz): 1.30-1.36 (m, 2H),
1.40-1.70 (m, 6H), 1.80 (m, 1H), 2.33 (t, J ) 9.7 Hz, 1H), 2.60
(m, 2H), 2.80 (m, 1H), 3.12 (dd, J ) 9, 16 Hz, 1H), 3.14 (s, 3H),
3.42 (dd, J ) 4, 16 Hz, 1H), 3.73 (t, J ) 5.6 Hz, 2H), 4.09 (t, J )
5.6 Hz, 2H), 4.39 (dd, J ) 4, 9 Hz, 1H), 6.76 (d, J ) 8 Hz, 2H),
7.08 (d, J ) 8 Hz, 2H), 10.4 (bs, 1H); 13C NMR (CDCl3, 75
MHz): 22.7, 24.9, 25.3, 27.0, 27.2,33.2, 33.7, 34.5, 38.0, 38.1, 39.1,
40.6, 43.1, 48.4, 49.5, 56.8, 65.6, 66.9, 115.0, 128.8, 129.2, 130.7,
130.8, 157.9, 158.2, 171.6, 171.7, 174.1, 175.5, 175.6; HRMS calcd
for C21H31N2O4S3[M + H]+ 471.1440, found 471.1482; IR (cm-1):
3032, 2926, 1752, 1698, 1609, 1513, 1303, 1244, 1154, 1055.
S,S′-{8-[(2-{4-[(2,4-Dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}-
ethyl)(methyl)amino]-8-oxooctane-1,3-diyl} Diethanethioate (11a).
To a 25 mL two-neck round-bottomed flask was added 11 (0.47 g,
1.0 mmol) in pyridine (5 mL). To this solution acetic anhydride
(0.336 g, 310µL, 3.3 mmol) was added. Stirring was continued for
an additional 2 h at ambient temperature. Upon completion, aqueous
HCl (10%v/v, 15 mL) was added, and the product was extracted
with chloroform (2 × 25 mL). The combined organic layers were
washed with water and brine and dried over anhydrous MgSO4.
Following concentration under vacuum, the crude diacetate was
further purified by column chromatography over silica gel (60%
ethyl acetate:hexanes) to yield 11a as a viscous liquid (0.49 g,
88%): 1H NMR (CDCl3, 300 MHz): 1.20-1.50 (m, 2H), 1.50-
1.70 (m, 4H), 1.70-1.90 (m, 2H), 2.30 (t, J ) 6 Hz, 2H), 2.31 (m,
6H), 2.70-3.02 (m, 2H), 3.12 (dd, J ) 9.3, 16 Hz, 1H), 3.13 (s,
3H), 3.40 (dd, J ) 4, 16 Hz, 1H), 3.60 (m, 1H), 3.72 (t, J ) 5.2
Hz, 2H), 4.09 (t, J ) 5.2 Hz, 2H), 4.70 (dd, J ) 4, 9.3 Hz, 1H),
6.70 (d, J ) 8.3 Hz, 2H), 6.80 (d, J ) 8.3 Hz, 2H), 7.12 (d, J )
8.3 Hz, 2H), 7.14 (d, J ) 8.3 Hz, 2H), 8.90 (bs, 1H); 13C NMR
(CDCl3, 75 MHz): 25.0, 25.2, 26.9, 27.3, 31.2, 32.6, 33.7, 34.2,
35.0, 35.1, 37.9, 38.1, 44.0, 48.3, 49.2, 54.0, 54.1, 66.7, 115.0,
128.5, 129.0, 130.7, 130.9, 157.0, 158.4, 171.2, 173.8, 174.0, 175.0,
196.1, 196.2; HRMS calcd for C25H36N2O6S3 [M + H]+ 555.1652,
found 555.1746; IR (film, cm-1): 3032, 2936, 1752, 1742, 1698,
1609, 1513, 1309, 1244, 1154, 1052. HPLC (Method 1): 95% pure
(2.14 min) at 233.2 nm; HPLC (Method 2): 93% pure (2.89 min)
at 229.1 nm.
Preparation of 11b and 11c. To a stirred solution of dithiol 11
(0.100 g 0.2 mmol) in pyridine (2 mL) was added succinic
anhydride (0.024 g, 0.24 mmol) at room temperature, and the
resulting mixture was stirred for an additional 8 h. After the
completion of the reaction, aqueous HCl (10%v/v, 10 mL) was
added, and the product was extracted with chloroform (2 × 10 mL).
The combined organic layers were washed with brine, dried over
anhydrous magnesium sulfate and concentrated to give the crude
monosuccinate which was further purified by column chromatog-
raphy over silica gel (1% methanol:chloroform) to yield monosuc-
cinate 11c (0.062 g, 51%) along with disuccinate 11b (0.018 g,
13%).
4,4′-[{8-[(2-{4-[(2,4-Dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}-
ethyl)(methyl)amino]-8-oxooctane-1,3-diyl}bis(thio)]bis(4-oxo-
butanoic acid) (11b): Viscous liquid; 1H NMR (CDCl3, 300
MHz): 1.43 (m, 4H), 1.83 (m, 4H), 1.79 (m, 1H), 2.35 (t, J ) 7.4
Hz, 2H), 2.64 (t, J ) 6.3 Hz, 4H), 2.80 (m, 1H), 2.78 (t, J ) 6.3
Hz, 4H), 3.10 (m, 1H), 3.16 (s, 3H), 3.33 (dd, J ) 3.8, 18 Hz,
1H), 3.72 (t, J ) 6 Hz, 2H), 4.08 (t, J ) 6 Hz, 2H), 4.52 (dd, J )
3.8, 9 Hz, 1H), 6.80 (d, J ) 8.1 Hz), 6.79 (d, J ) 8.1 Hz, 2H),
7.13 (d, J ) 8.1 Hz, 2H), 7.15 (d, J ) 8.1 Hz, 2H), 8.30 (bs, 1H),
9.79 (bs, 2H);13C NMR (CDCl3, 75 MHz): 24 1, 26.5, 29.1, 30,
33.3(2C), 33.9, 37.4, 38.3(2C), 48.0, 53.5, 66.4, 114.6, 128.0, 130.3,
157.8, 171.0, 174.1, 174.8, 197.9; HRMS calcd for C29H39N2O10S3
[M + H]+ 671.1689, found 671.1654.
