Design and structural analysis of novel pharmacophores for potent and selective peroxisome proliferator-activated receptor γ agonists

Article abstract of DOI:10.1021/jm801594x

Utilizing medicinal chemistry design strategies such as benzo splitting and ring expansion, we converted PPARα/γ dual agonist 1 to selective PPARα agonists 19 and 20. Compounds 19 and 20 were 2- to 4-fold better than rosiglitazone at PPARγ receptor, with

Full text of DOI:10.1021/jm801594x

2618
J. Med. Chem. 2009, 52, 2618–2622
Design and Structural Analysis of Novel Pharmacophores for Potent and Selective Peroxisome
Proliferator-activated Receptor γ Agonists
Chia-Hui Lin,†,‡,¶ Yi-Hui Peng,†,|,¶ Mohane Selvaraj Coumar,†,¶ Santhosh Kumar Chittimalla,‡ Chun-Chen Liao,‡,#
Ping-Chiang Lyn,| Chin-Chieh Huang,† Tzu-Wen Lien,† Wen-Hsing Lin,† John T.-A. Hsu,†,§ Jai-Hong Cheng,† Xin Chen,†
Jian-Sung Wu,† Yu-Sheng Chao,† Hwei-Jen Lee, Chiun-Gung Juo,∞ 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, ROC, Departments of Chemistry and Life Sciences, National Tsing Hua UniVersity, 101, Section 2, Kuang Fu Road, Hsinchu 300,
Taiwan, ROC, Department of Chemistry, Chung Yuan Christian UniVersity, 200 Chung-Pei Road, Chungli 320, Taiwan, ROC, Department of
Biological Science and Technology, National Chiao Tung UniVersity, Hsinchu 300, Taiwan, ROC, Department of Biochemistry, National
Defense Medical Center, No.161, Section 6, Min-Chuan East Road, Taipei 114, Taiwan, ROC, and Molecular Medicine Research Center,
Chang Gung UniVersity, 259 Wen-Hwa first Road, Kwei-Shan, Tao-Yuan 333, Taiwan, ROC
ReceiVed December 17, 2008
Utilizing medicinal chemistry design strategies such as benzo splitting and ring expansion, we converted
PPARR/γ dual agonist 1 to selective PPARγ agonists 19 and 20. Compounds 19 and 20 were 2- to 4-fold
better than rosiglitazone at PPARγ receptor, with 80- to 100-fold PPARγ selectivity over PPARR receptor.
X-ray cocrystal studies in PPARγ and modeling studies in PPARR give molecular insights for the improved
PPARγ potency and selectivity for 19 when compared to 1.
Introduction
marketed PPARγ selective agonists for the treatment of diabetes,
which are in clinical use since 2000. However, side effects such
as heart failure, edema, fluid retention, and weight gain in
patients treated with these drugs warrant development of newer
drugs with better pharmacological and safety profiles.4 In
contrast to a selective PPARγ agonist, PPARR/γ dual agonist
combines the insulin sensitizing potential of PPARγ agonist with
the beneficial lipid modulating activities of the PPARR agonist.
Thus, it was thought that a PPARR/γ dual or PPARR/γ/δ pan
agonist would be an all-in-one therapy for T2D, correcting
insulin resistance and lipid imbalances associated with metabolic
syndrome simultaneously, and might overcome some of the side
effects of a selective PPARγ agonist.5 On the basis of this
concept, several PPARR/γ-dual and PPARR/γ/δ-pan agonists
were developed and tested in clinics; however, some of their
developments were terminated because of concerns over car-
diovascular safety in clinical trials and propensity to cause
cancer in rodent models on prolonged administration. Neverthe-
less, development of PPAR agonists with various degrees of
isoform selectivity would be helpful to better understand the
biology of PPARs, as new roles and possible utilities beyond
T2D for PPARs are being identified from time to time. For
example, it was recently found that targeting PPARδ could be
an alternative/mimic to endurance exercise in mouse models.6
In view of these opportunities, identification of structural
components controlling the selectivity for PPAR isoforms would
be advantageous in designing the next generation of PPAR
agonists.
