Synthesis and evaluation of azaindole-α-alkyloxyphenylpropionic acid analogues as PPARα/γ agonists

Article abstract of DOI:10.1016/j.bmc.2005.09.040

A series of azaindole-α-alkyloxyphenylpropionic acid analogues was synthesized and evaluated for PPAR agonist activities. Structure-activity relationship was developed for PPARα/γ dual agonism. One of the synthesized compound 7a was identified as a potent

Full text of DOI:10.1016/j.bmc.2005.09.040

Bioorganic & Medicinal Chemistry 14 (2006) 866–874
Synthesis and evaluation of azaindole-a-alkyloxyphenylpropionic
acid analogues as PPARa/c agonists
Zhefeng Cai, Jun Feng, Yanshen Guo, Pingping Li, Zhufang Shen,
Fengming Chu and Zongru Guo*
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College,
1 Xian Nong Tan Street, Beijing 100050, China
Received 15 July 2005; revised 2 September 2005; accepted 3 September 2005
Available online 24 October 2005
Abstract—A series of azaindole-a-alkyloxyphenylpropionic acid analogues was synthesized and evaluated for PPAR agonist activ-
ities. Structure–activity relationship was developed for PPARa/c dual agonism. One of the synthesized compound 7a was identified
as a potent, selective PPARa/c dual agonist.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
homeostasis via its role in fatty acid catabolism includ-
ing fatty acid binding, uptake, and oxidation as well as
lipoprotein assembly and transport.7 Fibrates (PPARa
agonists, e.g., fenofibrate and clofibrate) primarily de-
crease serum triglyceride levels and increase HDL cho-
lesterol (HDLc) levels, but they also improve glucose
tolerance in type 2 diabetic patients.8,9 Furthermore,
fibrates have been reported to reduce weight gain in
rodents without effects on food intake.10 PPARc is an
important component in the adipogenic signaling cas-
cade, and in lipid storage and utilization. A lot of syn-
thetic compounds, such as the thiazolidinediones
(TZDs), have been reported to function as high affinity
PPARc agonists.11,12 These selective PPARc agonists
are potent agents with the ability to improve insulin sen-
sitivity and glucose tolerance, and normalize elevated
plasma glucose and insulin levels in type 2 diabetic
patients. But the improvement in insulin sensitivity is
accompanied with a body weight gain.13,14 Therefore,
recently, there has been considerable interest in combin-
ing the beneficial activities of PPARa activation and
PPARc activation, because the dual agonist approach
should be well suited for the treatment of patients with
type 2 diabetes.15–17
Peroxisome proliferator-activated receptors (PPARs)
are members of the nuclear receptor superfamily, which
includes the receptors for steroid hormones, retinoids,
thyroid hormone, and vitamin D.1 Like other nuclear
receptors, PPARs are ligand-dependent transcription
factors. Upon binding an agonist, the conformation of
a PPAR is altered and stabilized such that a binding
cleft is created and recruitment of transcriptional coacti-
vators occurs.2 After heterodimerization with another
nuclear receptor, retinoid X receptor (RXR), the PPARs
regulate target gene expression by binding to specific
consensus DNA sequences, termed PPRE (peroxisome
proliferator responsive element),3 which are located in
the regulatory regions of the target gene,4 and result in
an increase in gene transcription.
The PPARs play a critical physiological role as regula-
tors of lipid and glucose metabolism. Three subtypes
of PPARs, termed PPARd, PPARa, and PPARc, have
been identified so far in various species, including hu-
mans.5 PPARd exhibits a wide tissue distribution and
is poorly understood to date. However, PPARd binds
fatty acids and eicosanoids, which suggests an involve-
ment in lipid metabolism.6 PPARa regulates lipid
We have designed several series of compounds by in sil-
ico screening of the virtual library of potential PPAR
agonists.18 The present paper reports the synthesis and
biological studies of the series of azaindole-a-alkyloxy-
phenylpropionic acid analogues.
*
Corresponding author. Tel.: +86 01 6316 5249; fax: +86 01 8315
5752; e-mail: zrguo@imm.ac.cn
0968-0896/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.09.040

Z. Cai et al. / Bioorg. Med. Chem. 14 (2006) 866–874
867
2. Chemistry
more downfield than the calculated value of 7.04 ppm
for that in the cis-isomer with an unsaturated R group.
Therefore, we assume the compounds exist in the cis-
configuration. Such an assumption was supported by
the X-ray crystallography of compound 61 (Fig. 1).
A general strategy to synthesize 6 and 7 is shown in
Scheme 1. The key intermediate 3 undergoes condensa-
tion with ethyl a-alkyloxyl acetate in the presence of
t-BuOK to give 5 in 30–60% yield.
The aldehydes 3 were synthesized as described in
Scheme 2. Dibromoethane or dibromopropane was
treated with 4-hydroxybenzaldehyde in acetone in the
presence of K2CO3 as base to give compound 2 in 60–
70% yield. The aldehyde 2 was then treated with 7-azain-
dole to give compound 3.
4. Results and discussion
4.1. In vitro
Compounds were screened in cell-based transcription
assays using GAL4-PPAR chimeric receptors. Rosiglit-
azone and WY14643 were used as reference agonists in
the PPARc and PPARa transactivation assays, respec-
tively. Maximal activation obtained with the reference
agonist was defined as 100%.
The compounds obtained are summarized in Table 1.
3. Characterization of the olefinic configuration of 6
The structures and transactivation activity of the series
of compounds are summarized in Table 1.
The configuration of olefinic intermediate 6 was identi-
fied by 1H NMR and X-ray crystallography. When R
is an alkyl group in compounds 6, the chemical shift
of the olefin proton ranged between 6.83 and
6.87 ppm. According to the theoretical calculation,19
the chemical shift of the olefinic proton in the cis-isomer
with an alkyl R group is 6.83 ppm, which coincides with
our observed values, while in the corresponding trans-
isomer, the calculated chemical shift of the proton is
6.27 ppm. With an unsaturated R group, the calculated
olefinic proton signal in the cis-isomers moved to
7.04 ppm. It can be derived that with an aryl R group,
the olefinic proton signal in the cis-isomer is expected
to further shift to downfield.20 For the synthesized com-
pounds with an aryloxy group, the observed olefin pro-
ton signal shifted to 7.28–7.35 ppm, which was indeed
As indicated in Table 1, the size of the substituent at
the a-position of the carboxyl group significantly
affected PPARc and PPARa transactivation activity.
Bulky groups generally led to decreased activity with
a
relative activity rank of p-methoxylphenyl
< p/m-methylphenyl < phenyl < cyclohexyl < cyclopentyl.