4-({8-[(2-{4-[(2,4-Dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}-
ethyl)(methyl)amino]-3-mercapto-8-oxooctyl}thio)-4-oxobutano-
1
ic acid (11c): Viscous liquid; H NMR (CDCl3, 300 MHz): 1.46
(m, 4H), 1.63 (m, 4H), 1.75 (m, 1H), 2.33 (t, J ) 7.4 Hz, 2H),
2.67 (t, J ) 6.3 Hz, 2H), 2.80 (m, 1H), 2.83 (t, J ) 6.3 Hz, 2H),
3.10 (m, 1H), 3.13 (s, 3H), 3.35 (dd, J ) 3.8, 18 Hz, 1H), 3.72 (t,
J ) 6 Hz, 2H), 4.08 (t, J ) 6 Hz, 2H), 4.50 (dd, J ) 3.8, 9 Hz,
1H), 6.80 (d, J ) 8.1 Hz), 6.81 (d, J ) 8.1 Hz, 2H), 7.11 (d, J )
8.1 Hz, 2H), 7.13 (d, J ) 8.1 Hz, 2H), 8.30 (bs, 1H), 9.79 (bs,
1H);13C NMR (CDCl3, 75 MHz): 24 1, 26.5, 29.1, 30.0, 33.3, 33.9,
37.4, 38.3, 48.0, 53.5, 66.4, 114.6, 128.0, 130.3, 157.8, 171.0, 174.1,
174.8, 197.9; HRMS calcd for C25H35N2O7S3 [M + H]+ 571.1601,
found 571.1654.
4-({3-(Acetylthio)-8-[(2-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)-
methyl]phenoxy}ethyl)(methyl)amino]-8-oxooctyl}thio)-4-oxo-
butanoic Acid (11d). Compound 11d was made from 11c by
following the acylation procedure mentioned in 11a preparation:
1
Viscous liquid, 76%; H NMR (CDCl3): 1.30 (m, 2H), 1.59 (m,
4H), 1.75 (m, 2H), 2.29 (s, 3H), 2.32 (t, J ) 7.4 Hz, 2H), 2.68 (m,
2H), 2.80 (m, 2H), 3.10 (dd, J ) 9, 18 Hz, 1H), 3.13 (s, 3H), 3.35
(dd, J ) 3.8, 18 Hz, 1H), 3.54 (m, 1H), 3.71 (t, J ) 6 Hz, 2H),
4.08 (t, J ) 6 Hz, 2H), 4.50 (dd, J ) 3.8, 9 Hz, 1H), 6.82 (d, J )
8.4 Hz, 2H), 7.11 (d, J ) 8.3 Hz, 2H); 13C NMR (CDCl3): 24 8,
25.3, 26.7, 26.8, 29.4, 30.0, 31.2, 33.2, 33.7, 34.5, 34.8, 38.0, 38.1,
38.8, 43.7, 48.5, 49.6, 54.0, 54.1, 65.6, 66.9, 115.0, 128.6, 129.0,
130.7, 130.9, 150.0, 158.3, 171.6, 171.7, 174.5, 174.6, 175.5, 175.7,
196.3, 198.3; HRMS calcd for C27H37N2O8S3 [M + H]+ 613.1634,
found 613.1649.
Preparation of 11g and 11h. To a suspension of N-tert-
butyloxycarbonyl glycine (0.32 g, 1.8 mmol) in dry CH2Cl2 (15
mL) was added triethylamine (0.370 g, 0.47 mL, 3.4 mmol), and
the mixture was stirred for 30 min at room temperature. HOBT
(0.24 g, 1.8 mmol) and compound 11 (0.4 g, 0.85 mmol) were
then added, and the resulting mixture was stirred for 10 min at
room temperature. EDAC (0.36 g, 1.8 mmol) was added, and the
mixture was stirred overnight at room temperature under a nitrogen
atmosphere. The white precipitate was removed by filtration, and
the filtrate was diluted with dichloromethane (30 mL), washed with
aqueous HCl (5%v/v, 10 mL), 5% NaHCO3 (10 mL), and brine,
and dried over anhydrous MgSO4. The organic layer was filtered

PPARγ Agonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14 4081
and concentrated under reduced pressure. The crude material was
purified by flash chromatography on a silica gel column using
chloroform:methanol (99:1) to yield diglycinate 11g (0.48 g, 72%)
and monoglycinate 11h (0.113 g, 21%).
under vacuum to yield 11f as a pale yellow amorphous hygroscopic
solid (0.018 g, 68%): 1H NMR (CDCl3, 500 MHz): 1.47 (m, 2H),
1.64 (m, 4H), 1.89 (m, 2H), 2.02 (s, 3H), 2.33 (s, 3H), 2.40 (dd,
J ) 7.5, 15.0 Hz, 1H), 2.49 (dd, J ) 8, 16 Hz, 1H), 3.10 (m, 2H),
3.17(s, 2H), 3.38 (dt, J ) 4 Hz, 1H), 3.58 (m, 1H), 3.76 (m, 1H),
3.80 (t, J ) 4.5 Hz, 1H), 4.14 (t, J ) 5 Hz, 1H), 4.18 (t, J ) 5 Hz,
1H), 4.70 (m, 1H), 6.88 (d, J ) 8.4 Hz, 2H),7.20 (d, J ) 8.3 Hz,
2H);13C NMR (CDCl3, 100 MHz, mixture of rotamers): 22.7, 24.9,
25.0, 27.1, 27.3, 33.1, 33.2, 33.6, 33.7, 34.5, 35.1, 38.0, 38.2, 38.9,
39.2, 39.8, 40.6, 43.1, 48.4, 49.6, 54.1, 54.2, 56.8, 65.7, 66.9, 78.0,
115.1 (2C), 128.8, 129.3, 130.7, 130.9, 158.0, 158.3, 174.3, 175.5,
193.0, 193.2; HRMS calcd for C25H36N3O6S3 [M + H]+ 569.1688,
found 569.1702.
S,S′-{8-[(2-{4-[(2,4-Dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}-
ethyl)(methyl)amino]-8-oxooctane-1,3-diyl} bis{[(tert-butoxy-
carbonyl)amino]ethanethioate} (11g): Viscous liquid;1H NMR
(CDCl3, 300 MHz, mixture of rotamers): 1.43 (bs, 20H), 1.58 (m,
4H), 1.82 (m, 2H), 2.28 (t, J ) 7.3 Hz, 2.4H), 2.93 (t, J ) 7.3 Hz,
0.6H), 2.97 (m, 4H), 2.98 (s, 0.5H), 3.10 (s, 2.5H), 3.40 (bd, J )
4 Hz, 1H), 3.51 (m, 1H), 3.71 (t, J ) 5.3 Hz, 2H), 4.03 (m, 6H),
4.46 (m, 1H), 5.31 (m, 2H), 6.80 (dd, J ) 8.3 Hz, 2H), 7.12 (dd,
J ) 8.3 Hz, 2H); 13C NMR (CDCl3, 75 MHz, mixture of
rotamers): 24.9, 25.3, 26.3, 26.8, 28.2, 28.7, 33.1, 33.6, 34.4, 35.0,
37.9, 38.2, 43.5, 48.4, 49.5, 50.7, 50.9, 54.1, 66.9, 77.7, 80.7, 115.0-
(2C), 128.8, 130.7, 156.1, 158.0, 158.3, 171.6, 173.8, 174.0, 175.5,
198.5, 198.8; HRMS calcd for C35H53N4O10S3 [M + H]+ 785.1846,
found 585.1614 [M-(2Boc)+H]+; IR (film, cm-1): 3032, 2934,
1757, 1745, 1698, 1609, 1513, 1309, 1244, 1154, 1052.