Type 2 diabetes (T2Da) is one of the most common chronic
diseases in developed and developing countries. T2D is
characterized by fasting and postprandial hyperglycemia and
relative insulin insufficiency. If left untreated, hyperglycemia
and associated dyslipidemia progress to long-term macrovascular
and microvascular complications such as nephropathy, neur-
opathy, and atherosclerosis.1 The treatments for T2D include
life style changes and use of antidiabetic medications. Despite
the availability of large number of antidiabetic agents for the
treatment of diabetes, WHO data show that the number of people
affected from diabetes has rapidly increased from 30 million in
1985 to at least 180 million people in 2000 worldwide; this
figure is likely to double by 2030.2 This epidemic dimension
of the disease necessitates the development of more effective
agents for the control of diabetes and associated complications.
Peroxisome proliferator-activated receptors (PPARs) are
members of nuclear hormone receptor superfamily, consisting
of three subtypes, PPARR, PPARγ, and PPARδ.3 PPARR is
expressed mainly in the liver and plays a pivotal role in the
uptake and oxidation of fatty acids and in lipoprotein metabo-
lism. PPARγ is abundant in adipocytes and acts as a transcrip-
tion factor regulating adipocyte differentiation and glucose
homeostasis, while PPARδ is expressed in most cells and plays
an important role in the regulation of lipid metabolism and
cholesterol efflux.3 Pioglitazone and rosiglitazone are two
* To whom correspondence should be addressed. For S.-Y.W.: phone,
+886-37-246-166, ext 35713; fax, +886-37-586-456; e-mail, suying@nhri.
org.tw. For H.-P.H.: phone, +886-37-246-166, ext 35708; fax, +886-37-
586-456; e-mail, hphsieh@nhri.org.tw.
In our quest to develop novel antidiabetes therapy, we have
recently disclosed a series of indole based compounds for PPAR
agonist activity with varying degree of selectivity toward the
three isoforms of PPAR.7-9 The design of these compounds
was based on the concept that most of the known PPAR ligands
have an acidic group attached to an aromatic head part, which
in turn is attached to an aromatic tail part through a linker.3
During that study, 1 with an indole head part and naphthophe-
none tail part was identified as PPARR/γ dual agonist (Figure
1).8 Here, the fibrate acid group was attached to the 5-position
of indole and the N-terminal was attached through a three-carbon
†
National Health Research Institutes.
Department of Chemistry, National Tsing Hua University.
These authors contributed equally to this work.
Department of Life Sciences, National Tsing Hua University.
Chung Yuan Christian University.
National Chiao Tung University.
‡
¶
|
#
§
National Defense Medical Center.
∞
Chang Gung University.
a Abbreviations: PDB ID, Protein Data Bank identification number;
PPAR, peroxisome proliferator-activated receptor; SAR, structure-activity
relationship; T2D, type 2 diabetes; TA, transactivation assay.
10.1021/jm801594x CCC: $40.75
2009 American Chemical Society
Published on Web 03/20/2009

Brief Articles
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8 2619
Scheme 2. Synthesis of PPAR Agonists 17-20a
a (a) KOH, DMSO, room temp, 4 h; (b) NaBH3CN, BF3 ethyrate, reflux,
1 h; (c) 1-bromo-3-chloropropane, K2CO3, DMF, 80 °C; (d) ROH, K2CO3,
cat. KI, DMF, 120 °C, 2 h; (e) LiOH, MeOH/H2O (4:1), reflux, 2 h.
Table 1. PPAR Agonist Activity of Indole Analogs 1-16
Figure 1. Identification of novel tail part building block for potent
and selective PPARγ agonist activity.