However, the methyl, ethyl, and iso-propyl substitu-
ents appear to be favorable for transactivation activi-
ty. In addition, the unsaturation of the compounds
conducts an interesting result. Vinyl derivatives with
small substituents, such as –CH3, –C2H5, and
–CH(CH3)2, at the a-position of the carboxyl group,
were less potent than their saturated congeners. In
contrast, vinyl derivatives with bulky substituents,
CHO
COOEt
COOEt
a
+
N
N
N
O
N
O
n
n
O
R
O
R
5
3
b
4
c,d
COOH
COOH
N
O
N
n
N
R
O
O
N
n
R
O
6
7
Scheme 1. Reagents and conditions: (a) t-BuOK, DMF, 2 h; (b) 1 N NaOH, EtOH; (c) 10% Pd/C, H2, EtOH; (d) 1 N NaOH, EtOH.
CHO
CHO
e
Br
+
Br
n
Br
n
O
HO
1
2
CHO
N
N
N
N
f
O
n
3
Scheme 2. Reagents and conditions: (e) K2CO3, acetone; (f) KOH, DMSO, rt, 2 h.

868
Z. Cai et al. / Bioorg. Med. Chem. 14 (2006) 866–874
Table 1. Structures and transactivation activity of the compounds
COOH
R
N
N
O
n
O
Compound
n
R
Single/double
PPARc
PPARa
EC50 (lM)
EC50 (lM)
% max
% max
6a
7a
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
Et
Et
Double
Single
0.6
0.11
129
109
104
89
93
108
85
93
85
79
60
70
85
78
66
47
88
49
68
102
21
50
7
3.63
0.75
4.57
0.46
3.09
0.50
3.24
3.89
3.80
6.03
5.13
5.50
65
65
15
21
18
24
16
23
19
12
6
6b
7b
Me
Me
Double
Single
1.413
0.091
0.603
0.024
0.871
0.977
0.776
2.951
1.413
4.365
1.122
3.715
0.81
6c
7c
i-Pr
i-Pr
Double
Single
6d
7d
Cyclopentyl
Cyclopentyl
Cyclohexyl
Cyclohexyl
Ph
Double
Single
6e
7e
Double
Single
6f
Double
Single
7f
6g
Ph
6
m-Me-Ph
m-Me-Ph
p-Me-Ph
p-Me-Ph
p-MeO-Ph
p-MeO-Ph
Et
Double
Single
ia
ia
3.46
ia
7g
6h
ia
Double
Single
37
37
14
14
17
25
7
7h
6i
5.37
2.57
4.27
5.50
5.37
0.79
5.50
5.37
Double
Single
1.230
5.623
5.370
1.318
4.467
3.236
6.026
6.457
0.068
7i
6j
Double
Single
7j
6k
Et
Cyclopentyl
Cyclopentyl
Ph
Double
Single
7k
6l
12
ia
Double
Single
ia
7l
Ph
6
100
ia
ia
Rosiglitazone
WY14643
39.0
100
ia, inactive.
Figure 1. Structure of compound 61 as determined by X-ray diffraction.
such as cyclopentyl, cyclohexyl, phenyl, methylphenyl,
and metheoxylphenyl, were slightly more potent than
their saturated congeners. The relative activity rank
is probably because of the conformational preference.
Due to a restriction in rotation caused by the double
bonds, the unsaturated compounds are rigid, there-
fore, the activity of these compounds would not sig-
nificantly change. As for the saturated congeners, the
flexibility of the molecules resulted in a fluctuation
in activity. Compounds with small a-substituents can
assume an energetically favorable conformation to fit
the receptor, which leads to a better activity. Howev-
er, compounds with bulky a-substituents may be
excluded by the receptor and cause unfavorable activ-
ity profiles. This interesting phenomenon showed a
strict steric restriction of the right pocket of the
PPARc and PPARa.
The distance between the azaindole group and middle
benzene ring also conveys an important impact on the
PPAR transactivation potency. The change of the spac-
er from two to three carbon atoms, as in 6j, 7j, 6k, 7k,
61, and 71, led to a decrease in potency.
The series of compounds were more potent on PPARc
than on PPARa. However, compound 7a was a full

Z. Cai et al. / Bioorg. Med. Chem. 14 (2006) 866–874
869
PPARc agonist and an almost full PPARa agonist. It
was selected for animal experiments.
300
250
200
150
100
50
Con
AZ-242
7a
4.2. In vivo
In vivo studies were carried out in KKAY mice, which were
used as a type 2 diabetic animal model. Mice (six to eight
per group) were orally administered with vehicle, com-
pound 7a or positive drug AZ242 at a dose of 7 lmol/kg
body weight daily. The blood was collected at days 0,
15, and 25 for measurement of the plasma glucose and tri-
glyceride. The insulin tolerance test (ITT) and the oral
glucose tolerance test (OGTT) were performed on the
15th and 25th day of treatment, respectively. Plasma glu-
cose level was significantly reduced by 7a (Table 2). More-
over, 7a improved the impaired insulin and glucose
tolerance of KKAY mice (Fig. 2, Fig. 3), suggesting that
7a is an effective anti-diabetic agent. Although 7a did
not produce a significant reduction in plasma triglyceride
level after 15 days of treatment in the KKAY mice that
may be insensitive to triglyceride metabolizing, there
was a decrease by 30.4% compared with the control group
(Table 3). The efficacy of 7a on hypetriglyceride is to be
evaluated in a diet-induced obese model or a genetic obese
model (ob/ob).
*
**
**
0
0
30
60
Time (min.)
90
120
Figure 3. Glucose tolerance test in KKAY mice. Glucose tolerance test
was conducted at 25 days of treatment. *p < 0.05, **p < 0.01 vs. Con
group in each group during the same time; n = 6–8.
Table 3. Effect of compound 7a on plasma triglycerides in KKAY mice
Group
Plasma triglycerides (mg/dl)
15 day
0 day
Con
AZ242
7a
263.2 37.3
252.8 37.6
249.0 45.7
394.9 53.3
201.2 8.2**
274.8 27.9
Values are means SE. n = 6–8.
** p < 0.01 vs. Con group in each group during the same day.
5. Experimental
5.1. Biology
or adipose tissues. Amplified cDNAs were cloned into
pcDNA3.1 expression vector and the inserts were con-
firmed by sequencing. U2OS cells were cultured in
McCoyÕs 5A with 10% heat-inactivated fetal bovine ser-
um in a humidified 5% CO2 atmosphere at 37 °C. Cells
were seeded in 96-well plates the day before transfection
to give a confluence of 50–80% at transfection. A total
of 60 ng DNA containing 10 ng hRXR, 10 ng of pCMV
Gal, 10 ng of nuclear receptor expression vectors, and
30 ng of the corresponding reporters were cotransfected
per well using FuGene6 transfection reagent according
to the manufacturerÕs instructions. Following 24 h after
transfection, cells were incubated with 10% charcoal-
stripped FBS DMEM and were treated with the individ-
ual compound dissolved in DMSO. The final concentra-
tion of DMSO in culture medium was 0.1%. Cells were
treated with compound for 24 h and then collected with
Cell Culture Lysis buffer. Luciferase activity was moni-
tored using the luciferase assay kit according to the
manufacturerÕs instructions. Light emission was read
in a Labsystems Ascent Fluoroskan reader. To measure
the galactosidase activity to normalize the luciferase
data, 50 lL of supernatant from each transfection lysate
was transferred to a new microplate. Galactosidase as-
says were performed in the microwell plates using a kit
from Promega and read in a microplate reader.
