Indol-1-yl acetic acids as peroxisome proliferator-activated receptor agonists: Design, synthesis, structural biology, and molecular docking studies

Article abstract of DOI:10.1021/jm0510373

A series of novel indole-based PPAR agonists is described leading to discovery of 10k, a highly potent PPAR pan-agonist. The structural biology and molecular docking studies revealed that the distances between the acidic group and the linker, when a ligan

Full text of DOI:10.1021/jm0510373

1212
J. Med. Chem. 2006, 49, 1212-1216
Indol-1-yl Acetic Acids as Peroxisome Proliferator-Activated Receptor Agonists: Design,
Synthesis, Structural Biology, and Molecular Docking Studies
Neeraj Mahindroo,† Chiung-Chiu Wang,† Chun-Chen Liao,‡ Chien-Fu Huang,† I-Lin Lu,†,§ Tzu-Wen Lien,† Yi-Huei Peng,†,]
Wei-Jan Huang,‡ Ying-Ting Lin,† Ming-Chen Hsu,† Chia-Hui Lin,‡ Chia-Hua Tsai,† John T.-A. Hsu,†,# Xin Chen,†
Ping-Chiang Lyu,] Yu-Sheng Chao,† Su-Ying Wu,*,† and Hsing-Pang Hsieh*,†
DiVision of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town,
Miaoli County 350, Taiwan, Republic of China, Department of Chemistry, Department of Life Sciences, and Department of
Chemical Engineering, National Tsing Hua UniVersity, Hsinchu 300, Taiwan, Republic of China, and Graduate Institute of Life Sciences,
National Defense Medical Center, Taipei 114, Taiwan, Republic of China
ReceiVed October 16, 2005
A series of novel indole-based PPAR agonists is described leading to discovery of 10k, a highly potent
PPAR pan-agonist. The structural biology and molecular docking studies revealed that the distances between
the acidic group and the linker, when a ligand was complexed with PPARγ protein, were important for the
potent activity. The hydrophobic tail part of 10k makes intensive hydrophobic interaction with the PPARγ
protein resulting in potent activity.
Introduction
The prevalence of type 2 diabetes mellitus, a multifactorial
heterogeneous group of disorders resulting from defects in
insulin secretion, insulin action, or both, has increased dramati-
cally over the past several decades.1 The changes in human
environment, behavior, and lifestyle have resulted in escalating
rates of both diabetes and obesity.2 The metabolic syndrome, a
deadly quartet of insulin resistance, central obesity, dyslipi-
daemia, and hypertension, is associated with increased risk of
cardiovascular diseases.3
The peroxisome proliferator-activated receptors (PPARs) are
lipid-activated transcription factors exerting several functions
in development and metabolism.4 They are targets of drugs
effective in treatment of metabolic disorders. The modulation
of PPAR activity might be an effective therapy for metabolic
syndrome including obesity. The three PPAR subtypes, PPARγ,
PPARR, and PPARδ, have been the focus of extensive research
during past decade.5 The currently marketed PPARγ agonists
have only modest net efficacy and have the potential for several
undesired side effects.6 Novel PPAR ligands are now being
developed that possess broader efficacies and improved toler-
ability compared with currently available therapeutic agents5
(Figure 1). The lipid-lowering and cardioprotective effect of
PPARR agonists, insulin-sensitizing effect of PPARγ agonists,
and fatty acid catabolism by PPARδ agonists are well
documented.5-8 The PPAR pan-agonist could represent a
significant novel potential drug for the clinical treatment of
metabolic disorders.
Figure 1. PPAR agonists.
hydrophobic building blocks as the tail part of the indole-based
PPAR agonists. This article describes the design, synthesis, and
structure-activity relationships (SARs) of novel highly potent
PPARR/γ/δ pan-agonists with hydrophobic tails selected from
20 commercially available building blocks, which were further
modified to improve the activity. The structural biology and
molecular docking studies were carried out to reveal the reasons
for variation in potency in 4-, 5-, and 6-substiuted indol-1-yl
acetic acids and to predict the structural requirements for the
acidic head of PPARγ agonists.