Compounds 15a and 15b were prepared from 13 and 14 based
on the general procedure mentioned above for the preparation of
3.
Methyl (4-{2-[(tert-butoxycarbonyl)(methyl)amino]ethoxy}-
3-chlorophenyl)acetate (15a): 69%, viscous liquid; 1H NMR
(CDCl3, 500 MHz): 1.46 (s, 9H), 3.05 (s, 3H), 3.54 (s, 2H), 3.64
(bs, 2H), 3.69 (s, 3H), 4.13 (m, 2H), 6.86 (d, J ) 8.0 Hz, 1H),
7.11 (dd, J ) 1.5, 8.5 Hz, 1H), 7.30 (s, 1H); 13C NMR (CDCl3,
125 MHz): 28.7 (3C), 40.1, 48.5, 52.3, 67.9, 68.3, 79.7, 112.9,
122.6, 122.8, 127.0, 127.3, 128.5, 130.9, 131.0, 153.2, 155.2, 155.6,
171.4. HRMS calcd for C17H24ClNO5Na [M + Na]+ 380.1241,
found 380.1258.
Methyl (4-{3-[(tert-butoxycarbonyl)(methyl)amino]propoxy}-
3-chlorophenyl)acetate (15b): 63%, viscous liquid; 1HNMR
(CDCl3, 400 MHz, mixture of rotamers): 1.41 (s, 9H), 2.03 (bs,
2H), 2.87 (s, 3H), 3.42 (t, J ) 6.4 Hz, 2H), 3.52 (s, 2H), 3.68 (s,
3H), 4.01 (bs, 2H), 6.86 (d, J ) 8.0 Hz, 1H), 7.09 (d, J ) 8.0 Hz,
1H), 7.28 (s, 1H); 13CNMR (CDCl3, 100 MHz): 27.7, 28.4(3C),
34.6, 39.9, 45.9, 52.0, 68.0, 79.3, 113.2, 122.9, 127.1, 128.5, 131.0,
153.5, 155.8, 171.7; HRMS calcd for C18H26ClNO5Na [M + Na]+
394.1251, found 394.1258.
S-{8-[(2-{4-[(2,4-Dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}-
ethyl)(methyl)amino]-3-mercapto-8-oxooctyl} [(tert-butoxycar-
bonyl)amino]ethanethioate (11h): Viscous liquid; 1H NMR
(CDCl3, 400 MHz): 1.47 (s, 9H), 1.53 (m, 2H), 1.64 (m, 4H), 1.92
(m, 2H), 2.34 (m, 2H), 2.81 (m, 1H), 3.01 (s, 0.5H), 3.10 (m, 4H),
3.13 (s, 2.5H), 3.42 (m, 1H), 3.74 (m, 2H), 4.05 (bd, J ) 5.2 Hz
1H), 4.10 (m, 4H), 4.49 (dd, J ) 4.0, 9.2 Hz 1H), 5.31 (bs, 1H),
6.82 (dd, J ) 8.3 Hz, 2H), 7.15 (dd, J ) 8.3 Hz, 2H); 13C NMR
(CDCl3, 75 MHz, mixture of rotamers): 22.3, 24.5, 26.3, 28.3, 33.3,
37.9, 38.5, 38.7, 39.9, 48.0, 53.6, 66.6, 114.7(2C), 128.1, 130.4,
158.0, 158.3, 171.6, 173.8, 174.0, 175.5, 198.5, 198.8; HRMS calcd
for C28H42N3O7S3 [M
+
H]+ 628.1582, found 528.1578
[M-Boc+H]+.
2,2′-[{8-[(2-{4-[(2,4-Dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}-
ethyl)(methyl)amino]-8-oxooctane-1,3-diyl}bis(thio)]bis(2-oxo-
ethanaminium) Dichloride (11e). A solution of 4 N HCl in dioxane
(2 mL) was added at once to a suspension of 11g (0.1 g, 0.13 mmol)
in anhydrous ether (10 mL) under a N2 atmosphere at 0 °C, and
the resulting mixture was allowed to stir for 30 min. The solvents
were removed under vacuum to yield 11e as a pale yellow
amorphous hygroscopic solid (0.064 g, 76%): 1H NMR (CD3OD,
300 MHz, mixture of rotamers): 1.17 (m, 2H), 1.64 (m, 4H), 1.93
(m, 2H), 2.38 (t, J ) 7.1 Hz, 1.2H), 2.47 (t, J ) 7.1 Hz, 0.8H),
2.97 (s, 0.5H), 3.07 (m, 4H), 3.14 (s, 2.5H), 3.32 (bd, 2H), 3.75
(m, 4H), 4.10 (s, 4H), 4.16 (m, 2H), 4.71 (m, 1H), 6.87 (d, J ) 8.3
Hz, 2H), 7.18 (dd, J ) 8.1 Hz, 2H); 13C NMR (CD3OD, 75 MHz,
mixture of rotamers): 24.7, 25.0, 26.4, 26.6, 32.7, 33.1, 33.3, 34.4,
34.6, 36.9, 37.3, 44.3, 47.4, 49.4, 53.8, 65.6, 66.0, 114.7(2C), 129.1,
129.4, 130.8, 130.9, 158.2, 158.4, 172.5, 174.8, 175.1, 176.4, 193.1,
193.2; HRMS calcd for C25H37N4O6S3 [M + H]+ 585.1893, found
585.1902; IR (film, cm-1): 3033, 2928, 1765, 1748, 1690, 1609,
1523, 1329, 1254, 1174, 1072. HPLC (Method 1): 94% pure (13.28
min) at 254 nm; HPLC (Method 2): 92% pure (13.48 min) at 254
nm.
The compounds 16a and 16b were prepared from 15a and 15b
following the procedure for the preparation of 7 as mentioned above.
2-[2-Chloro-4-(2-methoxy-2-oxoethyl)phenoxy]-N-methyleth-
anaminium chloride (16a): 93%, viscous liquid; 1HNMR (CDCl3,
500 MHz): 2.50 (s, 3H), 2.58 (bs, NH), 2.99 (bs, 2H), 3.51 (s,
2H), 3.66 (s, 3H), 4.10 (t, J ) 5.0 Hz, 2H), 6.86 (d, J ) 8.5 Hz,
1H), 7.08 (dd, J ) 1.5, 8.5 Hz, 1H), 7.26 (d, J ) 1.5 Hz, 1H);
13CNMR (CDCl3, 125 MHz): 36.4, 40.1, 50.6, 52.3, 68.6, 113.7,
122.9, 127.3, 128.5, 130.9, 153.2, 171.4; HRMS calcd for C12H17-
ClNO3 [M + H]+ 258.0897, found 258.0896.