Scheme 1. Synthesis of PPAR Agonists 2-16a
TA EC50 (µM)a
indole
position part R
tail
substitution
X
compd
R
γ
δ
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
5
5
4
5
4
5
4
5
5
A
B
C
A
A
A
A
A
D
D
E
Ph
0.12 0.65 >10
0.2
3.5
>10
1.07 >10
2.07 >10
>10
>10
>10
>10
>10
CH3
4-pyridyl
3-furanyl
4-F-Ph
4-OCH3-Ph 0.13 0.51 >10
0.03 0.37 >10
a (a) (i) ROH, K2CO3, cat. KI, DMF, 120 °C, 2 h; (ii) LiOH, MeOH/
H2O (4:1), reflux, 2 h.
0.13 0.43 >10
>10 2.12 >10
9
linker to the tail part hydrophobic naphthophenone moiety. In
continuation of our studies to develop therapeutically useful
PPAR agonists with potent PPAR isoform selectivity, we have
undertaken further structural modification of 1 by varying the
aromatic tail part. Here we report our focused SAR exploration
in the tail part which has led to the identification of 4-phenyl-
benzophenone as a novel tail part building block, which confers
potent and selective PPARγ agonist activity in two different
series of compounds. Additionally, X-ray cocrystal and molec-
ular modeling studies of these compounds give molecular insight
to the observed potency and selectivity.
10
11
12
13
14
15
16
0.03 2.8
1.92 0.12 >10
4.07 0.3 >10
0.04 0.42 5.27
>10
Ph
Ph
H
H
F
E
E
E
E
0.03 >10
0.13 0.9
>10
>10
E
OCH3
0.05 0.47 4.45
>10 0.22 >10
rosiglitazone
a Values are expressed as the mean of at least two independent
determinations and are within (15%.
the carboxylic esters. Hydrolysis of the esters afforded the
desired products 17-20.
Results and Discussion
Table 1 summarizes the in vitro PPARR, PPARγ, and PPARδ
transactivation (TA)7-9 EC50 data for new indole series of 2-16
synthesized. Rosiglitazone was used as PPARγ selective agonist
control. The lead 1 previously reported by us containing a fibrate
acid group attached to the 5-postion of indole and linked though
a three-carbon linker to naphthophenone tail part showed a
potent PPARR/γ dual agonist activity.8 On the basis of our
previous observation7 and literature report10 that a three-carbon
linker between the aromatic head and tail part is appropriate
for maintaining optimum activity levels, we retained the three-
carbon linker with the indole head part and varied the tail part
naphthophenone building block of 1 to get insight into the role
Appropriately substituted indole 218 was synthesized from
4-hydroxy- or 5-hydroxyindole as reported earlier and linked
to the tail part building blocks employing base-induced SN2
reaction as indicated in Scheme 1. Subsequent hydrolysis of
the esters provided the required 2-16 (Scheme 1) with free
carboxylic acid head units. For the synthesis of 17-20 (Scheme
2), 5- or 6-hydroxyquinoline 22 was O-alkylated with 2-bromo-
2-methylpropionic acid, followed by partial hydrogenation of
the quinoline ring to give 24a,b. N-Alkylation of the tetrahy-
droquinoline ring with 1-bromo-3-chloropropane and then
linking them to the appropriate tail part building blocks gave

2620 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8
Brief Articles
played by the tail part in providing potent PPAR agonist activity.
Thus, changing the 2-naphthophenone tail part to 1-naphtho-
phenone as in 2 led to a loss of potency for PPARγ receptor.