5.1.1. In vitro transactivation. cDNAs for Human RXR,
PPAR were obtained by RTPCR from the human liver
Table 2. Effect of compound 7a on plasma glucose in KKAY mice
Group
Plasma glucose (mg/dl)
15 day
0 day
25 day
Con
AZ242
149.1 31.8
163.7 52.5
228.4 49.0
95.6 5.5*
159.3 31.3
85.6 2.8*
7a
139.0 26.5
101.0 4.4*
85.9 1.1*
Values are means SE. n = 6–8.
* p < 0.05 versus Con group in each group during the same day.
120
Con
AZ242
7a
100
80
60
40
20
0
*
*
5.1.2. In vivo animal study. Spontaneous diabetic KKAY
mice were procured from Institute of Laboratory Ani-
mal Science, Chinese Academy of Medical Sciences
(Beijing, China), and were used experimentally when
they reach an age of 10–12 weeks. KKAY mice were
bred at specific pathogen free (SPF) animal house.
0
30
60
90
Time (min.)
Figure 2. Insulin tolerance test in KKAY mice. Insulin tolerance test
was conducted at 15 days of treatment. *p < 0.05 versus Con group in
each group during the same time; n = 6–8.

870
Z. Cai et al. / Bioorg. Med. Chem. 14 (2006) 866–874
All animals were maintained at controlled tempera-
ture (22 1 °C), under 12 h light/dark cycles, and
given high fat diet and water ad libitum. For insulin
and glucose tolerance tests, animals were fasted for
4 h and a basal blood sample was taken, followed
by sc insulin (0.5 IU/kg) or i.g. injection of glucose
(2 g/kg). Blood samples were drawn at 0, 40, and
90 min or at 0, 30, 60, and 120 min after the
administration.
6.3. 2-Ethoxy-3-[4-(2-pyrrolo[2,3-b]pyridine-1-yl-ethoxy)-
phenyl]-propionic acid (7a)
A solution of the appropriate 2-ethoxy-3-[4-(2-pyrrol-
o[2,3-b]pyridine-1-yl-ethoxy)-phenyl]-arylic acid ethyl
ester (300 mg, 0.78 mmol) in ethanol was added to
10% Pd-C and hydrogenated at 3 atm for 6 h. The mix-
ture was filtered and the filtrate was evaporated to dry-
ness under reduced pressure. The residue was
hydrolyzed according to the procedure described for
6a and recrystallized to give white crystals in 66.9%
yield. Mp 124–126 °C.
6. Chemistry
1H NMR (DMSO-d6, 300 MHz) d ppm: 8.246 (dd, 1H,
J = 5.1 Hz, J = 1.5 Hz, ArH), 7.959 (dd, 1H, J = 7.5 Hz,
J = 1.5 Hz, ArH), 7.606 (d, 1H, J = 3.3 Hz, ArH), 7.090
(d, 2H, J = 8.7 Hz, ArH), 7.076 (d, 1H, J = 7.5 Hz,
ArH), 6.805 (d, 2H, J = 8.7 Hz, ArH), 6.470 (d, 1H,
J = 3.3 Hz, ArH), 4.620 (t, 2H, J = 5.4 Hz, –OCH2–),
4.300 (t, 2H, J = 5.4 Hz, –NCH2–), 3.927–3.883 (m,
1H, –OCH–), 3.502–3.209 (m, 2H, –OCH2–), 2.878–
2.721 (m, 2H, –ArCH2–), 1.008 (t, 3H, –CH3).
6.1. General methods
All melting points were determined with a Yanaco
micromelting point apparatus without correction.1H
NMR spectra were measured using a Varian Unity
INOVA 300 MHz instrument. Chemical shifts were
reported in ppm (d) values, based on tetramethylsilane
as an internal standard. Ms spectra were recorded using
an AutoSpec Ultima-TOF mass spectrometer. Column
chromatography was performed on silica gel (QingDao
HaiYang Chemical Co., Ltd., 200–300 mesh).
HRFAB-MS calcd for C20H23N2O4 [M+H]+:
355.165782. Found: 355.165161.
6.2. 2-Ethoxy-3-[4-(2-pyrrolo[2,3-b]pyridine-1-yl-ethoxy)-
phenyl]-arylic acid (6a)
6.4. 2-Methoxy-3-[4-(2-pyrrolo[2,3-b]pyridine-1-yl-eth-
oxy)-phenyl]-arylic acid (6b)
4-(2-Pyrrolo[2,3-b]pyridine-1-yl-ethoxy)-benzaldehyde
(1.622 g, 6 mmol) and ethyl-ethoxyl acetate (0.872 g,
6.6 mmol) were added to 20 ml anhydrous DMF sol-
vent. Then IN t-BuOK(7 ml) was added dropwise to
the solution under ice bath cooling and the mixture
was stirred for 4 h at room temperature. After adding
1 N HCl to pH 7, the solution was diluted with H2O
and extracted with AcOEt. The extract was washed
with brine, dried over Na2SO4, and concentrated in
vacuo. The residue was separated by silica gel column
chromatography (hexanes/AcOEt, 6:1 as an eluent) to
The compound was prepared from 4-(2-pyrrolo[2,3-
b]pyridine-1-yl-ethoxy)-benzaldehyde and ethyl a-me-
thoxyl acetate according to the procedure described
for 6a. Mp 157–159 °C.
1H NMR (DMSO-d6, 300 MHz) d ppm: 8.253 (d, 1H,
J = 4.2 Hz, ArH), 7.966 (d, 1H, J = 7.8 Hz, ArH),
7.673 (d, 2H, J = 8.7 Hz, ArH), 7.618 (d, 1H,
J = 3.5 Hz, ArH), 7.093 (dd, 1H, J = 7.8 Hz,
J = 4.2 Hz, ArH), 6.939 (d, 2H, J = 8.7 Hz, ArH),
6.855 (s, 1H, @CH–), 6.478 (d, 1H, J = 3.5 Hz, ArH),
4.649 (t, 2H, J = 5.4 Hz, –OCH2–), 4.389 (t, 2H,
J = 5.4 Hz, –NCH2–), 3.656 (s, 3H, –CH3).
give
2-ethoxy-3-[4-(2-pyrrolo[2,3-b]pyridine-1-yl-eth-
oxy)-phenyl]-arylic acid ethyl ester 853 mg (36.8%).