3-[2-Chloro-4-(2-methoxy-2-oxoethyl)phenoxy]-N-methylpro-
pan-1-aminium chloride (16b): 87%, viscous liquid; 1HNMR
(CDCl3, 400 MHz): 2.15 (bs, 2H), 2.46 (s, 3H), 2.52 (bs, NH),
2.92 (bs, 2H), 3.52 (s, 2H), 3.68 (s, 3H), 4.13 (t, J ) 5.0 Hz, 2H),
6.84 (d, J ) 8.5 Hz, 1H), 7.08 (d, J ) 8.5 Hz, 1H),7.28 (s, 1H);
13CNMR (CDCl3, 100 MHz): 27.4, 36.2, 38.4, 50.4, 52.7, 68.3,
113.9, 123.1, 127.7, 128.7, 131.3, 153.2, 171.6; HRMS calcd for
C13H19ClNO3 [M + H]+ 272.1053, found 272.1044.
The compounds 17a and 17b were prepared from 16a and 16b
by following the procedure for the preparation of amides 9a-c as
mentioned above.
2-({3-(Acetylthio)-8-[(2-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)-
methyl]phenoxy}ethyl)(methyl)amino]-8-oxooctyl}thio)-2-oxo-
ethanaminium Chloride (11f). To a 25 mL two-neck round-
bottomed flask was added 11h (0.05 g, 0.080 mmol) in pyridine (1
mL). To this solution was added acetic anhydride (0.112 g, 100
µL, 1 mmol). Stirring was continued for an additional 2 h at ambient
temperature. Upon completion, cold 1 N HCl (15 mL) was added,
and the product was extracted with chloroform (2 × 10 mL). The
combined organic layers were washed with water and brine and
dried over anhydrous MgSO4. Following concentration under
vacuum, the crude acetate was further purified by column chro-
matography over silica gel (70% ethyl acetate:hexanes) to yield
monoacetate (0.035 g, 66%) which was further subjected to Boc
deprotection.
Methyl [3-chloro-4-(2-{[5-(1,2-dithiolan-3-yl)pentanoyl](meth-
1
yl)amino}ethoxy)phenyl]acetate (17a): 79%, viscous liquid; H
NMR (CDCl3, 500 MHz, mixture of rotamers): 1.47 (m, 2H), 1.68
(m, 4H), 1.89 (m, 1H), 2.33 (t, J ) 7.5 Hz, 1.5H), 2.44 (m, 1H),
2.52 (t, J ) 7.5 Hz, 0.5H), 3.02 (s, 0.7H), 3.09 (m, 1H), 3.14 (m,
1H), 3.22 (s, 2.3H), 3.53 (s, 2H), 3.57 (m, 1H), 3.68 (s, 3H), 3.78
(m, 2H), 4.11 (t, J ) 5.0 Hz, 0.5H), 4.16 (t, J ) 5.0 Hz, 1.5H),
6.84 (d, J ) 8.5 Hz, 1H), 7.11 (m, 1H), 7.26 (s, 1H); 13CNMR
(CDCl3, 125 MHz): 25.0, 25.3, 29.3, 29.5, 33.1, 33.5, 34.2, 35.1,
35.13, 38.3, 38.8, 40.2, 40.5, 48.2, 49.3, 52.4, 56.6, 56.7, 66.8, 68.1,
112.8, 113.1, 122.4, 122.8, 127.1, 127.8, 128.5, 128.6, 130.9, 131.2,
152.8, 153.1, 171.3, 171.4, 172.8, 172.9. HRMS calcd for C20H29-
ClNO4S2 [M + H]+ 446.1227, found 446.1238. HPLC (Method
1): 100% pure (2.04 min) at 219.2 nm; HPLC (Method 2): 98%
pure (1.80 min) at 233.4 nm.
A solution of 4 N HCl in dioxane (2 mL) was added at once to
a suspension of monoacetate (0.03 g, 0.045 mmol) in anhydrous
ether (10 mL) under a N2 atmosphere at 0 °C, and the resulting
mixture was allowed to stir for 30 min. The solvents were removed

4082 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14
Chittiboyina et al.
Methyl [3-chloro-4-(3-{[5-(1,2-dithiolan-3-yl)pentanoyl](meth-
yl)amino}propoxy)phenyl]acetate (17b): 69%, viscous liquid;, 1H
NMR (CDCl3, 500 MHz): 1.40 (m, 2H), 1.65 (m, 4H), 1.90 (m,
1H), 1.98 (t, J ) 6.3 Hz, 2H), 2.30 (t, 1H), 2.36 (t, 1H), 2.45 (m,
1H), 2.90 (s, 1H), 3.03 (s, 1H), 3.15 (m, 1H), 3.59 (t, J ) 6.7 Hz,
2H), 3.69 (s, 3H), 4.01 (m, 2H), 6.80 (t, J ) 8.Hz, 1H), 7.11 (dt,
J ) 2, 8 Hz, 1H), 7.29 (dd, J ) 2, 8.8 Hz, 1H); 13C NMR (CDCl3,
125 MHz): 25 0, 25.5, 27.5, 28.3, 29.3, 29.4, 32.8, 33.5, 33.6,
35.0, 35.1, 36.3, 38.8, 38.9, 40.1, 40.2, 40.5, 40.6, 45.6, 46.5, 52.4,
52.5, 56.8, 65.4, 67.2, 113.3, 113.6, 122.9, 127.4, 127.8, 129.0,
129.1, 131.3, 131.4, 153.3, 153.7, 172.0, 172.1, 173.2, 173.3; HRMS
calcd for C21H31ClNO4S2 [M + H]+ 460.1305, found 460.1316.
HPLC (Method 1): 100% pure (2.11 min) at 229.2 nm; HPLC
(Method 2): 99.2% pure (1.84 min) at 229.1 nm.
General Procedure for the Preparation of Acids 18a and 18b.
To a solution of ester 17 (0.5 mmol) in methanol (10 mL) was
added 1 N NaOH (1.5 mL, 1.5 mmol) solution in water, and the
mixture was stirred at room temperature for 3 h. The methanol
was removed under vacuum, and the residue was acidified to pH
5 with 1 N HCl. The product was extracted with chloroform (2 ×
25 mL). The combined organic layers were dried over anhydrous
MgSO4 and concentrated to provide the crude acid which was
further purified over silica gel (ethyl acetate:hexanes 4:6).
