Indanylacetic acid derivatives carrying 4-thiazolyl-phenoxy tail groups, a new class of potent PPAR α/γ/δ pan agonists: Synthesis, structure-activity relationship, and in vivo efficacy

Article abstract of DOI:10.1021/jm061299k

Compounds that simultaneously activate the three peroxisome proliferator-activated receptor (PPAR) subtypes alpha, gamma, and delta hold potential to address the adverse metabolic and cardiovascular conditions associated with diabetes and the metabolic sy

Full text of DOI:10.1021/jm061299k

984
J. Med. Chem. 2007, 50, 984-1000
Indanylacetic Acid Derivatives Carrying 4-Thiazolyl-phenoxy Tail Groups, a New Class of
Potent PPAR r/γ/δ Pan Agonists: Synthesis, Structure-Activity Relationship, and In Vivo
Efficacy
Joachim Rudolph,*,† Libing Chen,† Dyuti Majumdar,† William H. Bullock,† Michael Burns,‡ Thomas Claus,‡
Fernando E. Dela Cruz,‡ Michelle Daly,‡ Frederick J. Ehrgott,† Jeffrey S. Johnson,† James N. Livingston,‡
Robert W. Schoenleber,† Jeffrey Shapiro,‡ Ling Yang,‡ Manami Tsutsumi,‡ and Xin Ma†
Department of Chemistry Research and Department of Metabolic Disorders Research, Bayer HealthCare Pharmaceuticals Corporation,
400 Morgan Lane, West HaVen, Connecticut 06516
ReceiVed NoVember 8, 2006
Compounds that simultaneously activate the three peroxisome proliferator-activated receptor (PPAR) subtypes
alpha, gamma, and delta hold potential to address the adverse metabolic and cardiovascular conditions
associated with diabetes and the metabolic syndrome. We recently identified the indanylacetic acid moiety
as a well-tunable PPAR agonist head group. Here we report the synthesis and structure-activity relationship
(SAR) studies of novel aryl tail group derivatives that led to a new class of potent PPAR pan agonists.
While most of the tail group modifications imparted potent PPAR delta agonist activity, improvement of
PPAR alpha and gamma activity required the introduction of new heterocyclic substituents that were not
known in the PPAR literature. Systematic optimization led to the discovery of 4-thiazolyl-phenyl derivatives
with potent PPAR alpha/gamma/delta pan agonistic activity. The lead candidate from this series was found
to exhibit excellent ADME properties and superior therapeutic potential compared to known PPAR gamma
activating agents by favorably modulating lipid levels in hApoA1 mice and hyperlipidemic hamsters, while
normalizing glucose levels in diabetic rodent models.
Introduction
Diabetes and its associated adverse cardiovascular conditions
are increasingly prevalent in the Western society and are
considered one of the main threats to human health in the 21st
century.1 The nuclear hormone receptors PPARRa and PPARγ
are important regulators of lipid and carbohydrate metabolism,
and agonists have shown therapeutic benefit for the treatment
of diabetes and dyslipidemia.2-5 PPARγ has been identified as
a key regulator for insulin sensitivity, and two PPARγ agonists,
rosiglitazone (1) and pioglitazone (2), have demonstrated clinical
success in the treatment of Type 2 diabetes since their
introduction in 1999.6,7 Agonists of PPARR, for example,
fenofibrate (3) or gemfibrozil (4), have been shown to lower
plasma lipid, triglyceride, and free fatty acid (FFA) levels and
have been in clinical use for the treatment of dyslipidemia since
the 1960s. As combined treatment with PPARγ and PPARR
agonists has been recognized for its potential to improve insulin
resistance and lower triglyceride levels, several companies have
been actively pursuing PPARR,γ dual-acting compounds.8-11
The clinically most extensively investigated candidates mura-
glitazar12,13 (5) and tesaglitazar14-16 (6) were shown to signifi-
cantly lower glucose and lipid levels in clinical trials. The role
of the third PPAR family member, PPARδ, is just beginning
to emerge. Animal studies revealed that activation of PPARδ,
for example by the selective PPARδ agonist 7 (GW501516),
induces fatty acid catabolism in skeletal muscle and is associated
with improved insulin sensitivity, attenuated weight gain, and
elevated high-density lipoprotein (HDL) levels.17-21
To effectively target insulin resistance/hyperglycemia and
associated conditions including dyslipidemia and hypertension
(i.e., the metabolic syndrome), the concept of simultaneously
activating PPARR, γ, and δ through a single compound has
attracted increasing interest over the past few years.22 A number
of PPAR pan agonists have been described in the literature,23-29
and animal studies with selected compounds suggest benefits
over selective PPARγ and PPARR,γ agonists, particularly with
respect to their effects on lipid levels and body weight.22 The
clinically most advanced PPAR pan agonist, sodelglitazar (8),
is currently in phase II clinical trials. Human efficacy and safety
evaluation of this first clinical example will be an important
step toward validation of this approach.
* To whom correspondence should be addressed. Tel.: +1 203 812 3290.
Fax: +1 203 812 2452. E-mail: joachim.rudolph.b@bayer.com.
† Department of Chemistry Research.