The ester (503 mg, 1.32 mmol) was dissolved in etha-
nol (20 ml) and 1 N sodium hydroxide (5 ml) was
added. The mixture was stirred for 3 h at room tem-
perature. The ethanol was evaporated in vacuo, water
and 1 N HCl were added to pH 2. The acid solution
was extracted three times with AcOEt. The extract
was washed with brine, dried over Na2SO4, and con-
centrated in vacuo. The residue was crystallized to
give title compound (6a) 147 mg (31.6%). Mp 135–
139 °C. 1H NMR (DMSO-d6, 300 MHz) d ppm:
8.246 (d, 1H, J = 4.8 Hz, ArH), 7.962 (d, 1H,
J = 7.8 Hz, ArH), 7.705 (d, 2H, J = 8.7 Hz, ArH),
7.608 (d, 1H, J = 3.6 Hz, ArH), 7.088 (dd, 1H,
J = 7.8 Hz, J = 4.8 Hz, ArH), 6.926 (d, 2H,
J = 8.7 Hz, ArH), 6.857 (s, 1H, @CH–), 6.472 (d,
1H, J = 3.6 Hz, ArH), 4.642 (t, 2H, J = 5.4 Hz,
–OCH2–), 4.379 (t, 2H, J = 5.4 Hz, –NCH2–), 3.905
(q, 2H, J = 6.9 Hz, –OCH2–), 1.233 (t, 3H, –CH3).
HRFAB-MS calcd for C19H19N2O4 [M+H]+:
339.134482. Found: 339.131874.
6.5. 2-Methoxy-3-[4-(2-pyrrolo [2,3-b] pyridine-1-yl-eth-
oxy)-phenyl]-propionic acid (7b)
The compound was prepared from 2-methoxy-3-[4-(2-
pyrrolo[2,3-b]pyridine-1-yl-ethoxy)-phenyl]-arylic acid
ethyl ester according to the procedure described for
7a. Mp 118–119 °C.
1H NMR (DMSO-d6, 300 MHz) d ppm: 8.25l (dd, 1H,
J = 4.8 Hz, J = 1.2 Hz, ArH), 7.963 (dd, 1H,
J = 7.5 Hz, J = 1.2 Hz, ArH), 7.611 (d, 1H, J = 3.6 Hz,
ArH), 7.109–7.070 (m, 3H, ArH), 6.811 (d, 2H,
J = 8.7 Hz, ArH), 6.480 (d, 1H, J = 3.6 Hz, ArH),
4.625 (t, 2H, J = 5.4 Hz, –OCH2–), 4.308 (t, 2H,
J = 5.4 Hz, –NCH2–), 3.862–3.820 (m, 1H, –OCH–),
HRFAB-MS calcd for C20H21N2O4 [M+H]+:
353.150132. Found: 353.152184.
3.183 (s, 3H, –OCH ), 2.898–2.726 (m, 2H, ArCH2–).
3

Z. Cai et al. / Bioorg. Med. Chem. 14 (2006) 866–874
871
HRFAB-MS calcd for C19H21N2O4 [M+H]+:
341.150132. Found: 341.149010.
HRFAB-MS calcd for C23H27N2O4 [M+H]+:
393.181433. Found: 393.181343.
6.9. 2-Cyclopentyloxy-3-[4-(2-pyrrolo[2,3-b]pyridine-1-yl-
ethoxy)-phenyl]-propionic acid (7d)
6.6. 2-Isopropoxy-3-[4-(2-pyrrolo[2,3-b]pyridine-1-yl-eth-
oxy)-phenyl]-arylic acid (6c)
The compound was prepared from 2-cyclopentyloxyl-3-
[4-(2-pyrrolo[2,3-b]pyridine-1-yl-ethoxy)-phenyl]-arylic
acid ethyl ester according to the procedure described
for 7a. Mp 94–96 °C.
The compound was prepared from 4-(2-pyrrolo[2,3-
b]pyridine-1-yl-ethoxy)-benzaldehyde and ethyl a-iso-
propoxyl acetate according to the procedure described
for 6a. Mp 112–113 °C.
1H NMR (DMSO-d6, 400 MHz) d ppm: 8.246 (d, 1H,
J = 4.8 Hz, ArH), 7.959 (d, 1H, J = 7.6 Hz, ArH),
7.600 (d, 1H, J = 3.6 Hz, ArH), 7.101–7.071 (m, 3H,
ArH), 6.805 (d, 2H, J = 8.0 Hz, ArH), 6.470 (d, 1H,
J = 3.6 Hz, ArH), 4.618 (t, 2H, J = 5.6 Hz, –OCH2–),
4.300 (t, 2H, J = 5.6 Hz, –NCH2–), 3.881–3.848 (m,
1H, –OCH–), 3.828–3.821 (m, 1H, –OCH–), 2.842–
2.649 (m, 2H, –ArCH2–), 1.567–1.276 (m, 8H,
–CH2–).
1H NMR (DMSO-d6, 400 MHz) d ppm: 8.249 (d, 1H,
J = 4.8 Hz, ArH), 7.959 (d, 1H, J = 7.6 Hz, ArH),
7.750 (d, 2H, J = 8.8 Hz, ArH), 7.615 (d, 1H,
J = 3.6 Hz, ArH), 7.088 (dd, 1H, J = 7.6 Hz,
J = 4.8 Hz, ArH), 6.912 (d, 2H, J = 8.8 Hz, ArH),
6.858 (s, 1H, @CH–), 6.472 (d, 1H, J = 3.6 Hz, ArH),
4.643 (t, 2H, J = 5.2 Hz, –OCH2–), 4.431–4.416 (m,
1H, –OCH–), 4.376 (t, 2H, J = 5.2 Hz, –NCH2–),
1.174 (s, 3H, –CH3), 1.158 (s, 3H, -CH3).
HRFAB-MS calcd for C23H27N2O4 [M+H]+:
395.197083. Found: 395.195595.
HRFAB-MS calcd for C21H23N2O4 [M+H]+:
367.165782. Found: 367.163269.
6.10. 2-Cyclohexyloxy-3-[4-(2-pyrrolo[2,3-b]pyridine-1-
yl-ethoxy)-phenyl]-arylic acid (6e)
6.7. 2-Isopropoxy-3-[4-(2-pyrrolo[2,3-b]pyridine-1-yl-eth-
oxy)-phenyl]-propionic acid (7c)
The compound was prepared from 4-(2-pyrrolo[2,3-
b]pyridine-1-yl-ethoxy)-benzaldehyde and ethyl a-cyclo-
hexyloxyl acetate according to the procedure described
for 6a. Mp 87–89 °C.
The compound was prepared from 2-isopropoxy-3-[4-(2-
pyrrolo[2,3-b]pyridine-1-yl-ethoxy)-phenyl]-arylic acid eth-
yl ester according to the procedure described for 7a. Mp
85–87 °C.