The review of the literature7,8 shows that a typical PPAR
agonist consists of an acidic head attached to an aromatic
scaffold, a linker, and a hydrophobic tail. In continuation of
our studies on indole-based PPAR agonists, the indole was
retained as a core skeleton for the acidic head, placing the acetic
acid group at the 1-position.9 The aliphatic linker length was
fixed at three carbons on the basis of our previous observations
and literature reports.9-11 A library of compounds was synthe-
sized by selecting various hydrophobic commercially available
building blocks. The building blocks 11 and 15 (Figure 2) were
short listed after preliminary in vitro screening. Sahoo et al.10,11
have reported improvement in PPARγ agonist activities upon
introduction of a propyl group in the hydrophobic tail. On similar
lines the n-propyl group was introduced at an ortho position to
We have recently reported a series of indole-based PPAR
pan-agonists with the lead compound 5 displaying a potent
glucose lowering efficacy and an excellent pharmacokinetic
profile.9 In continuation of this work we further explored new
* To whom correspondence should be addressed. S.-Y. Wu: phone: 886-
37-246-166 ext. 35713; fax: 886-37-586-456; e-mail: suying@nhri.org.tw;
H.-P. Hsieh: phone: 886-37-246-166 ext. 35708; fax: 886-37-586-456;
e-mail: hphsieh@nhri.org.tw.
† National Health Research Institutes.
‡ Department of Chemistry, National Tsing Hua University.
§ Graduate Institute of Life Sciences, National Defense Medical Center.
] Department of Life Sciences, National Tsing Hua University.
# Department of Chemical Engineering, National Tsing Hua University.
10.1021/jm0510373 CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/14/2006

Brief Articles
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3 1213
indoles (6a-c) were alkylated with 1-bromo-3-chloropropane
in the presence of an equimolar amount of potassium hydroxide
in DMSO, yielding 7a-c. Compounds 7a-c were coupled with
the desired building block 11, 14, 15, or 18 to give 8a-l. The
esters 9a-l were obtained by reacting 8a-l with methyl-2-
bromoacetate in the presence of potassium carbonate and
potassium iodide in acetonitrile. Finally, 9a-l were deprotected
with lithium hydroxide in methanol-water mixture to give the
desired compounds 10a-l.
Results and Discussion
The compounds were screened in competitive binding assay9
and cell-based reporter gene efficacy assay9 for all three PPAR
isoforms, as shown in Table 1. In the benzophenone series, the
5-substituted indole 10b showed strong binding at PPARγ, while
its 4- and 6-indole-substituted analogues 10a and 10c showed
weak binding in the scintillation proximity assay. But 10a-c
showed weak or almost no activity in the transactivation assay
against all three PPAR subtypes, the only exception being 10c,
which showed sub-micromolar activity as PPARR agonist.
Similarly, the naphthophenone analogue 10h displayed sub-
micromolar affinity in PPARγ and PPARR binding assays, but
its positional analogues 10g and 10i showed only weak binding
at PPARγ. Only 5-substituted indole analogue 10h showed sub-
micromolar activity at PPARR and micromolar potency of
activation at PPARγ in the cell based functional assays.
Figure 2. Selection and optimization of building blocks for the tail
part.
Scheme 1. Synthetic Route to 10a-la
In an effort to improve the activity, the building blocks 11
and 15 were modified to 14 and 18, respectively. Compound
10e, a 5-substituted indole with the n-propyl substituted ben-
zophenone tail, displayed sub-micromolar binding as well as
functional activity on all three PPAR subtypes. Moving the
hydrophobic benzophnone tail to 4-position of indole resulted
in a selective PPARR agonist 10d. Further, shifting of the linker
and hydrophobic benzophenone tail to 6-position of indole 10f
resulted in substantial decrease or loss of activity at all three
subtypes. The SARs indicated that 5-substituted indoles might
be providing the appropriate distance for the molecule to orient
in the binding site to dock the acetic acid group at N1-position
of indole in the binding pocket for the acidic head. To confirm
a Reagents: (a) KOH, DMSO, rt; (b) R-OH, K2CO3, KI, DMF, 110
°C; (c) methyl 2-bromoacetate, K2CO3, KI, ACN; (d) LiOH, MeOH, H2O.
the hydroxyl group in 11 and 15 by Claisen rearrangement to
give 14 and 18, respectively.