‡ Department of Metabolic Disorders Research.
a Abbreviations: PPAR, peroxisome proliferator-activated receptor; HDL,
high-density lipoprotein; LDL, low-density lipoprotein; FFA, free fatty acid;
IRBA, insulin receptor binding assay.
10.1021/jm061299k CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/03/2007

Indanylacetic Acid DeriVatiVes as PPAR Agonists
Scheme 1. Synthesis of the Target Compoundsa
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5 985
a Reagents and conditions: (a) ethyl bromoacetate, zinc, THF; (b) H2, Pd/C, EtOH; (c) 10-30% lipase PS (amano enzymes), 99% ee 38% (3 steps); (d)
TMSCl, EtOH, 99%; (e) AlCl3, EtSH, CH2Cl2, 96%; (f) 1,3-dibromopropane, cesium carbonate, DMF, RT, 60%; (g) substituted phenol, Cs2CO3, DMF; (h)
LiOH, THF, H2O, MeOH.
Scheme 2. Synthesis of 2-Propylphenol Derivatives via Claisen
We recently described PPARR,γ dual agonists containing the
Rearrangementa
new indanylacetic acid head group.30 In the course of our SAR
studies with this core, we discovered that derivatives lacking a
substituent at the R position of the acetic acid moiety show
markedly increased PPARδ agonistic activity, however, at the
expense of either PPARR or PPARγ agonist activity.31 While
our initial efforts focused on combining the indanylacetic acid
moiety with oxazole or thiazole tail groups,32 we later sought
to expand the structural variety of the tail group portion.33 One
of the first derivatives emerging from this effort was compound
9, which contains an established PPAR agonist benzisoxazole
tail portion.23,34 Compound 9 was a potent full agonist at all
three PPAR receptors in vitro but was hampered by unfavorable
drug properties, among them poor aqueous solubility (<1 µM).
a Reagents and conditions: (a) allylbromide, Cs2CO3, DMF; (b) 200 °C;
(c) BCl3, CH2Cl2; (d) H2, Pd/C, EtOH; (e) NH+HCOO-, Pd/C, EtOH.
Chemistry
Target compounds 17a-17x were synthesized according to
Scheme 1. Reformatsky reaction of 5-methoxyindanone with
ethylbromoacetate yielded the exocyclic alkene 10, which was
subsequently hydrogenated to the indanylacetic acid ester 11.
Treatment with lipase PS (Amano enzyme) led to the selective
hydrolysis of the (S)-enantiomer of ester 11 to its corresponding
(S)-acid 12. The absolute configuration was indirectly deter-
mined by X-ray crystallography of a derivative containing
Evans’ oxazolidinone chiral auxiliary (see Supporting Informa-
tion). Enantiomerically pure 12 was esterified (13), demethylated
(14), and reacted with a 1,3-dibromopropane group to furnish
the head-linker fragment 15. This compound was then coupled
with substituted phenols comprising the tail portion to form the
ester intermediates 16a-16x, which were hydrolyzed to afford
the final compounds 17a-17x.
Tail groups were commercially available, synthesized ac-
cording to Scheme 2, and modified after attachment to the head-
linker fragment 15 (Schemes 3-5). Intermediates carrying a
propyl chain ortho to the phenol OH group were synthesized
by allylation of the corresponding phenols, thermal or Lewis
acid mediated Claisen rearrangement reaction, and subsequent
hydrogenation of the allyl group (Scheme 2).
Initial structure-activity relationship (SAR) studies focused
on close analogs of 9 having fused ring systems such as
benzisoxazoles, benzofurans, and indoles with various substit-
uents.33 The SAR from these studies suggested that the propyl-
substituted trifluoromethylbenzisoxazole group in compound 9
is, among fused ring systems, optimized for PPARγ and PPARR
activity (see Supporting Information). Further optimization of
the tail group concentrated on substituted aryl rings instead of
fused ring systems. This effort led to the discovery of the potent
and balanced PPAR triple activating 4-thiazolyl-phenoxy series,
the details of which will be described in this account. Optimiza-
tion within this series culminated in the identification of 34r, a
compound with favorable drug properties and robust in vivo
efficacy in a number of therapeutically relevant animal models.
The R3 group of intermediate 16 was used as a handle to
introduce structural diversity, because SAR studies had identified
this position as an important structural feature for achieving
PPAR pan agonistic activity. Emphasis was placed on the
introduction of heterocyclic groups at this position. Such analogs

986 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5
Rudolph et al.
Scheme 3. Tail Group Modification via Suzuki Coupling Reactiona
a Reagents and conditions: (a) R3B(OH)2, PdCl2(dppf), Na2CO3, toluene, dioxane; (b) bis(pinacolato)diboron, PdCl2(dppf), KOAc, DMF, 80 °C; (c)
R3-Br, PdCl2(dppf), Na2CO3, DMF, 80 °C; (d) LiOH, THF, H2O, MeOH.
Scheme 4. Tail Group Modification via Hantzsch Thiazole Synthesisa
a Reagents and conditions: (a) H2S, HNEt2, DMF, rt f 60 °C; (b) R-bromo/chloroketone, EtOH; (c) LiOH, THF, H2O, MeOH.