[3-Chloro-4-(2-{[5-(1,2-dithiolan-3-yl)pentanoyl](methyl)ami-
no}ethoxy)phenyl]acetic acid (18a): 97%; viscous liquid;1H NMR
(CDCl3, 500 MHz, mixture of rotamers): 1.46 (m, 2H), 1.65 (m,
4H), 1.87 (m, 1H), 2.34 (t, J ) 7.5 Hz, 1.5H), 2.41 (m, 1H), 2.52
(t, J ) 7.5 Hz, 0.5H), 3.03 (s, 0.7H), 3.09 (m, 1H), 3.14 (m, 1H),
3.24 (s, 2.3H), 3.55 (s, 2H), 3.56 (m, 1H), 3.79 (t, 2H), 4.10 (t,
J ) 5.0 Hz, 0.5H), 4.15 (t, J ) 5.0 Hz, 1.5H), 6.84 (m, 1H), 7.12
(m, 1H), 7.30 (m, 1H), 9.93 (bs, 1H); 13C NMR (CDCl3, 125
MHz): 25.0, 25.3, 29.3, 29.4, 33.2, 33.6, 34.5, 35.0, 35.04, 38.5,
38.8, 40.2, 40.5, 48.4, 49.5, 56.6, 56.7, 66.7, 68.0, 112.8, 113.1,
122.3, 122.8, 127.0, 127.6, 128.66, 128.7, 131.0, 131.2, 152.8,
153.1, 173.6, 173.8, 175.5, 175.7. HRMS calcd for C19H27ClNO4S2
[M + H]+ 432.1070, found 432.1057.
[3-Chloro-4-(3-{[5-(1,2-dithiolan-3-yl)pentanoyl](methyl)ami-
no}propoxy)phenyl]acetic acid (18b): 93%, viscous liquid;, 1H
NMR (CDCl3, 500 MHz, mixture of rotamers): 1.38 (m, 2H), 1.67
(m, 4H), 1.89 (m, 1H), 1.94 (t, J ) 6.3 Hz, 2H), 2.32 (t, 1H), 2.37
(t, 1H), 2.45 (m, 1H), 2.89 (s, 1H), 3.01 (s, 1H), 3.17 (m, 1H),
3.63 (t, J ) 6.7 Hz, 2H), 4.05 (m, 2H), 6.81 (t, J ) 8.Hz, 1H),
7.13 (dt, J ) 2, 8 Hz, 1H), 7.32 (dd, J ) 2, 8.8 Hz, 1H); 13C NMR
(CDCl3, 125 MHz): 25 0, 25.5, 27.5, 28.3, 29.3, 29.4, 32.8, 33.5,
33.6, 35.0, 35.1, 36.3, 38.8, 38.9, 40.1, 40.2, 40.5, 40.6, 45.6, 46.5,
52.4, 52.5, 56.8, 65.4, 67.2, 113.3, 113.6, 122.9, 127.4, 127.8, 129,
129.1, 131.3, 131.4, 153.3, 153.7, 172.0, 172.1, 173.2, 173.3; HRMS
calcd for C20H29ClNO4S2 [M + H]+ 446.1227, found 446.1217
(5Z)-5-[4-(Methylamino)benzylidene]-1,3-thiazolidine-2,4-di-
one (22). A mixture of 4-aminomethyl benzaldehyde 21 (0.250 g,
1.85 mmol), thiazolidine-2,4-dione (0.2 g, 1.7 mmol), benzoic acid
(0.01 g), and piperidine (0.2 mL) in 15 mL of toluene was refluxed
for 6 h with continuous removal of water using a Dean-Stark
apparatus. The reaction mixture was cooled to room temperature,
and the resulting crystalline compound was filtered, washed with
water, and dried to afford 22 as orange-yellow solid: 0.39 g, 89%,
viscous liquid; 1H NMR (CDCl3, 400 MHz, mixture of rotamers):
2.75 (d, 3H, J ) 3.2 Hz), 6.65 (d, 2H, J ) 8.4 Hz), 7.36 (d, 2H,
J ) 8.8 Hz), 7.63 (s, 1H), 12.2 (bs, 1H); 13C NMR (CDCl3, 100
MHz): 29.7, 112.3, 118.6, 120.9, 131.6, 132.5, 152.0, 170.6, 171.6;
HRMS calcd for C11H10N2O2S [M + H]+ 234.0463, found 234.0457
5-[4-(Methylamino)benzyl]-1,3-thiazolidine-2,4-dione (23). A
solution of thiazolidine-2,4-dione 22 (0.2 g, 0.85 mmol) and
magnesium turnings (0.2 g, 8.3 mmol) in dry MeOH (10 mL) was
stirred at room temperature for 12 h. The reaction mixture was
neutralized with 1 N HCl and extracted with dichloromethane
(2 × 15 mL). The combined organic layers were washed with water
(10 mL) and brine (5 mL), dried over MgSO4, and evaporated under
reduced pressure. The residue was chromatographed over silica gel
using ethyl acetate and hexanes (4:6) to afford 23 as a yellow
viscous liquid: 0.15 g, 73%; 1H NMR (DMSO-d6, 400 MHz,
mixture of rotamers): 2.76 (s, 3H), 3.01 (dd, 1H, J ) 9.0, 14.0
Hz), 3.33 (dd, 1H, J ) 4.4, 14.0 Hz), 4.64 (dd, 1H, J ) 4.4, 9.0
Hz), 6.59 (d, 2H, J ) 8.4 Hz), 7.03 (d, 2H, J ) 8.4 Hz); 13C NMR
(DMSO-d6, 100 MHz): 29.5, 37.2, 53.9, 112.3, 124.4, 129.7, 149.2,
172.3, 176.2; HRMS calcd for C11H12N2O2S [M + H]+ 236.0619,
found 236.0623.
N-{4-[(2,4-Dioxo-1,3-thiazolidin-5-yl)methyl]phenyl}-5-(1,2-
dithiolan-3-yl)-N-methylpentanamide (24). To a suspension of
racemic lipoic acid (0.093 g, 0.45 mmol) in dry CH2Cl2 (15 mL)
was added triethylamine (0.135 g, 170 µL, 1.2 mmol), and the
mixture was stirred for 30 min at room temperature. HOBT (0.060
g, 0.45 mmol) and 23 (0.070 g, 0.3 mmol) were added, and the
resulting mixture was stirred for 10 min at room temperature. EDAC
(0.087 g, 0.45 mmol) was added, and the mixture was stirred
overnight at room temperature under a nitrogen atmosphere. The
white precipitate was removed by filtration, and the filtrate was
diluted with dichloromethane (20 mL), washed with 5% HCl (10
mL), 5% NaHCO3 (10 mL), and brine (10 mL), and dried over
anhydrous MgSO4. The filtrate was concentrated under vacuum,
and the residue was chromatographed over silica gel (ethyl acetate:
hexanes, 3:7) to yield 24 (0.098 g, 78%): 1H NMR (CDCl3, 300
MHz): 1.32 (m, 2H), 1.58(m, 4H), 2.03 (dddd, J ) 6.2,7.2, 18.6
Hz, 1H), 2.04 (t, 2H), 2.41 (dddd, J ) 6.2, 7.2, 18.7 Hz,1H), 3.07-
3.22 (m, 3H), 3.25 (s, 3H), 3.49 (m, 1H), 3.53 (dd, J ) 4, 14 Hz,
1H), 4.54 (dd, J ) 4, 9 Hz, 1H), 7.15 (d, J ) 8.15 Hz), 7.29 (d,
J ) 8.15 Hz, 2H), 8.7 (bs, 1H); 13C NMR (CDCl3, 75 MHz): 25.5,
29.2, 34.2, 34.9, 37.2, 38.5, 38.8, 40.6, 53.3, 56.8, 128.0, 131.1,
136.1, 143.8, 170.6, 173.5, 174.6; HRMS calcd for C19H25N2O3S3
[M + H]+ 425.1022, found 425.1007; IR (cm-1): 2925, 2852, 1753,
1699, 1624, 1601, 1511, 1461, 1390. HPLC (Method 1): 100%
pure (1.56 min) at 229.2 nm; HPLC (Method 2): 97.6% pure (4.31
min) at 237.3 nm.