Chemistry. Compounds 10a-l were synthesized as shown
in Scheme 1. The commercially available 4-, 5-, or 6-hydroxy-
Table 1. In Vitro Human PPAR Activities of Indol-1-yl Acetic Acids
SPA IC50 (µM)a,c
TA EC50 (µM)b,c
indole
compd
structure
position
Y
R
γ
δ
R
γ
δ
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
1
A
A
A
A
A
A
B
B
B
B
B
B
4
5
6
4
5
6
4
5
6
4
5
6
H
H
H
n-Pr
n-Pr
n-Pr
H
H
H
1.016
>10
2.960
0.213
2.072
2.409
0.129
1.287
2.707
0.629
1.580
0.824
0.050
2.024
0.092
0.152
>10
>10
3.153
>10
>10
0.765
>10
>10
>10
4.350
2.160
>10
0.116
0.414
0.470
1.047
1.079
0.484
4.486
0.578
0.113
4.486
3.256
0.649
7.616
0.773
0.050
>10
4.000
0.610
5.290
0.160
4.000
>10
>10
>10
0.270
>10
0.019
>10
>10
5.600
>10
>10
0.500
4.430
2.568
5.377
0.223
2.398
-
1.630
>10
n-Pr
n-Pr
n-Pr
2.300
0.070
3.870
0.220
0.230
0.008
2.475
-
4.900
-
0.010
>10
5
0.496
0.096
0.014
a Concentration of the test compound required to displace 50% of tritiated ligand. b Concentration of test compound which produced 50% of the maximal
reporter activity. c All data within (15% (n ) 3).

1214 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3
Brief Articles
the role of the indole positions in selectivity, we synthesized
the naphthophenone analogues with 4-, 5-, and 6-substituted
indoles.
A similar trend was observed in case of naphthophenone
analogues. Compound 10k, with the n-propyl-substituted naph-
thophenone tail attached at the 5-position of indole through a
linker, was the most active of all compounds exhibiting potent
binding at all three PPAR subtypes and displaying stronger
binding and functional activity for PPARγ (IC50 ) 50 nM,
EC50 ) 70 nM) as compared to rosiglitazone (1). It also showed
potent PPARR (EC50 ) 8 nM) and substantial PPARδ
(EC50 ) 500 nM) transactivation potencies. Shifting the
naphthophenone hydrophobic tail to the 4-position of indole 10j
gave a PPARR agonist with 100-fold selectivity over PPARγ.
Moving the hydrophobic tail to the 6-position of indole 10l
resulted in a substantial decrease in activity at all three subtypes.
The SAR shows that compounds with a hydrophobic tail
attached through a linker at the 5-position of the indole exhibited
potent activity at all three subtypes. The 4-substitued indoles
showed approximately 100-fold selectivity for PPARR over
PPARγ, while 6-substituted indoles were inactive or very weak
agonists at all three subtypes. The naphthophenone analogue
10k displayed more potent activity as compared to the ben-
zophenone 10e as well as benzisoxazole (5) analogues, thus
indicating that a larger more lipophilic group might be interact-
ing in a better way in the binding pocket for the hydrophobic
tail. The addition of the propyl group dramatically enhanced
the activity in the functional assay.
Figure 3. Superposition of the crystal structure of 10k (orange) with
docking structures of 10j (magenta) and 10l (cyan) in the PPARγ
protein. The red and black dotted lines represent hydrogen bond and
hydrophobic interactions of 10k with PPARγ protein, respectively.
Table 2. The Distances between the Oxygens in the Acidic Head and
Oxygen in the Linker of PPAR Agonists, and Protein-Ligand
Intermolecular Energy as Calculated by Insight II
A structural biology study was carried out to elucidate the
interactions of 10k with the PPARγ protein. The structure of
PPARγ ligand binding domain (LBD) complexed with 10k was
determined to 2.07 Å with the R factor of 21.85% and Rfree of
28.83% (PDB ID 2F4B). PPARγ formed a dimer, and super-
imposition of one monomer (monomer A) on the other
(monomer B) revealed that the difference between the two
monomers occurs in the regions of residues 264-273 and
residues 468-477. The loop region, residues 264-273, was
located at the entrance of the ligand-binding site and was highly
flexible in all published structures. The C-terminal region,
residues 468-477, was rigid and showed a clear density map
in monomer A whereas it was very flexible in monomer B.