Scheme 5. Synthesis of 4-(Alkoxythiazolyl)phenyl Derivativesa
a Reagents and conditions: (a) R′OH, 70 °C; (b) LiOH, THF, H2O, MeOH.
were prepared via Suzuki-type coupling chemistry using het-
erocyclic boronic acids (Scheme 3, approach A) or inverse
Suzuki coupling conditions using the borylated scaffold (Scheme
3, approach B).
at the respective PPAR receptor subtypes. Previous studies
suggested that the indanylacetic acid group with no further
substitution at the R and â positions offers an opportunity to
simultaneously address all three PPAR receptor subtypes, R, γ,
and δ.31
To derive basic SAR information, we started our effort by
appending the phenyl tail group with small substituents. As can
be seen in Table 1, PPARδ activity was generally high for this
series, regardless of the nature of the phenyl substitution.
Substitutions at both the 2- and 4-positions (R1 and R3,
respectively) were found to play an important role for achieving
PPARγ as well as PPARR agonistic activities, but the potencies
were not satisfactory. The highest PPARR agonistic activities
were observed for compounds 17n and 17r, indicating that
increasing steric bulk of the R3 substituent, combined with an
extended R1 alkyl or alkoxy chain, held promise for achieving
more balanced PPAR pan agonistic activity.
We then turned to analogs bearing larger R3 substituents. To
improve the aqueous solubility of the compounds shown in
Table 1 (mostly <5 µM; data not shown), a series of
heterocycles were explored. As shown in Table 2, most analogs
in this series are potent PPARδ agonists with relatively weak
PPARγ or PPARR activity. However, the thiadiazole 17x
showed a markedly better PPAR pan activity profile compared
to other heterocyclic variants, stimulating further SAR inves-
tigation of similar structure classes.
As a replacement for the thiadiazole group, we continued our
optimization efforts with the structurally related thiazole moiety
for the advantages of accessibility, feasibility of further deriva-
tization, and drug likeness. The SAR of the previous analog
series (Tables 1 and 2) indicated that a propyl/methoxy group
in the 2-position of the phenyl tail moiety could further improve
the PPARγ activity.
SAR analysis (vide infra) identified thiazoles as preferred R3
substituents. Because availability of suitable thiazole building
blocks was too limited for generating sufficient diversity through
Suzuki coupling chemistry, Hantzsch thiazole synthesis35 was
used to install functionalized thiazoles. Suitable nitrile templates
were converted to thioamides that were subsequently reacted
with structurally diverse R-bromo/chloro carbonyl building
blocks36 to yield the corresponding thiazoles.37
When 2-chloro-N,N-dimethylacetamide was used as the
R-halo carbonyl precursor, Hantzsch reaction in an alcoholic
solvent (e.g., EtOH, i-PrOH) was accompanied by replacement
of the dimethylamino group by the alkoxy group (Scheme 5).
This unexpected outcome was utilized to generate a number of
analogs with R5 ) alkoxy (34ae-34an).
Results and Discussion
In Vitro SAR Studies. Compounds were evaluated for
human PPARR and human PPARδ in vitro potency using
fluorescence resonance energy transfer (FRET) assays. Their
PPARR and PPARδ cell potency were measured in cell-based
GAL-4 transactivation assays in CV-1 cells either transfected
with PPARR or PPARδ ligand binding domain. PPARγ activity
was assessed using a cell-based functional assay (IRBA) in
mouse 3T3-L1 cells.38 This assay measures the ability of the
test compound to cause an increase in the number of insulin
receptors and, hence, is an index of the insulin sensitizing
activity.
The SAR studies covered in this account describe variation
of the phenyl tail group in combination with a fixed head group,
indanylacetic acid, and a fixed 1,3-bis(oxy)-propylidene tether.
The indanylacetic acid group had been established in our
laboratories as a well-suited head group for modulating activity
As shown in Table 3, this undertaking led to compounds with
significantly improved PPARR and PPARγ activities. For the
first time within the class of indanylacetic acids carrying

Indanylacetic Acid DeriVatiVes as PPAR Agonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5 987
Table 3. In Vitro Activities of 4-Thiazolylphenyl Analogsa
Table 1. In Vitro Activities of Indanylacetic Acid Analogs Containing
Substituted Phenyl Tail Groupsa
IRBA,d
EC50
[nM]
hPPARR
hPPARδ
hPPARR
FRET,b
EC50 [nM]
hPPARδ
FRET,c
EC50 [nM]
FRET,b EC50 FRET,c EC50 IRBA,d
no.
R4
R5
R1
[nM]
[nM]
EC50 [nM]
no.