1H NMR (DMSO-d6, 400 MHz) d ppm: 8.248 (d, 1H,
J = 4.4 Hz, ArH), 7.958 (d, 1H, J = 8.0 Hz, ArH),
7.733 (d, 2H, J = 8.8 Hz, ArH), 7.612 (d, 1H,
J = 3.2 Hz, ArH), 7.087 (dd, 1H, J = 8.0 Hz,
J = 4.4 Hz, ArH), 6.910 (d, 2H, J = 8.8 Hz, ArH),
6.826 (s, 1H, @CH–), 6.472 (d, 1H, J = 3.2 Hz, ArH),
4.643 (t, 2H, J = 5.2 Hz, –OCH2–), 4.377 (t, 2H,
J = 5.2 Hz, –NCH2–), 4.154–4.107 (m, 1H, –OCH–),
1.897–1.093 (m, 10H, –CH2–).
1H NMR (DMSO-d6, 400 MHz) d ppm: 8.236 (d, 1H,
J = 3.3 Hz, ArH), 7.949 (d, 1H, J = 7.6 Hz, ArH),
7.595 (d, 1H, J = 3.6 Hz, ArH), 7.096–7.060 (m, 3H,
ArH), 6.794 (d, 2H, J = 8.4 Hz, ArH), 6.459 (d, 1H,
J = 3.6 Hz, ArH), 4.609 (t, 2H, J = 5.6 Hz, –OCH2–),
4.289 (t, 2H, J = 5.6 Hz, –NCH2–), 3.958–3.926 (m,
1H, –OCH–), 3.456–3.426 (m, 1H, –OCH–), 2.836–
2.658 (m, 2H, –ArCH2–), 1.008 (d, 2H, J = 6.0 Hz,
–CH3), 0.845 (d, 2H, J = 6.0 Hz, –CH3).
HRFAB-MS calcd for C24H27N2O4 [M+H]+:
407.197083. Found: 407.193535.
HRFAB-MS calcd for C21H25N2O4 [M+H]+:
369.181433. Found: 369.182716.
6.8. 2-Cyclopentyloxy-3-[4-(2-pyrrolo[2,3-b]pyridine-1-yl-
ethoxy)-phenyl]-arylic acid (6d)
6.11. 2-Cyclohexyloxy-3-[4-(2-pyrrolo[2,3-b]pyridine-1-
yl-ethoxy)-phenyl]-propionic acid (7e)
The compound was prepared from 4-(2-pyrrolo[2,3-
b]pyridine-1-yl-ethoxy)-benzaldehyde and ethyl a-cyclo-
pentyloxyl acetate according to the procedure described
for 6a. Mp 123–125 °C.
The compound was prepared from 2-cyclohexyloxy-3-
[4-(2-pyrrolo[2,3-b]pyridine-1-yl-ethoxy)-phenyl]-arylic
acid ethyl ester according to the procedure described for
7a. Mp 83–85 °C.
1H NMR (DMSO-d6, 400 MHz) d ppm: 8.248 (d, 1H,
J = 4.4 Hz, ArH), 7.960 (d, 1H, J = 7.6 Hz, ArH),
7.678 (d, 2H, J = 8.4 Hz, ArH), 7.616 (d, 1H,
J = 3.6 Hz, ArH), 7.088 (dd, 1H, J = 7.6 Hz,
J = 4.4 Hz, ArH), 6.909 (d, 2H, J = 8.4 Hz, ArH),
6.835 (s, 1H, @CH–), 6.472 (d, 1H, J = 3.6 Hz, ArH),
4.83l (s, 1H, –OCH–), 4.640 (t, 2H, J = 5.2 Hz,
–OCH2–), 4.372 (t, 2H, J = 5.2 Hz, –NCH2–), 1.633–
1.487 (m, 8H, –CH2–).
1H NMR (DMSO-d6, 400 MHz) d ppm: 8.246 (dd, 1H,
J = 4.8 Hz, J = 1.6 Hz, ArH), 7.957 (dd, 1H, J = 7.6 Hz,
J = 1.6 Hz, ArH), 7.596 (d, 1H, J = 3.6 Hz, ArH),
7.113–7.069 (m, 3H, ArH), 6.805 (d, 2H, J = 8.8 Hz,
ArH), 6.469 (d, 1H, J = 3.6 Hz, ArH), 4.618 (t, 2H,
J = 5.6 Hz, –OCH2À), 4.303 (t, 2H, J = 5.6 Hz,
–NCH2–), 4.007–3.974 (m, 1H, –OCH–), 3.196–3.153
(m, 1H, –OCH–), 2.857–2.679 (m, 2H, –ArCH2–),
1.708–0.974 (m, 10H, –CH2–).

872
Z. Cai et al. / Bioorg. Med. Chem. 14 (2006) 866–874
HRFAB-MS calcd for C24H29N2O4 [M+H]+:
409.212733. Found: 409.213448.
6.15. 2-m-Tolyloxy-3-[4-(2-pyrrolo[2,3-b]pyridine-1-yl-
ethoxy)-phenyl]-propionic acid (7g)
6.12. 2-Phenoxy-3-[4-(2-pyrrolo[2,3-b]pyridine-1-yl-eth-
oxy)-phenyl]-arylic acid (6f)
The compound was prepared from 2-m-tolyloxy-3-[4-(2-
pyrrolo[2,3-b]pyridine-1-yl-ethoxy)-phenyl]-arylic acid
ethyl ester according to the procedure described for
7a. Mp 160–162 °C.
The compound was prepared from 4-(2-pyrrolo[2,3-
b]pyridine-1-yl-ethoxy)-benzaldehyde and ethyl a-phe-
noxyl acetate according to the procedure described for
6a. Mp 192–193 °C.
1H NMR (DMSO-d6, 300 MHz) d ppm: 8.238 (dd, 1H,
J = 5.1 Hz, J = 1.2 Hz, ArH), 7.950 (dd, 1H, J = 8.1 Hz,
J = 1.2 Hz, ArH), 7.595 (d, 1H, J = 3.9 Hz, ArH), 7.182
(d, 2H, J = 9.0 Hz, ArH), 7.114–7.058 (m, 2H, ArH),
6.826 (d, 2H, J = 9.0 Hz, ArH), 6.707 (d, 1H,
J = 7.5 Hz, ArH), 6.620–6.571 (m, 2H, ArH), 6.459 (d,
1H, J = 3.9 Hz, ArH), 4.809-4.767 (m, 1H, –OCH–),
4.612 (t, 2H, J = 5.4 Hz, –OCH2–), 4.301 (t, 2H,
J = 5.4 Hz, –NCH2–), 3.066–3.022 (m, 2H, –ArCH2–),
2.206 (s, 3H, –CH3).
1H NMR (DMSO-d6, 400 MHz) d ppm: 8.226 (d, 1H,
J = 4.8 Hz, ArH), 7.942 (d, 1H, J = 7.6 Hz, ArH),
7.617 (d, 2H, J = 8.8 Hz, ArH), 7.579 (d, 1H,
J = 3.6 Hz, ArH), 7.339 (s, 1H, @CH–), 7.315–7.274
(m, 2H, ArH), 7.072 (dd, 1H, J = 7.6 Hz, J = 4.8 Hz,
ArH), 7.026–6.989 (m, 1H, ArH), 6.937–6.900 (m, 4H,
ArH), 6.449 (d, 1H, J = 3.6 Hz, ArH), 4.612 (t, 2H,
J = 5.2 Hz, –OCH2–), 4.354 (t, 2H, J = 5.2 Hz,
–NCH2–).