Compound 10k was found bound to monomer A but was
absent in monomer B. The stoichiometry of one compound to
two monomers was also observed in other published PPAR
complex structures.12,13 The structure of monomer A in complex
with 10k is presented to discuss the interactions between PPARγ
and 10k (Figure 3). The carboxylic acid head of 10k formed
two H-bonds with Tyr473, a residue located in AF-2 helix, and
His449. This H-bonding pattern was conserved in most PPAR-
agonist complex structures, and in some cases, an additional
H-bond was formed with His323 or Ser289.
The indole ring of 10k formed strong hydrophobic interac-
tions with His449, Cys285, and Phe282. The linker of 10k was
close to the hydrophobic pocket of PPAR consisting of Leu330,
Met334, Phe368, Val339, and Met364. Finally, the hydrophobic
tail part of 10k occupied the region near the entrance of the
binding pocket and had close contacts with the surrounding
residues Met348, Ile341, Leu330, Cys285, Gly284, Glu259,
Leu255, and Arg280.
The naphthalene group was sandwiched between Cys285 and
Ile341 and made intensive hydrophobic interactions with these
two residues, particularly the latter one. The phenyl group in
the 6-benzoyl-1-propylnaphthalen-2-yl moiety extended into the
hydrophobic site close to the entrance, formed by the Ile249,
PPARγ PPARγ
protein-ligand
intermolecular
energy (kcal/mol)
Ph-O to Ph-O to OH
compd dO (Å) or NH (Å)
IC50
EC50
(µM)
(µM)
10j
10k
10l
1
6.4
7.9
5.5
8.6
8.6
8.0
8.7
6.1
9.0
8.8
0.824
0.050
2.024
0.092
2.300
-18.5073
-57.4929
-12.3153
-56.0647
-59.1996
0.070
3.870
0.220
3
0.0018 0.000288
Val277, Ile341, Leu255, Ile281, and Met348, and made a strong
hydrophobic interaction with Leu255. As revealed by the 10k
complex structure, the substitution of a hydrophobic functional
group in the phenyl ring is suggested to increase the binding
affinity, as it would make additional interactions with Ile249,
Ile341, Ile281, or Met348.
The substantial difference in activities of 5-hydroxy indole
analogues as compared to the 4-hydroxy and 6-hydroxy
analogues compelled us to study the reasons for it. We decided
to study the X-ray cocrystal of 10k and docking structures for
compounds 10j and 10l. The molecular docking studies were
carried out by docking compounds 10j and 10l into the binding
pocket of PPARγ using the cocrystal structure of compound
10k as the template with the program GOLD 2.2.14 The top
pose, ranked by the scoring function, GoldScore, was chosen
as the predicted binding mode of compound 10j and 10l. The
distances between carboxylic acid oxygens and the oxygen on
the 4-, 5-, or 6-position of indole in compounds 10j-l were
measured to determine whether the positional difference on
indole contributed to the difference in activity. These distances
were selected because the linker part and the hydrophobic tail
were similar for all three molecules and the linker part was quite
flexible to maneuver in the binding site; thus, the core skeleton
for the acidic head, with different hydroxy indoles, seemed to
be the most likely reason for the difference in activity for the
three analogues, 10j-l. Table 2 lists the distances between the
desired atoms. We also decided to carry out a similar study for
X-ray cocrystals of potent PPAR agonists, rosiglitazone (1) and

Brief Articles
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3 1215
graphed over silica gel eluting with hexane:ethyl acetate (95:5) to
3 to determine if the distance between acidic group and linker
could be criteria for potent PPARγ activity. Compounds 1 and
3 displayed distances between 8 and 9 Å for their acidic part
and linker. The X-ray cocrystal of compound 10k, the most
active of all synthesized compounds, with PPARγ also exhibited
similar distances between the carboxylic acid oxygens and the
oxygen on the 5-position of indole. Shifting the hydrophobic
tail to the 4-position (10j) decreased the distance between the
carboxylic acid and oxygen, correspondingly decreasing the
PPARγ agonist activity. Moving the hydrophobic tail to the
6-position in 10l further decreased the distance and the activity.