R1
R2
R3
34a
34b
n-Pr
OMe
111
255
1.6
0.58
48
374
17a
17b
17c
17d
17e
17f
17g
17h
17i
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
OMe
H
H
H
H
H
H
H
H
Et
>10,000
1,980
1,610
44
8.9
4.2
13
6.7
6.6
7.3
43
>10,000
6,200
5,580
1,020
3,000
940
H
H
H
34c
Me
OMe
268
2.7
960
CF3
OCF3
OMe
OEt
CN
Ph
H
Me
H
Me
H
CF3
CN
OPh
Me
Et
6,800
34d
34e
34f
H
n-Pr
OMe
1,280
147
254
4.4
11
2.5
874
45
65
>10,000
>10,000
5,700
>10,000
>10,000
>10,000
>10,000
9,360
>10,000
1,140
3,950
>10,000
>10,000
700
7,500
>10,000
H
Et
637
34g
H
H
t-Bu
n-Pr
87
11
18
n.d.e
H
H
H
56
67
8,000
>10,000
n.d.e
2,180
1,520
303
34h
34i
n-Pr
OMe
197
437
3.3
2.9
55
327
CF3
17j
17k
17l
117
4.6
2.4
1.6
25
1.9
7.5
2.7
14
34j
34k
H
OMe
1,250
83
2.9
4
280
33
Me
n-Pr
n-Pr
n-Pr
n-Pr
OMe
OMe
OMe
OEt
Me
Me
17m
17n
17o
17p
17q
17r
17s
17t
34l
34m
34n
H
n-Pr
OMe
112
328
53
1.3
3.5
4.1
1,200
94
116
570
n.d.e
1,670
1,650
700
34o
34p
34q
H
n-Pr
OMe
391
43
44
2.2
1.9
3.3
294
12
84
H
H
CN
Me
2.2
1,240
34r
34s
n-Pr
OMe
101
328
4.0
1.3
42
181
a Reported in vitro values are an average of at least two replicates.
b PPARR compound activity was assessed by measuring the human PPARR
ligand binding domain with the co-activator protein CBP. c PPARδ
compound activity was assessed by measuring the ligand-dependent
association of the human PPARδ ligand binding domain with the co-
activator protein TRAP220. d PPARγ compound activity was assessed by
using the IRBA in mouse 3T3-L1 cells. e Not determined.
34t
OMe
526
5.2
214
34u
34v
34w
H
n-Pr
OMe
2,530
175
560
6.9
18
3.4
480
17
49
COCH3
Me
Table 2. In Vitro Activity of Indanylacetic Acid Analogs Containing
34x
34y
n-Pr
OMe
140
803
4.4
2.1
20
4-Heteroaryl-Substituted Aryl Tail Groupsa
CONMe2 Me
34z
H
n-Pr
OMe
10,000
1,690
10,000
218
46
28
312
238
1,000
34aa COOH
34ab
Me
34ac COOH
CH2OH
CH2CO2H n-Pr
n-Pr
6,490
2,480
12
4.6
891
27
34ad
H
34ae
34af
H
OMe
5,800
755
1.3
3.0
300
69
H
OMe
34ag
34ah
34ai
H
n-Pr
OMe
100
105
1,350
1.2
2
3.4
753
41
920
H
OEt
34aj
34ak
n-Pr
OMe
47
180
2.3
3
45
44
H
Oi-Pr
34al
34am
n-Pr
OMe
61
150
3.2
6
34
177
Me
OEt
OEt
34an Et
OMe
520
5.4
362
a-d See corresponding footnotes from Table 1.
is an alkoxy group (e.g., 34al) and where R4 and R5 form a
fused cycloalkyl ring (e.g., 34o-34q) are the highest and most
balanced within the series. (2) A substituent at the R1 position
is important to achieve PPARγ and especially PPARR activity
in most of the examples. However, if R4 and R5 form a
cycloalkyl ring (especially cyclohexyl, as in 34o), an R1
substituent does not appear to be as crucial for achieving potent
PPARγ and PPARR activities. (3) In most cases, compounds
with an n-propyl group in the R1 position show higher PPARγ
and PPARR activities than compounds with a methoxy group
in this position.
a-d See corresponding footnotes from Table 1. e Compounds were
synthesized according to Scheme 3, approaches A or B, or using a preformed
heterocycle-substituted phenol building block (approach C).
Further in vitro and in vivo evaluation of these compounds
revealed the tetrahydrobenzothiazoles 34o and 34p and the
dihydropyranothiazole 34r to have the best overall profiles. To
support the interpretation of in vivo efficacy data from different
substituted phenyl tail groups, potent activities at all three
receptor subtypes were achieved. The key SAR trends are the
following: (1) The in vitro activities of the thiazoles where R5

988 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5
Table 4. Cellular Activities of Selected Analogs Across Speciesa
Rudolph et al.
PPARR, EC50 [nM]
PPARδ, EC50 [nM]
(% agonism)
(% agonism)
IRBA, EC50 [nM]
no.
human
mouse
hamster
human
mouse
hamster
human
170
mouse
294
34o
152
(100)
5
(100)
116
(88)
>10 000
(28)
7700
(79)
>10 000
(25)
135
(78)
40
(85)
2.6
(93)
2.7
(64)
84
144
(79)
(43)
8.6
(82)
16
34p
34r
81
12
42
923
(100)
8
102
(60)
(100)
a See corresponding footnote from Table 1.
Table 5. Solubility, CYP450 Inhibition, and Mouse Pharmacokinetic
gene were conducted. This model has proven useful in the
assessment of hypolipidemic drugs such as fenofibrate (3;
PPARR agonist) and 7 (PPARδ agonist). Compound 7 is known
to reduce triglyceride levels and raise HDL-cholesterol (HDLc)
in mice by activating the PPARδ receptor.19-21 Male hApoA1
mice were treated with 10 mg/kg of 34r or 10 mg/kg of 7 for
7 days. Both compounds caused significant dose-dependent
reduction in plasma triglycerides and increase in HDLc, and
the magnitude of the effects were comparable (Figure 2).