Acknowledgment. The research was supported by NIH
Grant 2R42AR44767-02A2 (H.A.P.), a Joint Venture Grant
from the California State University Program for Education and
Research in Biotechnology (S.C.B.), and a grant from Bethesda
Pharmaceuticals, Inc. (A.G.C, M.S.V, M.A.A).
Supporting Information Available: HRMS and HPLC data
for the target compounds, biological methods, and computational
methods are available free of charge via Internet at http://
pubs.acs.org.
References
(1) Willson, T. M.; Brown, P. J.; Sternbach, D. D.; Henke, B. R. The
PPARs: From orphan receptors to drug discovery. J. Med. Chem.
2000, 43, 527-550.
(2) Caldwell, S. H.; Hespenheide, E. E.; Redick, J. A.; Iezzoni, J. C.;
Battle, E. H.; Sheppard, B. L. A pilot study of a thiazolidinedione,
troglitazone, in nonalcoholic steatohepatitis. Am. J. Gastroenterol.
2001, 96, 519-525.
(3) Das, S. K.; Reddy, K. A.; Abbineni, C.; Iqbal, J.; Suresh, J.;
Premkumar, M.; Chakrabarti, R. Novel thieno oxazine analogues as
antihyperglycemic and lipid modulating agents. Bioorg. Med. Chem.
Lett. 2003, 13, 399-403.
(4) Devasthale, P. V.; Chen, S.; Jeon, Y.; Qu, F.; Shao, C.; Wang, W.;
Zhang, H.; Farrelly, D.; Golla, R.; Grover, G.; Harrity, T.; Ma, Z.;
Moore, L.; Ren, J.; Seethala, R.; Cheng, L.; Sleph, P.; Sun, W.;
Tieman, A.; Wetterau, J. R.; Doweyko, A.; Chandrasena, G.; Chang,
S. Y.; Humphreys, W. G.; Sasseville, V. G.; Biller, S. A.; Ryono,
D. E.; Selan, F.; Hariharan, N.; Cheng, P. T. W. Design and Synthesis
of N-[(4-Methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-
oxazolyl)ethoxy]phenyl]methyl]glycine [Muraglitazar/BMS-298585],
a Novel Peroxisome Proliferator-Activated Receptor R/γ Dual
Agonist with Efficacious Glucose and Lipid-Lowering Activities. J.
Med. Chem. 2005, 48, 2248-2250.
(5) Henke, B. R. Peroxisome Proliferator-Activated Receptor R/γ Dual
Agonists for the Treatment of Type 2 Diabetes. J. Med. Chem. 2004,
47, 4118-4127.

PPARγ Agonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14 4083
(6) Koyama, H.; Miller, D. J.; Boueres, J. K.; Desai, R. C.; Jones, A.
B.; Berger, J. P.; MacNaul, K. L.; Kelly, L. J.; Doebber, T. W.; Wu,
M. S.; Zhou, G.; Wang, P.-R.; Ippolito, M. C.; Chao, Y.-S.; Agrawal,
A. K.; Franklin, R.; Heck, J. V.; Wright, S. D.; Moller, D. E.; Sahoo,
S. P. (2R)-2-Ethylchromane-2-carboxylic Acids: Discovery of Novel
PPARR/γ Dual Agonists as Antihyperglycemic and Hypolipidemic
Agents. J. Med. Chem. 2004, 47, 3255-3263.
(7) Rybczynski, P. J.; Zeck, R. E.; Dudash, J., Jr.; Combs, D. W.; Burris,
T. P.; Yang, M.; Osborne, M. C.; Chen, X.; Demarest, K. T.
Benzoxazinones as PPARγ Agonists. 2. SAR of the Amide Sub-
stituent and In Vivo Results in a Type 2 Diabetes Model. J. Med.
Chem. 2004, 47, 196-209.
(24) Field, L.; Lawson, J. E. Organic disulfides and related substances. I.
Oxidation of thiols to disulfides with lead tetraacetate. J. Am. Chem.
Soc. 1958, 80, 838-841.
(25) Gunsalus, I. C.; Barton, L. S.; Gruber, W. Biosynthesis and structure
of lipoic acid derivatives. J. Am. Chem. Soc. 1956, 78, 1763-1766.
(26) Adams, A. D.; Berger, J. P.; Berger, G. D.; Fitch, K. J.; Graham, D.
W.; Jones, A. B.; Von Langen, D.; et al. Preparation of [(heterocy-
clyloxy)alkoxy- and -alkylthio]phenylalkanoates and analogs as
peroxisome proliferator-activated receptor antagonists Application:
WO 97-US1749 9728137.
(27) Goswami, A.; Goswami, B. N.; Borthakur, N.; Rastogi, R. C. A
convenient synthesis of amines from phenols. J. Chem. Res., Synop.
1996, 424-425.
(28) Nolte, R. T.; Wisely, G. B.; Westin, S.; Cobb, J. E.; Lambert, M.
H.; Kurokawa, R.; Rosenfeld, M. G.; Willson, T. M.; Glass, C. K.;
Milburn, M. V. Ligand binding and co-activator assembly of the
peroxisome proliferator-activated receptor-γ. Nature 1998, 395, 137-
143.
(29) Ostberg, T.; Svensson, S.; Selen, G.; Uppenberg, J.; Thor, M.;
Sundbom, M.; Sydow-Backman, M.; Gustavsson, A. L.; Jendeberg,
L. A new class of peroxisome proliferator-activated receptor agonists
with a novel binding epitope shows antidiabetic effects. J. Biol. Chem.
2004, 279, 41124-41130.
(30) Thor, M.; Beierlein, K.; Dykes, G.; Gustavsson, A. L.; Heidrich, J.;
Jendeberg, L.; Lindqvist, B.; Pegurier, C.; Roussel, P.; Slater, M.;
Svensson, S.; Sydow-Backman, M.; Thornstrom, U.; Uppenberg, J.
Synthesis and pharmacological evaluation of a new class of peroxi-
some proliferator-activated receptor modulators. Bioorg. Med. Chem.
Lett. 2002, 12, 3565-3567.
(31) Venkatraman, M. S.; Chittiboyina, A.; Meingassner, J.; Ho, C. I.;
Varani, J.; Ellis, C. N.; Avery, M. A.; Pershadsingh, H. A.; Kurtz,
T. W.; Benson, S. C. R-Lipoic acid-based PPARgamma agonists for
treating inflammatory skin diseases. Arch. Dermatol. Res. 2004, 296,
97-104.