Superimposition of docking structures of compound 10j and
10l on the crystal structure of 10k (Figure 3) revealed that the
headgroups of these three analogues superimposed well with
each other, whereas the linker and the tail parts adopt different
conformations. The 5-substituted indole in 10k allows the best
fit to the binding site by providing the optimum distance (8-9
Å) between the carboxylic head and oxygen at the 5-position
of indole, thus moving the linker and the hydrophobic tail close
to the hydrophobic region of protein consisting of Leu330,
Leu333, Val339, Ile341, Met348, and Leu353, resulting in
strong hydrophobic interactions with these residues. Decreasing
the head-linker distance by shifting the tail to 4-position (10j)
or 6-position (10l) moved the linker and the tail away from
this hydrophobic region and consequently weakened the interac-
tions with the protein as revealed by significantly higher
protein-ligand intermolecular energy for 10j and 10l as
compared to 10k (Table 2). For example, the distances between
the tail of 10k and Val339, Ile341, and Met348 were 3.77, 3.46,
and 3.88 Å, respectively, while the tail of 10l shifted away from
Val339, Ile341, and Met348, increasing the distances to 5.29,
4.1, and 4.31 Å, respectively. Thus, the structural biology and
the docking studies clearly indicate that distance and placement
of the carboxylic group in relation to the oxygen atom on the
phenyl ring correlate with the binding affinity of the ligand to
the PPARγ, and that the 5-substituted indole provides the
optimum distance, explaining its better potency as compared
to 4- or 6-substituted indoles.
give 5-(3-chloropropoxy)-1H-indole 7b (0.631 g, 80%) as a
1
colorless oil. H NMR (300 MHz, CDCl3) δ 2.21-2.29 (m, 2H),
3.77 (t, J ) 6.3 Hz, 2H), 4.14 (t, J ) 6.3 Hz, 2H), 6.46 (m, 1H),
6.84 (dd, J ) 2.4, 9.0 Hz, 1H), 7.11 (d, J ) 2.1 Hz, 1H), 7.17 (t,
J ) 2.1 Hz, 1H), 7.26 (d, J ) 9.0 Hz, 1H), 8.05 (br, 1H); MS (ESI
m/z) 210.1 (M + H)+.
Compounds 7a and 7c were prepared in similar manner starting
from 6a and 6c, respectively.
5-[3-(6-Benzoyl-1-propylnaphthalen-2-yloxy)propoxy]-1H-in-
dole (8k). A mixture of 7b (0.100 g, 0.48 mmol), 18 (0.139 g,
0.48 mmol), potassium carbonate (0.099 g, 0.72 mmol), and
potassium iodide (0.016 g, 0.10 mmol) in 5 mL of DMF was heated
at 110 °C for 2 h. The mixture was cooled to room temperature
and quenched with water (10 mL). The mixture was extracted with
ethyl acetate (2 × 20 mL). The combined organic layer was washed
water (6 × 20 mL) followed by brine (2 × 20 mL) and then dried
over anhydrous sodium sulfate. The solvent was removed in vacuo
to give an oily residue, which was filtered through a short silica
column eluting with hexane:dichloromethane (50:50) to give
compound 8k (0.165 g, 75%). 1H NMR (300 MHz, CDCl3) δ 1.01
(t, J ) 7.4 Hz, 3H), 1.57-1.70 (m, 2H), 2.29-2.38 (m, 2H), 3.08
(t, J ) 7.5 Hz, 2H), 4.27 (t, J ) 6.0 Hz, 2H), 4.35 (t, J ) 6.0 Hz,
2H), 6.45 (t, J ) 2.1 Hz, 1H), 6.86 (dd, J ) 2.4, 9.0 Hz, 1H), 7.13
(d, J ) 2.1 Hz, 1H), 7.18 (t, J ) 2.7 Hz, 1H), 7.27 (d, J ) 9.0 Hz,
1H), 7.33 (d, J ) 8.7 Hz, 1H), 7.49 (m, 2H), 7.58 (d, J ) 7.5 Hz,
1H), 7.76 (d, J ) 8.7 Hz, 1H), 7.83 (d, J ) 6.6 Hz, 2H), 7.92 (dd,
J ) 1.8, 9.0 Hz, 1H), 8.01 (d, J ) 9.0 Hz, 1H), 8.04 (br, 1H), 8.19
(d, J ) 1.8 Hz, 1H). MS (ESI m/z) 486.1 (M + Na)+.
Compounds 8a-j and 8l were synthesized in similar manner
starting from appropriate starting materials selected from 7a-c.