In female hApoA1 mice, the 10 mg/kg dose of 34r as well
as reference compound 7 significantly increased HDLc levels,
however compound 34r was not as efficacious as 7 at the same
dose levels. Neither compound showed statistically significant
effects on triglyceride levels in this model (data not shown).
In addition to its effects on lipid levels, compound 34r caused
reduction in glucose levels in the hApoA1 mice model to a
Data of Selected Analogsa
mouse PKd
(10 mg/kg, p.o.);
aq. solubility,b
CYP450 inhibition,c
no.
pH 6.8 [µM]
IC50 [µM]
C
max [µM]
34o
34p
34r
31
< 5
55
all >10
all >10
all >10
20
5.1
18
a See corresponding footnote from Table 1 b Kinetic solubility deter-
mined by HPLC; buffered aqueous test solution contained 1% DMSO.
c Determined for CYP 1A2, 2C8, 2C9, 2D6, and 3A4 by enzyme assays
using appropriate fluorescent substrates. d Compounds were administered
in 0.5% methylcellulose.
animal models, we determined the cellular activities at PPAR
subtypes from different species, including cellular activity in
the IRBA using human preadipocytes.
As can be seen from Table 4, PPARγ activities from mouse
and human cells are comparable for all three compounds.
Likewise, no substantial species dependency is seen in the case
of PPARδ. However, all compounds show pronounced activity
differentiation across species at the PPARR receptor, with
significantly higher activity at human and hamster PPARR
compared to mouse PPARR. Spot checking of other compounds
from Table 3 revealed that the species dependency trends are
general for this compound class (data not shown). Selectivities
toward the key members of the human nuclear hormone receptor
family were also examined. Compounds 34o, 34p, and 34r
showed EC50 values of >10 µM in a binding assay of the
androgen, estrogen, glucocorticoid, and progesterone receptors.
Solubility, cytochrome P450 (CYP450) enzyme inhibition,
and mouse pharmacokinetic data of compounds 34o, 34p, and
34r are shown in Table 5. Oral exposure of compound 34p is
significantly lower than those of the other two compounds,
which may be at least partly due to its poor aqueous solubility.
Comparison of the in vivo activities of compounds 34o, 34p,
and 34r revealed a clear superiority of compound 34r. Com-
pound 34o only showed a weak glucose-lowering effect, which
is in agreement with its in vitro data (least active among the
three compounds in the IRBA). Compound 34p, despite its
excellent in vitro profile, likewise did not reach the overall
efficacy profile of compound 34r, presumably due to its lower
oral exposure.
Figure 1. Effects of compound 34r (0.3, 1, 3, and 10 mg/kg) and
rosiglitazone (1; 1, 3, and 10 mg/kg) on blood glucose levels in db/db
mice after 8 days of dosing (qd, p.o.).
Effects of Compound 34r in db/db and hApoA1 Mice.
Female db/db mice were dosed once daily for 7 days with 0.3,
1, 3, and 10 mg/kg 34r and with 1, 3, and 10 mg/kg of
rosiglitazone (1), respectively. Compound 1 is known to lower
glucose levels in this animal model39 and in man40 by activating
the PPARγ receptor. Both 1 (all doses) and the 1, 3, and 10
mg/kg doses of 34r significantly and dose-dependently reduced
blood glucose levels. The estimated ED50 for compound 34r in
this model is 0.4 mg/kg (Figure 1).
Figure 2. Effects of compound 34r and 7 (both 10 mg/kg) on plasma
triglyceride and HDLc levels in male hApoA1 mice after 7 days of
dosing (qd, p.o.). Each bar is the mean ( SEM for 6-8 mice. **p <
0.01, ***p < 0.001 versus vehicle.
To assess the effect of compound 34r on improving lipid
levels, studies in transgenic mice expressing the human apoA1

Indanylacetic Acid DeriVatiVes as PPAR Agonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5 989
Figure 3. Summary of the effects of compound 34r (0.3, 1, 3, and 10
mg/kg) on blood glucose levels in db/db mice and on triglycerides/
HDLc in male hApoA1 mice after 8 days of dosing (qd, p.o.).
Figure 5. Effects of compound 34r (10 mg/kg), rosiglitazone (1; 10
mg/kg), and fenofibrate (3; 100 mg/kg) on lipoprotein distribution in
fat-fed hyperlipidemic hamsters after 14 days of dosing (qd, p.o.). Each
bar is the mean ( SEM for 10 hamsters.
Figure 4. Effects of compound 34r (1 and 3 mg/kg) and rosiglitazone
(1; 10 mg/kg) on blood glucose levels in ZDF rats after 21 days of
dosing (qd, p.o.). The rats were dosed as described in the Experimental
Section. Each bar is the mean ( SEM for 7 rats. **p < 0.01, ***p <
0.001 versus vehicle.
Figure 6. Effects of compound 34r (10 mg/kg), rosiglitazone (1; 10
mg/kg), and fenofibrate (3; 100 mg/kg) on triglyceride levels in fat
fed hyperlipidemic hamsters after 14 days of dosing (qd, p.o.). Each
bar is the mean ( SEM for 10 hamsters.
similar extent as seen in the db/db model (ED50 in both models
around 0.5 mg/kg). Figure 3 summarizes the combined effects
of compound 34r on glucose, triglyceride, and HDLc levels in
female db/db mice and male hApoA1 mice.