(32) Usui, S.; Suzuki, T.; Hattori, Y.; Etoh, K.; Fujieda, H.; Nishizuka,
M.; Imagawa, M.; Nakagawa, H.; Kohda, K.; Miyata, N. Design,
synthesis, and biological activity of novel PPARγ ligands based on
rosiglitazone and 15d-PGJ2. Bioorg. Med. Chem. Lett. 2005, 15,
1547-1551.
(33) Iwata, Y.; Miyamoto, S.; Takamura, M.; Yanagisawa, H.; Kasuya,
A. Interaction between peroxisome proliferator-activated receptor γ
and its agonists: docking study of oximes having 5-benzyl-2,4-
thiazolidinedione. J. Mol. Graphics Model. 2001, 19, 536-542.
(34) Yanagisawa, H.; Takamura, M.; Yamada, E.; Fujita, S.; Fujiwara,
T.; Yachi, M.; Isobe, A.; Hagisawa, Y. Novel oximes containing a
5-benzyl-2,4-thiazolidinedione moiety as antihyperglycemic agents:
synthesis and structure-activity relationship. Bioorg. Med. Chem.
Lett. 2000, 10, 373-375.
(35) Sinkula, A. A.; Yalkowsky, S. H. Rationale for design of biologically
reversible drug derivatives: prodrugs. J. Pharm. Sci. 1975, 64, 181-
210.
(36) Stwlla, V. J. Preface. AdV. Drug DeliVery ReV. 1996, 19, 111-114.
(37) Jiang, C.; Ting, A. T.; Seed, B. PPAR-γ agonists inhibit production
of monocyte inflammatory cytokines. Nature 1998, 391, 82-86.
(38) Ricote, M.; Li, A. C.; Willson, T. M.; Kelly, C. J.; Glass, C. K. The
peroxisome proliferator-activated receptor-γ is a negative regulator
of macrophage activation. Nature 1998, 391, 79-82.
(39) Yang, X. Y.; Wang, L. H.; Chen, T.; Hodge, D. R.; Resau, J. H.;
DaSilva, L.; Farrar, W. L. Activation of human T lymphocytes is
inhibited by peroxisome proliferator-activated receptor gamma
(PPARgamma) agonists. PPARgamma co-association with transcrip-
tion factor NFAT. J. Biol. Chem. 2000, 275, 4541-4544.
(40) Barak, Y.; Nelson, M. C.; Ong, E. S.; Jones, Y. Z.; Ruiz-Lozano,
P.; Chien, K. R.; Koder, A.; Evans, R. M. PPARγ is required for
placental, cardiac, and adipose tissue development. Mol. Cell 1999,
4, 585-595.
(41) Kubota, N.; Terauchi, Y.; Miki, H.; Tamemoto, H.; Yamauchi, T.;
Komeda, K.; Satoh, S.; Nakano, R.; Ishii, C.; Sugiyama, T.; Eto, K.;
Tsubamoto, Y.; Okuno, A.; Murakami, K.; Sekihara, H.; Hasegawa,
G.; Naito, M.; Toyoshima, Y.; Tanaka, S.; Shiota, K.; Kitamura, T.;
Fujita, T.; Ezaki, O.; Aizawa, S.; Nagai, R.; Tobe, K.; Kimura, S.;
Kadowaki, T. PPARγ mediates high-fat diet-induced adipocyte
hypertrophy and insulin resistance. Mol. Cell 1999, 4, 597-609.
(42) Rosen, E. D.; Sarraf, P.; Troy, A. E.; Bradwin, G.; Moore, K.;
Milstone, D. S.; Spiegelman, B. M.; Mortensen, R. M. PPARγ is
required for the differentiation of adipose tissue in vivo and in vitro.
Mol. Cell 1999, 4, 611-617.
(8) Xu, Y.; Rito, C. J.; Etgen, G. J.; Ardecky, R. J.; Bean, J. S.; Bensch,
W. R.; Bosley, J. R.; Broderick, C. L.; Brooks, D. A.; Dominianni,
S. J.; Hahn, P. J.; Liu, S.; Mais, D. E.; Montrose-Rafizadeh, C.;
Ogilvie, K. M.; Oldham, B. A.; Peters, M.; Rungta, D. K.; Shuker,
A. J.; Stephenson, G. A.; Tripp, A. E.; Wilson, S. B.; Winneroski,
L. L.; Zink, R.; Kauffman, R. F.; McCarthy, J. R. Design and
Synthesis of R-Aryloxy-R-methylhydrocinnamic Acids: A Novel
Class of Dual Peroxisome Proliferator-Activated Receptor R/γ
Agonists. J. Med. Chem. 2004, 47, 2422-2425.
(9) Vasudevan, A. R.; Balasubramanyam, A. Thiazolidinediones:
a
review of their mechanisms of insulin sensitization, therapeutic
potential, clinical efficacy, and tolerability. Diabetes Technol. Ther.
2004, 6, 850-863.
(10) Executive Summary of The Third Report of The National Cholesterol
Education Program (NCEP) Expert Panel on Detection, Evaluation,
And Treatment of High Blood Cholesterol In Adults (Adult Treatment
Panel III). JAMA 2001, 285, 2486-2497.
(11) Jacob, S.; Streeper, R. S.; Fogt, D. L.; Hokama, J. Y.; Tritschler, H.
J.; Dietze, G. J.; Henriksen, E. J. The antioxidant R-lipoic acid
enhances insulin-stimulated glucose metabolism in insulin-resistant
rat skeletal muscle. Diabetes 1996, 45, 1024-1029.
(12) Vasdev, S.; Gill, V.; Longerich, L. Antihypertensive effect of R-lipoic
acid supplementation. Curr. Topics Nutraceut. Res. 2004, 2, 137-
151.
(13) Mervaala, E.; Finckenberg, P.; Lapatto, R.; Muller, D. N.; Park, J.-
K.; Dechend, R.; Ganten, D.; Vapaatalo, H.; Luft, F. C. Lipoic acid
supplementation prevents angiotensin II-induced renal injury. Kidney
Int. 2003, 64, 501-508.
(14) Mizuno, C. S.; Chittiboyna, A. G.; Venkatraman, M. S.; Avery, M.
A.; Meingassner, J.; Ho, C.; Benson, S. C.; Varani, J.; Ellis, C. N.;
Kurtz, T. W.; Pershadsingh, H. A. R-lipoic acid-based PPAR
γ-agonists for treating type II diabetes. Abstracts of Papers; 229th
ACS National Meeting, San Diego, CA, Mar 13-17, 2005; American
Chemical Society: Washington, DC, 2005; MEDI-203.