Methyl 2-{5-[3-(6-Benzoyl-1-propylnaphthalen-2-yloxy)pro-
poxy]indol-1-yl}ethanoate (9k). A mixture of compound 8k (0.100
g, 0.22 mmol), methyl-2-bromoacetate (0.098 g, 0.65 mmol, 0.06
mL), potassium carbonate (0.045 g, 0.32 mmol), and potassium
iodide (0.007 g, 0.04 mmol) in 15 mL of acetonitrile was heated at
reflux for 12 h. The mixture was cooled to room temperature and
filtered to remove suspended salts. The solvent was removed in
vacuo and residue partitioned between dichloromethane and water.
The organic layer was washed water (2 × 20 mL) followed by
brine (2 × 20 mL) and then dried over anhydrous sodium sulfate.
The solvent was removed and the residue chromatographed over
silica gel eluting with hexane:ethyl acetate (95:5) to give methyl
2-{5-[3-(6-benzoyl-1-propylnaphthalen-2-yloxy)propoxy]indol-1-
Conclusion
1
yl}ethanoate (9k) (0.079 g, 68%). H NMR (300 MHz, CDCl3) δ
In conclusion, we have discovered a highly potent PPAR pan-
agonist 10k, with more potent PPARγ agonist activity as
compared to rosiglitazone. The structural biology studies reveal
strong hydrophobic interactions contributed by the hydrophobic
tail 6-benzoyl-1-propylnaphthalen-2-yl, occupying the region
near the entrance to the binding pocket. The substitution of a
hydrophobic functional group on the phenyl ring of hydrophobic
tail may further increase the binding affinity. The molecular
docking studies showed that 5-substituted indole provides an
appropriate distance to dock the molecule in to the PPARγ
binding site to elicit maximum activity. The distances between
the acidic group and the linker, when a ligand was complexed
with PPARγ protein, were important for the potent activity.
1.05 (t, J ) 7.4 Hz, 3H), 1.58-1.73 (m, 2H), 2.30-2.39 (m, 2H),
3.09 (t, J ) 7.5 Hz, 2H), 3.73 (s, 3H), 4.29 (t, J ) 6.0 Hz, 2H),
4.36 (t, J ) 6.0 Hz, 2H), 4.69 (s, 2H), 6.46 (d, J ) 2.7 Hz, 1H),
6.88 (dd, J ) 2.4, 9.0 Hz, 1H), 7.14 (d, J ) 2.1 Hz, 1H), 7.20 (t,
J ) 2.7 Hz, 1H), 7.28 (d, J ) 9.0 Hz, 1H), 7.33 (d, J ) 8.7 Hz,
1H), 7.50 (m, 2H), 7.58 (d, J ) 7.5 Hz, 1H), 7.77 (d, J ) 8.7 Hz,
1H), 7.83 (d, J ) 6.6 Hz, 2H), 7.93 (dd, J ) 1.8, 9.0 Hz, 1H), 8.01
(d, J ) 9.0 Hz, 1H), 8.20 (d, J ) 1.8 Hz, 1H). MS (ESI m/z) 536.2
(M + H)+.
Compounds 9a-j and 9l were synthesized in similar manner
starting from 8a-j and 8l, respectively.