Effects of Compound 34r in Zucker Diabetic Fatty (ZDF)
Rats. The ZDF rat is an inbred rat model that, through genetic
mutation and a managed diet, closely mimics human adult onset
type 2 diabetes and related complications.41 To assess the
glucose lowering effect of compound 34r versus benchmark,
male ZDF rats were dosed once daily for 21 days with 10 mg/
kg rosiglitazone (1) and 1 and 3 mg/kg of compound 34r. As
shown in Figure 4, compound 34r (at 3 mg/kg) was significantly
more efficacious in lowering glucose levels than 1. The effects
of both 1 and 34r on plasma triglycerides and HDLc were not
pronounced in this model under the chosen starting glucose and
lipid levels, however, both compound 34r (at 1 and 3 mg/kg
doses) and 1 (at 10 mg/kg) lowered FFA levels in the same
study (data not shown).
Effects of Compound 34r in Fat-Fed Hyperlipidemic
Hamsters. Hamsters are considered a good model for the study
of plasma lipoprotein regulation due to similarities in lipid
metabolism to man. For example, this model has been shown
to be highly predictive of the human lipid modulating efficacy
of fibrates.42 Furthermore, cellular activities of compound 34r
at the hamster PPARδ and PPARR receptors are more predictive
than murine of the activities at the human receptors (Table 4).
Hence, the hamster model was considered a well-suited model
for assessing the impact of 34r on lipid homeostasis with
potential utility for predicting the lipid effects of this compound
in man.
lipoprotein) and an increase of HDL/LDL ratios (Figure 5).
Compound 34r also lowered triglyceride and total cholesterol
levels to a similar or greater extent than that of fenofibrate,
whereas rosiglitazone had no effect on lipid levels (Figure 6).
Summary and Conclusion
4-Thiazolylphenyl groups were identified as novel PPAR
agonist tail portions. In combination with the recently established
indanylacetic acid head group, these compounds were shown
to give balanced PPAR R/γ/δ pan agonistic activities in vitro
and good selectivities against other nuclear hormone receptor
family members, including androgen, estrogen, glucocorticoid,
and progesterone receptors. Optimization efforts within the
thiazolylphenyl series led to the identification of 34r, a
compound with a good in vitro pharmacology profile and
excellent ADME properties. Compound 34r was found to dose-
dependently reduce blood glucose and was significantly more
potent than the standard of care agent rosiglitazone in db/db
mice. In ZDF rats, 34r showed superior glucose-lowering
efficacy compared to rosiglitazone. In male hApoA1 mice, 34r
dose-dependently lowered triglyceride and raised HDL choles-
terol levels. Compound 34r also caused a significant change in
lipoprotein distribution in fat-fed hyperlipidemic hamsters
highlighted by reduction of total cholesterol, increase of the
HDL/LDL ratio, and reduction of triglyceride levels. In sum-
mary, 34r displays a highly attractive in vivo pharmacology
profile. The magnitude of effects seen in the in vivo experiments
is equal or superior to standard of care agents and corroborates
earlier reports that PPAR R/γ/δ pan agonists hold potential for
the treatment of diabetes and associated dyslipidemia.
Fat-fed hyperlipidemic Golden Syrian hamsters were treated
with 34r (10 mg/kg), rosiglitazone (1; 10 mg/kg), and fenofibrate
(3; 100 mg/kg) for two weeks. All compounds, except rosigli-
tazone, caused significant changes in lipoprotein distribution,
characterized by a lowering of vLDL and LDL (low-density

990 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5
Rudolph et al.
Harbor, ME). Male ZDF rats were purchased from Genetic Models,
Inc. (Indianapolis, IN). All animals were purchased at 6 weeks of
age and were maintained on standard laboratory rodent chow ad
libitum. The hApoA1 mice were used within two weeks of their
arrival, whereas the db/db mice and ZDF rats were maintained on
diet for 3-4 and 4-8 weeks, respectively, to ensure that they
exhibited hyperglycemia prior to starting the study. The average
body weight was 50, 25, and 356 g for the db/db mice, hApoA1
mice, and the ZDF rats, respectively.
Male Syrian Golden Hamsters (Mesocricetus auratus, Lak:LVG-
(SYR)BR) were obtained from a Charles River Laboratories barrier
or isolator colony. The hamsters were no older than 7 weeks, and
the weight was between 120 and 150 g. The animals were fed either
a high fat diet (groups 2-10) or rodent chow (group 1) ad libitum
for the duration of the study. In addition, a 10% fructose drinking
water solution was used for all groups except group 1.