HRFAB-MS calcd for C25H25N2O4 [M+H]+:
417.181433. Found: 417.180496.
HRFAB-MS calcd for C24H21N2O4 [M+H]+:
401.150132. Found: 401.149345.
6.16. 2-p-Tolyloxy-3-[4-(2-pyrrolo[2,3-b]pyridine-1-yl-
ethoxy)-phenyl]-arylic acid (6h)
6.13. 2-Phenoxy-3-[4-(2-pyrrolo[2,3-b]pyridine-1-yl-eth-
oxy)-phenyl]-propionic acid (7f)
The compound was prepared from 4-(2-pyrrolo[2,3-
b]pyridine-1-yl-ethoxy)-benzaldehyde and ethyl a-p-tol-
yloxyl acetate according to the procedure described for
6a. Mp 187–190 °C.
The compound was prepared from 2-phenoxy-3-[4-(2-
pyrrolo[2,3-b]pyridine-1-yl-ethoxy)-phenyl]-arylic acid
ethyl ester according to the procedure described for
7a. Mp 120–123 °C.
2H NMR(DMSO-d6, 300 MHz) 5 ppm: 8.225 (d, 1H,
J = 4.2 Hz, ArH), 7.942 (d, 1H, J = 6.6 Hz, ArH),
7.609 (d, 2H, J = 8.7 Hz, ArH), 7.577 (d, 1H,
J = 3.3 Hz, ArH), 7.304 (s, 1H, @CH–), 7.102–7.052
(m, 3H, ArH), 6.905 (d, 2H, J = 8.7 Hz, ArH),
6.806(d, 2H, J = 8.1 Hz, ArH), 6.449 (d, 1H,
J = 3.3 Hz, ArH), 4.613 (t, 2H, J = 5.4 Hz, –OCH2–),
4.354 (t, 2H, J = 5.4 Hz, –NCH2À), 2.216 (s, 3H, –CH3).
1H NMR (DMSO-d6, 300 MHz) d ppm: 8.243 (d, 1H,
J = 4.5 Hz, ArH), 7.947 (d, 1H, J = 7.8 Hz, ArH),
7.599 (d, 1H, J = 3.6 Hz, ArH), 7.250–7.057 (m, 5H,
ArH), 6.918–6.784 (m, 5H, ArH), 6.458 (d, 1H,
J = 3.6 Hz, ArH), 4.841–4.799 (m, 1H, –OCH–), 4.612
(t, 2H, J = 5.4 Hz, –OC2–), 4.301 (t, 2H, J = 5.4 Hz,
–NCH2–), 3.129–2.994 (m, 2H, –ArCH2–).
HRFAB-MS calcd for C25H23N2O4 [M+H]+:
415.165782. Found: 415.165710.
HRFAB-MS calcd for C24H23N2O4 [M+H]+:
403.165782. Found: 403.167694.
6.17. 2-p-Tolyloxy-3-[4-(2-pyrrolo[2,3-b]pyridine-1-yl-
ethoxy)-phenyl]-propionic acid (7h)
6.14. 2-m-Tolyloxy-3-[4-(2-pyrrolo[2,3-b]pyridine-1-yl-
ethoxy)-phenyl]-arylic acid (6g)
The compound was prepared from 2-p-tolyloxy-3-[4-(2-
pyrrolo[2,3-b]pyridine-1-yl-ethoxy)-phenyl]-arylic acid
ethyl ester according to the procedure described for
7a. Mp 109–115 °C.
The compound was prepared from 4-(2-pyrrolo[2,3-
b]pyridine-1-yl-ethoxy)-benzaldehyde and ethyl a-m-tol-
yloxyl acetate according to the procedure described for
6a. Mp 165–167 °C.
1H NMR (DMSO-d6, 300 MHz) d ppm: 8.240 (d, 1H,
J = 4.5 Hz, ArH), 7.953 (d, 1H, J = 8.1 Hz, ArH),
7.593 (d, 1H, J = 3.3 Hz, ArH), 7.177 (d, 2H,
J = 8.1 Hz, ArH), 7.087 (m, 1H, ArH), 7.071 (m, 1H,
ArH), 7.014 (m, 1H, ArH), 6.837–6.794 (m, 2H, ArH),
6.689 (d, 2H, J = 8.1 Hz, ArH), 6.459 (d, 1H,
J = 3.3 Hz, ArH), 4.780–4.738 (m, 1H, –OCH–), 4.612
(t, 2H, J = 5.4 Hz, –OCH2–), 4.300 (t, 2H, J = 5.4 Hz,
–NCH2–), 3.058–3.021 (m, 2H, ArCH2–), 2.176 (s, 3H,
–CH3).
1H NMR (DMSO-d6, 300 MHz) d ppm: 8.230 (d, 1H,
J = 4.8 Hz, ArH), 7.946 (d, 1H, J = 7.5 Hz, ArH),
7.618 (d, 2H, J = 8.7 Hz, ArH), 7.582 (d, 1H,
J = 3.3 Hz, ArH), 7.319 (s, 1H, @CH–), 7.197–7.145
(m, 1H, ArH), 7.076 (dd, 1H, J = 7.5 Hz, J = 4.8 Hz,
ArH), 6.917 (d, 2H, J = 8.7 Hz, ArH), 6.838–6.694 (m,
3H, ArH), 6.453 (d, 1H, J = 3.3 Hz, ArH), 4.617 (t,
2H, J = 5.4 Hz, –OCH2–), 4.359 (t, 2H, J = 5.4 Hz,
–NCH2–), 2.254 (s, 3H, –CH3).
HRFAB-MS calcd for C25H23N2O4 [M+H]+:
415.165782. Found: 415.166252.
HRFAB-MS calcd for C25H25N2O4 [M+H]+:
417.181433. Found: 417.180962.

Z. Cai et al. / Bioorg. Med. Chem. 14 (2006) 866–874
873
6.18. 2-(4-Methoxy-phenoxy)-3-[4-(2-pyrrolo[2,3-b]pyri-
dine-1-yl-ethoxy)-phenyl]-arylic acid (6i)
6.21. 2-Ethoxy-3-[4-(3-pyrrolo[2,3-b]pyridine-1-yl-prop-
oxy)-phenyl]-propionic acid (7j)
The compound was prepared from 4-(2-pyrrolo[2,3-
b]pyridine-1-yl-ethoxy)-benzaldehyde and (4-methoxy-
phenoxy)-acetic acid ethyl ester according to the proce-
dure described for 6a. Mp 170–173 °C.
The compound was prepared from 2-ethoxy-3-[4-(3-pyr-
rolo[2,3-b]pyridine-1-yl-propoxy)-phenyl]-arylic acid
ethyl ester according to the procedure described for
7a. Mp 90–92 °C.