Moving the benzoyl group from C-2 position to C-1 position
of the naphthyl ring might disrupt the molecule from achieving
a proper U-shaped structure for binding to the receptor which
was observed in the X-ray cocrystal structure of indole series
of compounds.8
compared to 11/12. Compound 13, where the fibrate acid group
is attached to the 5-postion of the indole, showed potent dual
PPARR/γ activity. However, moving the fibrate acid group to
the 4-postion of the indole led to potent PPARR isoform
selectivity in 12 similar to that observed in 10. In this study 12
displayed maximum potency for PPARR (EC50 ) 30 nM) with
more than 300-fold selectivity over PPARγ/δ receptors. Next,
replacement of the 4-phenyl moiety with an electron withdraw-
ing 4-F or electron donating 4-OCH3 substituent was done to
give 15 or 16, respectively. Both 15 and 16 showed dual
PPARR/γ activation. In effect, 13-16 were dual PPARR/γ or
PPARR selective compounds, clearly showing the importance
of tail part 4-phenylbenzophenone scaffold in imparting selective
PPARγ activity. The hydrophobic nature and the steric bulk of
the 4-phenyl moiety in 11/12 might play an important role for
selective interaction with the PPARγ receptor.
Moreover, reduction of the carbonyl group in the tail part of 1
to methylene linker as in 3 led to a change in the sp2 hybridized
planar carbonyl function to sp3 hybridized methylene group with
a tetrahedral geometry, effecting a change in the relative positioning
of naphthalene and phenyl ring of the tail part. This modification
led to a complete loss of activity toward the PPAR receptor, which
again shows that the orientation of the tail part building block is
essential for maintaining the activity at PPAR receptor.
As replacement of the naphthophenone tail part of 1 with
4-phenylbenzophenone resulted in a shift from dual PPARR/γ
to selective PPARγ activity in 11, to get structural biology
insight into the role played by 4-phenylbenzophenone tail part
in imparting selective and potent PPARγ activity, the X-ray
cocrystal complex of 11-PPARγ was solved. The carboxylic
acid of 11 conserved four H-bonds with Tyr473, His 449,
His323, and Ser289. The H-bond interactions with these residues
have been reported to stabilize the activation function helix
(AF-2 helix) in PPARγ and consequently assist the recruitment
of coactivators.12 The indole ring of 11, located around helixes
3, 5, 7, and 10, formed strong hydrophobic interactions with
Tyr327, Leu330, and His449. The linker of 11 was close to the
hydrophobic pocket of PPAR consisting of Leu330, Met334,
Phe367, Val339, and Met364. The hydrophobic tail part of 11
and the propyl moiety occupied the region near the entrance of
the binding pocket and had extensive interactions with the
surrounding residues, including Cys285, I341, Met348, L255,
and Glu259. Moreover, the fibrate moiety of 11 made close
interactions with Phe282, Cys285, Gln286, and Ser289.
Since 2 and 3 showed loss of PPAR activation, we turned
our attention to the phenyl ring in the naphthophenone moiety.
Replacement of the terminal phenyl ring with a smaller methyl
group as in 4 led to a decrease in activity that is more
pronounced in PPARR than in the PPARγ receptor. Moreover,
when the phenyl ring was replaced with a sterically equivalent
4-pyridyl ring (5), there was a loss of activity compared to 1.
However, replacement of the phenyl group with 3-furanyl group
as in 6 retained the activity, showing that electronic factors might
have major influence for PPAR activity. Consequently, this led
us to retain the naphthophenone tail part building block of 1
and make changes by introducing electron-donating substituent
“-OMe” and electron-withdrawing substituent “F” in the phenyl
ring of the tail part. Subsequently, 8 with an electron-donating
substitution was found to be as potent as 1 for PPARR/γ dual
agonist activity, but the electron-withdrawing substitution in 7
led to loss of activity.