2-{5-[3-(6-Benzoyl-1-propylnaphthalen-2-yloxy)propoxy]in-
dol-1-yl}ethanoic Acid (10k). The mixture of compound 9 (0.075
g, 0.140 mmol) and LiOH (0.013 g, 0.561 mmol) in methanol and
water mixture (4:1) was refluxed for 2 h. The solvent was removed
in vacuo added 0.5 N HCl to residue and extracted with ether (2 ×
20 mL). The combined organic layer was washed with water (2 ×
20 mL) followed by brine (2 × 10 mL). The solvent was removed
in vacuo and the residue chromatographed over a short column of
silica gel eluting with dichloromethane:methanol (98:2) to give
2-{5-[3-(6-benzoyl-1-propylnaphthalen-2-yloxy)propoxy]indol-1-
yl}ethanoic acid 10l (0.062 g, 85%). 1H NMR (300 MHz, CDCl3)
δ 1.01 (t, J ) 7.4 Hz, 3H), 1.61-1.70 (m, 2H), 2.32-2.38 (m,
2H), 3.07 (t, J ) 7.8 Hz, 2H), 4.25 (t, J ) 6.0 Hz, 2H), 4.33 (t,
J ) 6.0 Hz, 2H), 4.80 (s, 2H), 6.45 (d, J ) 3.0 Hz, 1H), 6.87 (dd,
J ) 2.1, 9.0 Hz, 1H), 7.01 (d, J ) 3.0 Hz, 1H), 7.08-7.12 (m,
Experimental Section
5-(3-Chloropropoxy)-1H-indole (7b). A mixture of 5-hydroxy-
indole (6b) (0.500 g, 3.76 mmol), powdered potassium hydroxide
(0.211 g, 3.76 mmol), and DMSO (10 mL) was stirred at room
temperature for 10 min, and then 1-bromo-3-chloropropane (0.590
g, 3.76 mmol) was added. The mixture was stirred at room
temperature for 0.5 h, and then 15 mL of water was added. The
mixture was extracted with ethyl acetate (2 × 30 mL). The
combined organic layer was washed with water (6 × 25 mL)
followed by brine (2 × 20 mL) and dried over anhydrous Na2SO4.
The solvent was removed in vacuo and the residue flash chromato-

1216 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3
Brief Articles
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2H), 7.31 (d, J ) 9.0 Hz, 1H), 7.45-7.51 (m, 2H), 7.56-7.61 (m,
1H), 7.74 (d, J ) 9.0 Hz, 1H), 7.81-7.83 (m, 2H), 7.91 (dd, J )
1.8, 9.0 Hz, 1H), 8.01 (d, J ) 9.0 Hz, 1H), 8.19 (d, J ) 1.5 Hz,
1H). HRMS (FAB+ m/z) 521.2208.
Compounds 10a-j and 10l were synthesized in similar manner
as 10k starting from 9a-j and 9l, respectively.
Acknowledgment. The authors thank Ms. Hsiao-Wen Edith
Chu, Ms. Huai-Tzu Chang, and Ms. Pey-Yea Yang for their
administrative support, the staff at the beamline SP12B2 for
technical assistance, National Health Research Institutes, Tai-
wan, and National Science Council of the Republic of China
(Grant Nos. NSC 92-2323-B-007-001 and NSC 93-2323-B-007-
001) for financial support.
(9) Mahindroo, N.; Huang, C. F.; Peng, Y. H.; Wang, C. C.; Liao, C.
C.; Lien, T. W.; Chittimalla, S. K.; Huang, W. J.; Chai, C. H.;
Prakash, E.; Chen, C. P.; Hsu, T. A.; Peng, C. H.; Lu, I. L.; Lee, L.
H.; Chang, Y. W.; Chen, W. C.; Chou, Y. C.; Chen, C. T.; Goparaju,
C. M. V.; Chen, Y. S.; Lan, S. J.; Yu, M. C.; Chen, X.; Chao, Y. S.;
Wu, S. Y.; Hsieh, H. P. Novel Indole-Based Peroxisome Proliferator-
Activated Receptor Agonists: Design, SAR, Structural Biology, and
Biological Activities. J. Med. Chem. 2005, 48, 8194-8208.
(10) Koyama, H.; Boueres, J. K.; Han, W.; Metzger, E. J.; Bergman, J.
P.; Gratale, D. F.; Miller, D. J.; Tolman, R. L.; MacNaul, K. L.;
Berger, J. P.; Doebber, T. W.; Leung, K.; Moller, D. E.; Heck, J.
V.; Sahoo, S. P. 5-Aryl Thiazolidine-2,4-diones as Selective PPARγ
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(11) Desai, R. C.; Han, W.; Metzger, E. J.; Bergman, J. P.; Gratale, D.
F.; MacNaul, K. L.; Berger, J. P.; Doebber, T. W.; Leung, K.; Moller,
D. E.; Heck, J. V.; Sahoo, S. P. 5-Aryl Thiazolidine-2,4-diones:
Discovery of PPAR Dual R/γ Agonists as Antidiabetic Agents.
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Supporting Information Available: Synthesis of 14 and 18,
the 1H NMR, HRMS, and HPLC purity data for compounds 10a-
l, in vitro biological assays and structural biology studies, X-ray
data collection and structure refinement for 10k/PPARγ complex.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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