Dosing Regimen. All animals were weighed and tail-bled prior
to the start of study. Blood from db/db mice or ZDF rats was
analyzed for glucose levels using either a Beckman Glucose
Analyzer 2 (Beckman Instruments, Fullerton, CA) or a Technicon
Axon autoanalyzer (Bayer Corporation, Tarrytown, NY). Plasma
from hApoA1 mice was analyzed for triglyceride and HDLc levels
using the Axon autoanalyzer. The animals were arranged into the
appropriate number of groups with each group having the same
mean blood glucose levels (db/db mice and ZDF rats) or plasma
triglyceride levels (hApoA1 mice) prior to dosing. All animals were
then orally dosed once daily with vehicle (0.5% methylcellulose
in water), a positive control compound, or test compound. The db/
db mice were dosed for 7 days, hApoA1 mice for 7 days, and ZDF
rats for 21 days. All animals were fed ad libitum throughout the
study. Approximately 24 h after the last dose, the animals were
weighed and bled again, and the plasma or serum was analyzed
for glucose, triglycerides, or HDLc. Livers from the hApoA1 mice
were removed and weighed, and the weight was expressed as
percent of body weight. All results are expressed as the mean (
SEM for the number of animals indicated in the figure legends.
For the hyperlipidemic hamster studies, on study day 0, hamsters
were individually weighed and distributed into one of 10 groups
prior to receiving a high fat diet and fructose supplemented water
(groups 2-10). All groups (1-10) had similar weight means, (10%
of the average weight of all study animals. On study day 10, animals
were individually weighed and had blood collected by a retro-orbital
eye bleed, except for four (4) hamsters from group 10, which were
dosed with vehicle and then euthanized and bled via a terminal
bleed. Blood was prepared as EDTA plasma. After the retro-orbital
eye bleed on study day 10, all hamsters were given a daily oral
dose (by weight) of either vehicle or one of the test compounds
for 14 continuous days. Individual hamster body weights were taken
and recorded on study days 0, 4, 10, 17, and 24. No test compound
was given at the day of sacrifice (day 24). On study day 24, all
animals were submitted to necropsy. Following euthanasia, blood
and tissue (liver, skeletal muscle and fat pads) were collected and
frozen. Blood was collected into EDTA tubes for plasma preparation
and frozen. Plasma samples were analyzed via fast protein liquid
chromatography (FPLC) using a published procedure.43
Experimental Section
In Vitro Assays. PPARR Activity. (a) PPARR FRET Assay:
Activity was assessed by measuring the human PPARR ligand
binding domain with the co-activator protein CBP. Europium-
labeled anti-GST antibody, streptavidin-labeled APC, biotin-labeled
CBP, and PPARR-GST were incubated at rt in buffer in the
presence or absence of test compound. Following a 2 h incubation,
fluorescence was measured at emission wavelengths of 615 or 655
nm, with excitation at 340 nm.
(b) Cell-Based GAL4 Transactivation Assay for PPARR in CV-1
Cells: CV-1 cells were plated in 96-well plates and incubated
overnight at 37 °C in 5% CO2. Cells were transfected with human
PPARR ligand binding domain, pFR LUC DNA, and pRLSV40
DNA using lipofectamine plus. Cells were incubated overnight at
37 °C in 5% CO2 and treated with test compound or vehicle.
Following overnight incubation, cells were assayed for luciferase
activity using Dual-Luciferase reporter 1000 assay system.
PPARδ Activity. (a) PPARδ FRET Assay: The same protocol
was used as described for the PPARR FRET assay, except
substituting PPARR-GST with PPARδ-GST.
(b) Cell-Based GAL4 Transactivation Assay for PPARδ in CV-1
Cells: The same protocol was used as described for the PPARR
cell assay, except substituting human PPARR ligand binding domain
with human PPARδ ligand binding domain.
PPARγ Activity. PPARγ activity was assessed by using the
IRBA in mouse 3T3-L1 cells. This assay measures the ability of
test compound to cause an increase in the number of insulin
receptors and, hence, is an index of the insulin sensitizing activity.
3T3-L1 cells were seeded in 96-well tissue culture plates using
DMEM media containing 10% fetal bovine serum, 1% pen/strep,
and 2 mM L-glutamine, and were grown until they were 2 days
postconfluent. Cells were then treated for 2 days with medium
containing 0.5 µM human IGF-1 and test compound. After
treatment, the medium was replaced with medium free of IGF-1
and compound and incubated for 4 days. After washing the cells
with buffer, they were incubated with 0.1 nM 125I-insulin and
(()100 nM unlabeled insulin and incubated at rt for 1 h. The cells
were then washed 3× with buffer, dissolved with 1 N NaOH, and
the amount of radioligand bound measured using a gamma counter.