As the above modifications of naphthophenone did not result
in improvement in PPAR activity, we switched the connectivity
of the naphthophenone tail part to the linker by attaching the
phenyl ring to the linker chain instead of the naphthyl ring;
thus, 9 was found to have improved activity with a 2-fold better
PPARγ activity and 4-fold better PPARR-selectivity when
compared to 1. Interestingly, when the fibrate acid group of 9
was moved from the 5-position to the 4-position of the indole
head part, 10 showed potent and selective PPARR activation
with more than 100-fold selectivity for the PPARR receptor over
the PPARγ and PPARδ isoforms. Next, we applied the “benzo-
splitting”11 concept to design two new compounds 11 and 12
with the 4-phenylbenzophenone tail part from 9 and 10. It was
found that the introduction of 4-phenylbenzophenone instead
of the naphthophenone led to PPARγ selective activity in 11
and 12. Introduction of 4-phenylbenzophenone instead of
naphthophenone resulted in changing the molecule’s PPAR
subtype selectivity pattern, with a net result that PPARR/γ dual
agonist 1 was converted to PPARγ selective agonist 11. Both
11 and 12 with the novel 4-phenylbenzophenone tail part showed
an order of selectivity toward PPARγ over PPARR receptor,
with the 5-position isomer 11 being 5-fold more potent at
PPARγ than the initial lead 1. Compounds 11 and 12 displayed
PPARγ selective agonist activity with a potency range similar
to rosiglitazone; however, rosiglitazone was more selective to
PPARγ than both compounds.
Comparison of the X-ray cocrystals of 1, which has a
naphthophenone tail part,8 with 11 which has the 4-phenylben-
zophenone tail part revealed that the carboxylic acid head, indole
ring, and linker superimposed very well with each other
(Figure 2a). The difference occurred in the tail parts where the
4-phenylbenzophenone tail of 11 extended deeper into the pocket
entrance and made extensive hydrophobic interactions with the
surrounding residues with more stable binding energy of -48.2
kcal/mol while the binding energy of 1 with the naphthophenone
tail part was -28.3 kcal/mol as calculated by the program
Insight II. Moreover, the propyl group of 11 moved closer to
the active site and formed additional interactions with R288,
S289, I326, and L330, which might also contribute to the
improved potency of 11, compared to 1.
As the introduction of 4-phenylbenzophenone tail in 11 leads
to a loss of PPARR activity compared to 1, structural alignment
of the 1-PPARγ and 11-PPARγ complexes with PPARR
protein (PDB ID 1K7L) was done (Figure 1s in Supporting
Information). It showed that the Gly284 in PPARγ, the residue
close to the benzophenone moiety, is replaced by Cys 275 in
PPARR. The more bulky side chain Cys275 in PPARR would
cause a steric clash with the 4-phenylbenzophenone moiety of
11. Cys275 is located at the entrance of the binding pocket,
and the steric hindrance with 11 might, at least partially, limit
the access to the binding pocket, which led to a decrease in
PPARR activity of 11, compared to 1.
Intrigued by this switch in selectivity from dual PPARR/γ to
PPARγ by varying the tail part, we explored the role of 4-phenyl
moiety of the tail part 4-phenylbenzophenone scaffold. Thus,
13 and 14 were synthesized by replacing 4-phenyl group with
4-H and they were found to regain ∼100-fold PPARR activity
Having identified a novel 4-phenylbenzophenone tail part,
which imparted PPARγ selective activity in indole series, we

Brief Articles
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8 2621
were interested to know if this tail part could improve PPARγ
selective activity in compounds where the indole head part
would be replaced with other heterocyclic rings. Moreover, 11
and 12 were only ∼15-fold more selective, while rosiglitazone
was >45-fold more selective to PPARγ over PPARR receptor.
Hence, to identify a potent and selective PPARγ agonist and to
investigate the PPARγ selectivity potential of the novel tail part,
we further carried out chemical exploration using 1,2,3,4-
tetrahydroquinoline instead of indole as the aromatic head part.
1,2,3,4-Tetrahydroquinoline ring was selected because of easy
synthetic derivatization and because it could be considered as
the ring expanded form of indole ring.