(15) Avery, M. A.; Patny, A.; Chittiboyina, A.; Desai, P. V.; Venkatraman,
M. S.; Mizuno, C.; Ho, C.; Benson, S. C.; Kurtz, T. W.; Pershadsingh,
H. A. R-Lipoic acid-based PPARγ agonists as anti-diabetic agents:
Design, synthesis and docking studies. Abstracts of Papers; 227th
ACS National Meeting, Anaheim, CA, Mar 28-Apr 1, 2004;
American Chemical Society: Washington, DC, 2004; COMP-227.
(16) Pershadsingh, H. A.; Avery, M. A. Dithiolane derivatives: PCT Int.
Appl. 2001, 117 pp. WO 2001025226 CAN 134: 290422.
(17) Pershadsingh, H. A.; Avery, M. A. Preparation of dithiolanyl
thiazolidinediones as peroxisome proliferator-activated receptor-γ
activators Application: U.S. 2002, 38 pp., Cont.-in-part of U.S. Ser.
No. 6, 204,288. US 6353011 CAN 136: 216739.
(18) Pershadsingh, H. A.; Ho, C. I.; Rajamani, J.; Lee, C.; Chittiboyina,
A. G.; Deshpande, R.; Kurtz, T. W.; Chan, J. Y.; Avery, M. A.;
Benson, S. C. R-lipoic acid is a weak dual PPARR/γ agonist: an
ester derivative with increased PPARR/γ efficacy and antioxidant
activity. J. Appl. Res. 2005, 5, 510-523. URL:
http://jrnl/appliedresearch.com/articles/Vol5Iss4/.
(19) Tomkinson, N. C. O.; Sefler, A. M.; Plunket, K. D.; Blanchard, S.
G.; Parks, D. J.; Willson, T. M. Solid-phase synthesis of hybrid
thiazolidinedione-fatty acid PPARγ ligands. Bioorg. Med. Chem. Lett.
1997, 7, 2491-2496.
(20) Fan, Y.-H.; Chen, H.; Natarajan, A.; Guo, Y.; Harbinski, F.; Iyasere,
J.; Christ, W.; Aktas, H.; Halperin, J. A. Structure-activity require-
ments for the antiproliferative effect of troglitazone derivatives
mediated by depletion of intracellular calcium. Bioorg. Med. Chem.
Lett. 2004, 14, 2547-2550.
(21) Dominguez, C.; Csaky, A. G.; Plumet, J. Chemoselective reduction
in carbonyl-conjugated vinylfurans by the magnesium-methanol
system. Tetrahedron Lett. 1991, 32, 4183-4184.
(22) Han, G.; Tamaki, M.; Hruby, V. J. Fast, efficient and selective
deprotection of the tert-butoxycarbonyl (Boc) group using HCl/
dioxane (4 M). J. Pept. Res. 2001, 58, 338-341.
(23) Marlett, E. M.; Park, W. S. Dimethylethylamine alane and N-
methylpyrrolidine alane. A convenient synthesis of alane, a useful
selective reducing agent in organic synthesis. J. Org. Chem. 1990,
55, 2968-2969.
(43) Wu, Z.; Xie, Y.; Bucher, N. L. R.; Farmer, S. R. Conditional ectopic
expression of C/EBPb in NIH-3T3 cells induces PPARγ and
stimulates adipogenesis. Genes DeV. 1995, 9, 2350-2363.

4084 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14
Chittiboyina et al.
(44) Hu, E.; Tontonoz, P.; Spiegelman, B. M. Transdifferentiation of
myoblasts by the adipogenic transcription factors PPARγ and
C/EBPR. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 9856-9860.
(45) Sawa, M.; Tsukamoto, T.; Kiyoi, T.; Kurokawa, K.; Nakajima, F.;
Nakada, Y.; Yokota, K.; Inoue, Y.; Kondo, H.; Yoshino, K. New
Strategy for Antedrug Application: Development of Metalloprotein-
ase Inhibitors as Antipsoriatic Drugs. J. Med. Chem. 2002, 45, 930-
936.
(46) Bhagavathula, N.; Nerusu, K. C.; Lal, A.; Ellis, C. N.; Chittiboyina,
A.; Avery, M. A.; Ho, C. I.; Benson, S. C.; Pershadsingh, H. A.;
Kurtz, T. W.; Varani, J. Rosiglitazone inhibits proliferation, motility,
and matrix metalloproteinase production in keratinocytes. J. InVest.
Dermatol. 2004, 122, 130-139.
(47) Theocharis, S.; Margeli, A.; Kouraklis, G. Peroxisome proliferator
activated receptor-γ ligands as potent antineoplastic agents. Curr.
Med. Chem.: Anti-Cancer Agents 2003, 3, 239-251.
(48) Chintharlapalli, S.; Smith, R., 3rd; Samudio, I.; Zhang, W.; Safe, S.
1,1-Bis(3′-indolyl)-1-(p-substitutedphenyl)methanes induce peroxi-
some proliferator-activated receptor γ-mediated growth inhibition,
transactivation, and differentiation markers in colon cancer cells.
Cancer Res. 2004, 64, 5994-6001.
(49) Reed, M. J.; Scribner, K. A. In-vivo and in-vitro models of type 2
diabetes in pharmaceutical drug discovery. Diabetes Obes. Metab.
1999, 1, 75-86.
(50) Phillips, M. S.; Liu, Q.; Hammond, H. A.; Dugan, V.; Hey, P. J.;
Caskey, C. J.; Hess, J. F. Leptin receptor missense mutation in the
fatty Zucker rat. Nat. Genet. 1996, 13, 18-19.
(51) Benson, S. C.; Pershadsingh, H. A.; Ho, C. I.; Chittiboyina, A.; Desai,
P.; Pravenec, M.; Qi, N.; Wang, J.; Avery, M. A.; Kurtz, T. W.
Identification of telmisartan as a unique angiotensin II receptor
antagonist with selective PPARgamma-modulating activity. Hyper-
tension 2004, 43, 993-1002.
(52) Berger, J. P.; Petro, A. E.; Macnaul, K. L.; Kelly, L. J.; Zhang, B.
B.; Richards, K.; Elbrecht, A.; Johnson, B. A.; Zhou, G.; Doebber,
T. W.; Biswas, C.; Parikh, M.; Sharma, N.; Tanen, M. R.; Thompson,
G. M.; Ventre, J.; Adams, A. D.; Mosley, R.; Surwit, R. S.; Moller,
D. E. Distinct properties and advantages of a novel peroxisome
proliferator-activated protein [gamma] selective modulator. Mol.
Endocrinol. 2003, 17, 662-676.
(53) Chaput, E.; Saladin, R.; Silvestre, M.; Edgar, A. D. Fenofibrate and
rosiglitazone lower serum triglycerides with opposing effects on body
weight. Biochem. Biophys. Res. Commun. 2000, 271, 445-450.
(54) Pershadsingh, H. A. Peroxisome proliferator-activated receptor-
gamma: therapeutic target for diseases beyond diabetes: quo vadis?
Expert Opin. InVestig. Drugs 2004, 13, 215-228.
JM0510880