1H NMR (DMSO-d6, 300 MHz) d ppm: 8.233 (d, 1H,
J = 4.5 Hz, ArH), 7.948 (d, 1H, J = 7.5 Hz, ArH),
7.628 (d, 2H, J = 8.7 Hz, ArH), 7.585 (d, 1H,
J = 3.6 Hz, ArH), 7.283 (s, 1H, @CH–), 7.078 (dd, 1H,
J = 7.5 Hz, J = 4.5 Hz, ArH), 6.915 (d, 2H, J = 8.7 Hz,
ArH), 6.880–6.823 (m, 4H, ArH), 6.456 (d, 1H,
J = 3.6 Hz, ArH), 4.621 (t, 2H, J = 5.4 Hz, –OCH2–),
4.361 (t, 2H, J = 5.4 Hz, –NCH2–), 3.677 (s, 3H,
–OCH3).
1H NMR (DMSO-d6, 400 MHz) d ppm: 8.229 (dd, 1H,
J = 4.4 Hz, J = 1.6 Hz, ArH), 7.948 (dd, 1H, J = 7.6 Hz,
J = 1.6 Hz, ArH), 7.532 (d, 1H, J = 3.6 Hz, ArH), 7.105
(d, 2H, J = 8.4 Hz, ArH), 7.066 (d, 1H, J = 7.6 Hz,
J = 4.4 Hz, ArH), 6.795 (d, 2H, J = 8.4 Hz, ArH),
6.452 (d, 1H, J = 3.6 Hz, ArH), 4.419 (t, 2H,
J = 6.8 Hz, –OCH2–), 3.938–3.884 (m, 3H, –NCH2–,
–OCH–), 3.535–3.248 (m, 2H, –OCH2–), 2.886–2.752
(m, 2H, –ArCH2–), 2.267–2.201 (m, 2H, –CH2–), 1.028
(t, 3H, –CH3).
HRFAB-MS calcd for C25H23N2O5 [M+H]+:
431.160697. Found: 431.162766.
HRFAB-MS calcd for C21H25N2O4 [M+H]+:
369.181433. Found: 369.182671.
6.19. 2-(4-Methoxy-phenoxy)-3-[4-(2-pyrrolo[2,3-
b]py ridine-1-yl-ethoxy)-phenyl]-propionic acid (7i)
6.22. 2-Cyclopentyloxy-3-[4-(3-pyrrolo[2,3-b]pyridine-1-
yl-propoxy)-phenyl]-arylic acid (6k)
The compound was prepared from 2-(4-methoxy-phen-
oxy)-3-[4-(2-pyrrolo[2,3-b]pyridine-1-yl-ethoxy)-phen-
yl]-arylic acid ethyl ester according to the procedure
described for 7a. Mp 152–153 °C.
The compound was prepared from 4-(3-pyrrolo[2,3-
b]pyridine-1-yl-propoxy)-benzaldehyde and ethyl a-
cyclopentyloxyl acetate according to the procedure
described for 6a. Mp 169–171 °C.
1H NMR (DMSO-d6, 300 MHz) d ppm: 8.243 (d, 1H,
J = 3.3 Hz, ArH), 7.956 (d, 1H, J = 7.8 Hz, ArH),
7.600 (d, 1H, J = 2.7 Hz, ArH), 7.181 (d, 2H,
J = 8.4 Hz, ArH), 7.088 (m, 1H, J = 3.3 Hz,
J = 7.8 Hz, ArH), 6.844–6.717 (m, 6H, ArH), 6.463(d,
1H, J = 2.7 Hz, ArH), 4.725–4.683 (m, 1H, –OCH–),
4.616 (t, 2H, J = 5.1 Hz, –OCH2–), 4.305 (t, 2H,
J = 5.1 Hz, –NCH2–), 3.650 (s, 3H, –OCH3, 3.035–
3.010 (m, 2H, ArCH2).
1H NMR (DMSO-d6, 400 MHz) d ppm: 8.214 (d, 1H,
J = 4.8 Hz, ArH), 7.947 (d, 1H, J = 7.6 Hz, ArH),
7.689 (d, 2H, J = 8.8 Hz, ArH), 7.542 (d, 1H,
J = 3.6 Hz, ArH), 7.06l (dd, 1H, J = 7.6 Hz,
J = 4.8 Hz, ArH), 6.883 (d, 2H, J = 8.8 Hz, ArH),
6.836 (s, 1H, @CH–), 6.454 (d, 1H, J = 3.6 Hz, ArH),
4.842 (s, 1H, –OCH–), 4.425 (t, 2H, J = 6.8 Hz,
–OCH2–), 3.967 (t, 2H, J = 6.8 Hz, –NCH2–), 2.285–
2.220 (m, 2H, –CH2–), 1.653–1.466 (m, 8H, –CH2–).
HRFAB-MS calcd for C25H25N2O5 [M+H]+:
433.176347. Found: 433.175362.
HRFAB-MS calcd for C24H27N2O4 [M+H]+:
407.197083. Found: 407.199821.
6.20. 2-Ethoxy-3-[4-(3-pyrrolo[2,3-b]pyridine-1-yl-prop-
oxy)-phenyl]-arylic acid (6j)
6.23. 2-Cyclopentyloxy-3-[4-(3-pyrrolo[2,3-b]pyridine-1-
yl-propoxy)-phenyl]-propionic acid (7k)
The compound was prepared from 4-(3-pyrrolo[2,3-
b]pyridine-1-yl-propoxy)-benzaldehyde and ethyl a-eth-
oxyl acetate according to the procedure described for
6a. Mp 166–167 °C.
The compound was prepared from 2-cyclopentyloxy-3-
[4-(3-pyrrolo[2,3-b]pyridine-1-yl-propoxy)-phenyl]-ary-
lic acid ethyl ester according to the procedure described
for 7a. Mp 118–121 °C.
1H NMR (DMSO-d6, 300 MHz) d ppm: 8.233 (d, 1H,
J = 4.8 Hz, ArH), 7.950 (d, 1H, J = 7.8 Hz, ArH),
7.723 (d, 2H, J = 8.7 Hz, ArH), 7.543 (d, 1H,
J = 3.3 Hz, ArH), 7.065 (dd, 1H, J = 7.8 Hz,
J = 4.8 Hz, ArH), 6.910 (d, 2H, J = 8.7 Hz, ArH),
6.873 (s, 1H, @CH–), 6.456 (d, 1H, J = 3.3 Hz, ArH),
4.428 (t, 2H, J = 6.9 Hz, –OCH2–), 3.991–3.894 (m,
4H, –CH2–), 2.302–2.216 (m, 2H, –CH2–), 1.255 (t,
3H, –CH3).