Compounds 17 and 18 (Table 2), bearing the fibrate acid
group at the 5- and 6-position of tetrahydroquinoline, respec-
tively, and linked from the N-terminal through a three-carbon
linker to the naphthophenone tail part, showed potent PPARR/γ
dual activity similar to indole 1. Compound 17 with the fibrate
acid group at the 5-position showed better activity at R and γ
receptors, compared to 18. Also tetrahydroquinoline 17 was 6.5-
fold more potent at PPARγ than indole 1, showing that the
replacement of indole with tetrahydroquinoline ring had led to
enhancement of PPARγ potency. Next, we investigated the
effect of replacing the naphthophenone ring with the novel
4-phenlybenzophenone tail part and retaining tetrahydroquino-
line head part in 17/18. Thus, 19 and 20 bearing the novel
4-phenlybenzophenone were synthesized. Compounds 19 and
20 with 5- and 6-position fibrate acidic headgroups, respectively,
were found to show highly potent and PPARγ selective activity.
Similar to the indole series 11/12, introduction of 4-phenylben-
zophenone tail part in tetrahydroquinoline series 19/20 had led
to potent PPARγ selective activity, confirming that 4-phenyl-
benzophenone indeed imparted potent and PPARγ selective
activity when incorporated as the tail part. Moreover, 19 was
∼4-fold more potent than rosiglitazone at PPARγ, while ∼80-
fold more selective to PPARγ over the PPARR receptor, similar
to rosiglitazone.
To further elucidate the improved potency and selectivity of
19, the X-ray cocrystal complex of 19-PPARγ was solved.
Superimposition of 19 with 11 revealed that the 1,2,3,4-
tetrahydroquinoline ring of 19 adopted a different conformation
from the indole ring of 11 where both rings are coplanar but
the tetrahydroquinoline ring of 19 was rotated 90.06° relative
to the indole ring of 11 along the axis perpendicular to the plane
of the ring. Therefore, the tetrahydroquinoline ring of 19 formed
more extensive interactions with the surrounding residues,
including Phe282, Cys285, Phe363, and Met364, which were
absent in the structure of 11 (Figure 2b). The additional
interactions of 1,2,3,4-tetrahydroquinoline ring would contribute
to the improved potency of 19. Apart from the different orientation
of the head part tetrahydroquinoline ring and slight movement of
the linker, the carboxylic acid head and the 4-phenylbenzophenone
tail of 19 superimposed well with that of 11.
Structural alignment of the PPARγ-19 with PPARR protein
(PDB ID 1K7L) showed that the bulkier side chain of Cys275
in PPARR (the corresponding residue Gly284 in PPARγ) would
cause steric clash with the 4-phenylbenzophenone tail of 19,
which explains the PPARγ selective activity of this compound
being similar to that of 11 with the same 4-phenylbenzophenone
tail part (Figure 1s of Supporting Information).
Figure 2. (a) Superposition of the X-ray structures of 1 (magenta)
and 11 (yellow) in the binding pocket of PPARγ. The head parts of
both compounds overlapped well, while the tail part building block
4-phenylbenzophenone of 11 extended deeper to the pocket entrance
and made extensive hydrophobic interactions with the surrounding
residues of PPARγ, explaining the improved PPARγ activity of 11
compared to 1. (b) Superposition of the X-ray structures of 11 (yellow)
and 19 (orange) in the binding pocket of PPARγ. Both compounds
overlap well except for the head part aromatic rings. The tetrahydro-
quinoline ring of 19 is rotated 90.06° relative to the indole ring of 11
along the axis perpendicular to the plane of the ring and forms extensive
hydrophobic interaction with the surrounding residues of PPARγ,
explaining for the improved PPARγ activity of 19 compared to 11.
Key interacting residues are labeled.
In conclusion, through a series of structural modifications in
the tail part of indole fibrates 1 identified earlier as PPARR/γ
dual agonist, we discovered 11 and 12 as PPARγ selective
agonists. Use of alternative tetrahydroquinoline fibrates led to
the synthesis of 19 as a potent and selective PPARγ agonist
with >4-fold better PPARγ activity than rosiglitazone, which
is currently used for antidiabetes therapy. X-ray cocrystal

2622 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8
Brief Articles
Table 2. PPAR Agonist Activity of Tetrahydroquinoline Analogs
17-20
Compounds 2-18, 20 were synthesized in a manner similar to
that for 19, using 21a,b/25a,b and tail part building blocks A-E.
Acknowledgment. Financial support from National Health
Research Institutes, Taiwan, National Science Council, Taiwan,
and National Tsing Hua University, Taiwan, is gratefully
acknowledged. We thank the staff of beamline BL13B1 and
BL13C1 at National Synchrotron Radiation Research Centre
(NSRRC), Taiwan, for technical assistance.
TA EC50 (µM)a
quinoline
position
tail
part R
Supporting Information Available: Synthetic procedures;
spectral data for tetrahydroquinoline head part 25a,b and tail part
building blocks A-E, 2-18, 20; HPLC purity of 9, 11, 12, 14,
19, 20; X-ray structure refinement for 11-PPARγ and 19-PPARγ
(PDB ID 3GBK); structural alignment of 11 and 19 in PPARR
binding pocket. This material is available free of charge via the
Internet at http://pubs.acs.org.
compd
R
γ
δ
17
18
19
20
5
6
5
6
A
A
E
E
0.12
0.24
3.99
>10
>10
0.1
>10
>10
>10
>10
>10
0.54
0.05
0.10
0.22
rosiglitazone
a Values are expressed as the mean of at least two independent
determinations and are within (15%.
References
analyses of 11 and 19 in complex with PPARγ reveal structural
insight for the high degree of potency and selectivity observed
with this novel tail part for the PPARγ isoform. Thus, focused
SAR exploration led to the identification of the novel tail part
building block 4-phenylbenzophenone, which confers selective
PPARγ agonist activity when incorporated in the standard PPAR
agonist design and could be useful in future endeavors to fine-
tune PPAR isoform selectivity.
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Experimental Section
2-(1-{3-[4-(Biphenyl-4-carbonyl)-2-propylphenoxy]propyl}-
1,2,3,4-tetrahydroquinolin-5-yloxy)-2-methylpropionic Acid 19.
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iodide (0.01 g, 0.06 mmol) in 10 mL of DMF was heated at 120
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1
19 (0.18 g, 59%). H NMR (400 MHz, CDCl3) δ 1.00 (t, J ) 7.6
Hz, 3H), 1.61 (s, 6H), 1.58 (m, 2H), 1.91-1.94 (m, 2H), 2.11-2.15
(m, 2H), 2.70 (t, J ) 7.6, 2H), 3.27 (t, J ) 5.6 Hz, 2H), 3.52 (t, J
) 7.2, 2H), 4.12 (t, J ) 5.6 Hz, 2H), 4.13 (t, J ) 5.6 Hz, 2H),
6.17 (d, J ) 7.6 Hz, 1H), 6.4 (d, J ) 8.4 Hz, 2H), 6.88 (d, J ) 8.8
Hz, 2H), 6.86-6.93 (m, 1H), 7.38-7.51 (m, 3H), 7.65-7.73 (m,
5H), 7.84-7.87 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 14.1
(CH3), 21.7 (CH2), 22.1 (CH2), 22.9 (CH2), 25.1 (CH3 × 2), 26.4
(CH2), 32.4 (CH2), 48.7 (CH2), 49.3 (CH2), 65.6 (CH2), 80.4 (C),
105.8 (CH), 106.0 (CH), 110.0 (CH), 114.1 (C), 126.5 (CH), 126.8
(CH × 2), 127.3 (CH × 2), 128.1 (CH), 128.9 (CH), 129.8 (C),
130.4 (CH × 2), 130.5 (CH), 131.0 (C), 131.0 (C), 132.2 (CH),
137.1 (C), 140.1 (C), 144.6 (C), 146.6 (C), 152.5 (C), 160.4 (C),
176.2 (C), 195.5 (C); HRMS (EI) calcd for C38H41NO5 (M+)
591.2985, found 591.2980.
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