1H NMR (DMSO-d6, 400 MHz) d ppm: 8.225 (d, 1H,
J = 4.4 Hz, ArH), 7.945 (d, 1H, J = 7.6 Hz, ArH),
7.517 (d, 1H, J = 3.2 Hz, ArH), 7.104–7.046 (m, 3H,
ArH), 6.787 (d, 2H, J = 7.6 Hz, ArH), 6.443 (d, 1H,
J = 3.6 Hz, ArH), 4.416 (t, 2H, J = 6.8 Hz, –OCH–),
3.907–3.838 (m, 3H, –NCH2–, –OCH–), 2.858–2.663
(m, 2H, –ArCH2–), 2.260–2.195 (m, 2H, –CH2–),
1.598–1.292 (m, 2H, -CH2–).
HRFAB-MS calcd for C21H23N2O4 [M+H]+:
367.165782. Found: 367.164642.
HRFAB-MS calcd for C24H29N2O4 [M+H]+:
409.212733. Found: 409.214523.

874
Z. Cai et al. / Bioorg. Med. Chem. 14 (2006) 866–874
6.24. 2-Phenoxy-3-[4-(3-pyrrolo[2,3-b]pyridine-1-yl-prop-
oxy)-phenyl]-arylic acid (6l)
References and notes
1. Port, D., Jr.; Schwartz, M. W. Science 1996, 272, 699.
2. Berger, J.; David, E. Annu. Rev. Med. 2002, 53, 409.
3. Kliewer, S. A.; Umesono, K.; Noonan, D. J.; Heyman, R.
A.; Evans, R. M. Nature (Lond.) 1992, 358, 771.
4. Keller, H.; Dreyer, C.; Medin, J.; Mahoudi, A.; Ozato, K.;
Wahli, W. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 2160.
5. Dreyer, C.; Krey, G.; Keller, H.; Givel, F.; Helftenbein,
G.; Wahli, W. Cell 1992, 68, 879.
6. Willson, T. M.; Brown, P. J.; Sternbach, D. D.; Henke, B.
R. J. Med. Chem. 2000, 43, 527.
7. Torra, I. P.; Gervois, P.; Staels, B. Curr. Opin. Lipidol.
1999, 10, 151.
8. Frick, M. H.; Elo, O.; Haapa, K.; Heinonen, O. P.;
Heinsalmi, P.; Helo, P.; Huttunen, J. K.; Kaitaniemi, P.;
Koskinen, P.; Manninen, V.; Maenpaa, H.; Malkonen,
M.; Manttari, M.; Norola, S.; Pasternack, A.; Pikkarai-
nen, J.; Romo, M.; Sjoblom, T.; Nikkila, E. A. N. Engl. J.
Med. 1986, 314, 488.
9. Staels, B.; Dallongeville, J.; Auwerx, J.; Schoonjans, K.;
Leitersdorf, E.; Fruchart, J. C. Circulation 1998, 98, 2088.
10. Chaput, E.; Saladin, R.; Silvestre, M.; Edgar, A. D.
Biochem. Biophys. Res. Commun. 2000, 271, 445.
11. Lehmann, J. M.; Moore, L. B.; Simth-Oliver, T. A.;
Wilkison, W. O.; Willson, T. M.; Kliewer, S. A. J. Biol.
Chem. 1995, 270, 12953.
12. Willlson, T. M.; Cobb, J. E.; Cowan, D. J.; Wiethe, R. W.;
Correa, I. D.; Prakash, S. R.; Beck, K. D.; Moore, L. B.;
Kliewer, S. A.; Lehmann, J. M. J. Med. Chem. 1996, 39, 665.
13. Aronoff, S.; Rosenblatt, S.; Braithwaite, S.; Egan, J. W.;
Mathisen, A. L.; Schneider, R. L. Diabetes Care 2000, 23,
1605.
The compound was prepared from 4-(3-pyrrolo[2,3-
b]pyridine-1-yl-propoxy)-benzaldehyde and ethyl a-phe-
noxyl acetate according to the procedure described for
6a. Mp 190–191 °C.
1H NMR (DMSO-d6, 400 MHz) d ppm: 8.193 (d, 1H,
J = 4.4 Hz, ArH), 7.929 (d, 1H, J = 7.6 Hz, ArH),
7.628 (d, 2H, J = 8.7 Hz, ArH), 7.510 (d, 1H,
J = 3.6 Hz, ArH), 7.347 (s, 1H, @CH–), 7.330-7.290
(m, 2H, ArH), 7.059–6.868 (m, 5H, ArH),6.432 (d, 1H,
J = 3.6 Hz, ArH), 4.393 (t, 2H, J = 6.8 Hz, –OCH2–),
3.939 (t, 2H, J = 6.8 Hz, –NCH2–), 2.258–2.210 (m,
2H, –CH2–).
HRFAB-MS calcd for C25H23N2O4 [M+H]+:
415.165782. Found: 415.169762.
6.25. 2-Phenoxy-3-[4-(3-pyrrolo[2,3-b]pyridine-1-yl-prop-
oxy)-phenyl]-propionic acid (71)
The compound was prepared from 2-phenoxy-3-[4-(3-
pyrrolo[2,3-b]pyridine-1-yl-propoxy)-phenyl]-arylic acid
ethyl ester according to the procedure described for
7a. Mp 106–108 °C.
1H NMR (DMSO-d6, 400 MHz) d ppm: 8.216 (dd, 1H,
J = 4.8 Hz, J = 1.6 Hz, ArH), 7.940 (dd, 1H, J = 8.0 Hz,
J = 1.6 Hz, ArH), 7.522 (d, 1H, J = 3.6 Hz, ArH),
7.254–7.191 (m, 4H, ArH), 7.055 (d, 1H, J = 8.0 Hz,
J = 4.8 Hz, ArH), 6.903 (t, 1H, J = 7.2 Hz, ArH),
6.827–6.799 (m, 4H, ArH), 6.443 (d, 1H, J = 3.6 Hz,
ArH), 4.848–4.816 (m, 1H, –OCH–),4.409 (t, 2H,
J = 6.8 Hz, –OCH2–), 3.895 (t, 3H, J = 6.0 Hz,
–NCH2–), 3.133–3.020 (m, 2H, –ArCH2–), 2.257–2.192
(m, 2H, –CH2–).
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Paterniti, J. R.; Tyhonas, J.; Karanewsky, D. S.; Kauff-
man, R. F.; Broderick, C. L.; Oldham, B. A.; Montrose-
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Gratale, D. F.; MacNaul, K. L.; Berger, J. P.; Doebber, T.
W.; Leung, K.; Moller, D. E.; Heck, J. V.; Sahoo, S. P.
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HRFAB-MS calcd for C25H25N2O4 [M+H]+:
417.181433. Found: 417.184296.
Acknowledgments
The authors acknowledge the analytical division of
Institute of Meteria Medica for the spectroscopic data.
We also thank Shenzhen Chipscreen Biosciences Ltd.
for the in vitro assays.
19. Pretsch, E.; Buhlmann, P.; Affolter, C. In Structure
¨
Determination of Organic Compounds: Tables of Spectral
Data; Springer-Verlag: Berlin, 2000; pp 172–173.
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