Selectivity Assays. Binding assays for androgen, progesterone,
estrogen, and glucocorticoid receptors were performed using a
similar protocol except for the source of the receptor and the ligand
used. The androgen receptor was recombinant human expressed in
SF9 baculovirus cells (10 µL per well) and 3H-dihydrotestosterone
as the radioligand (NEN NET453, use at 1:800 dilution). Nonspe-
cific binding was determined using cold DHT. Estrogen receptor
binding was performed using a cytosolic preparation from black
Swiss Mouse uteri (20 µL per well) with 3H-O-estradiol, (Amer-
sham TRK 587 at 1:666.7 dilution) and cold estradiol as a
nonspecific ligand. Glucocorticoid receptor binding was determined
using a cytosol preparation from HUH cells with 3H-dexamethaxone
(Amersham TRK 645 at 1:312.5 dilution) and cold dexamethasone
as a nonspecific ligand. Progesterone receptor binding was per-
3
formed using the cytosol from T47D cell line, H-progesterone
Calculation of Percent Change Due to Drug Treatment. To
compare the effects of test compound treatment on glucose levels
in db/db mice with its effects on triglyceride levels in hApoA1
mice, it is useful to calculate the percent change in glucose or
triglyceride that is due to drug treatment. This takes into account
any changes that may have occurred in the vehicle-treated animals
during the study. The percent change due to drug treatment is
calculated as follows
(NEN NEX 381 at 1:1100 dilution), and progesterone as the
nonspecific ligand. Briefly, 65 µL of diluted cytosol was added to
each well of a 96-well polypropylene plate. An amount equal to
10 µL of 10× test compound, control DMSO (total binding), or 1
3
µM cold ligand (nonspecific binding) was added next. H-ligand
in the amount of 25 µL was then added to a final concentration of
10 nM. The assay was incubated overnight at 4 °C. An aliquot of
50 µL of the assay volume was added to a prespun (2 min at 2100
rpm) spin plate (Edge Biosystems catalog no. 31909). The plate
was spun for 5 min at 2500 rpm, and the flow through was caught
on a Wallac isoplate (catalog no. 1450-514). Scintillant (ScintiSafe
or Ultima Gold) in the amount of 175 µL was added, and the plate
was allowed to equilibrate for 1 h. Finally, the plate was counted
for 1 min in the Wallac Microbeta.
(((Tf/Ti)/(Vf/Vi)) - 1) × 100
where Tf and Ti are the final and initial values of either blood
glucose or plasma triglyceride levels in the drug-treated animals,
respectively, and Vf and Vi are the same for the vehicle-treated
animals. A positive number denotes a drug-induced increase,
whereas a negative number denotes a drug-induced decrease.
In Vivo Models. Animals. Female db/db mice and male/female
hApoA1 mice were purchased from The Jackson Laboratory (Bar

Indanylacetic Acid DeriVatiVes as PPAR Agonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5 991
Statistical Analysis. ANOVA was used to evaluate the effects
of positive control drugs and test compound using InStat (GraphPad
Software, Inc., San Diego, CA). The Tukey-Kramer Multiple
Comparisons Test was used for the parametric ANOVA. Whenever
a nonparametric ANOVA was required, the Kruskal-Wallis Test
was used. Results were considered significant at p < 0.05.
General Chemistry. Purchased reagents and anhydrous solvents
were used as received. Air and moisture sensitive liquids and
solutions were transferred via syringe or cannula, and introduced
into reaction vessels through rubber septa.
ppm for DMSO-d6, 1.93 ppm for CD3CN, 3.30 ppm for CD3OD,
5.32 ppm for CD2Cl2, and 7.26 ppm for CDCl3.
Ethyl (5-Methoxy-2,3-dihydro-1H-inden-1-ylidene)ethanoate
(10). To a solution of 5-methoxyindanone (150 g, 0.91 mol) in
anhydrous tetrahydrofuran (4.5 L), was added zinc (30 mesh, 103.64
g, 1.59 mol) and copper(I) chloride (4.53 g, 0.045 mol). The
suspension was stirred under argon atmosphere and heated under
reflux for 15 min; approximately a 25% portion of ethyl bromo-
acetate (133 mL, 1.18 mol) was added to the refluxing mixture in
a slow dropwise fashion. After allowing cooling and stirring for
12 h at rt, TLC showed the presence of desired product. The
remainder of ethyl bromoacetate was added dropwise, and the
internal temperature was increased to 35 °C. After 4 h, TLC showed
complete reaction. After the solids settled to the bottom of the flask,
the liquid was siphoned off, leaving a small amount behind to cover
the solids. The flask was recharged with 5-methoxyindanone (157.6
g, 1.86 mol total), anhydrous tetrahydrofuran (4.5 L), and zinc
(80.92 g, 2.73 mol total). Ethyl bromoacetate (140 mL, 2.36 mol)
was added dropwise, and the internal temperature was increased
to 35 °C. When the stirred mixture was cooled to rt, TLC showed
the reaction to be complete. The solids were allowed to settle and
the liquid was siphoned off. The combined reaction solutions were
concentrated under reduced pressure to a volume of about 2 L.
The liquid was then poured into HCl (1 N aqueous solution, cooled
in ice water) to bring the pH to 1. The product was extracted with
ethyl acetate (2 × 1 L, 1 × 500 mL). The combined extracts were
washed with water (1 L) and brine (1 L), dried over Na2SO4,
filtered, and concentrated under reduced pressure to afford a dark
red oil which solidified gradually (438.3 g; theoretical yield ) 432
Column chromatography was performed on a Biotage system
using 32-63 micron, 60 Å, silica gel pre-packed cartridges.
Purification using preparative reversed-phase HPLC chromatog-
raphy was accomplished using a Gilson 215 system, using a YMC
Pro-C18 AS-342 (150 × 20 mm I.D.) column and 1 mL/min flow
rate. Typically, the mobile phase used was a mixture of H2O (A)
and MeCN (B). The water could be mixed or not with 0.1% TFA.
A typical gradient was: 0.5 min, 90% A, 10% B; 11.0 min, 0% A,
100% B.
Chiral analytical HPLC experiments were performed using one
of the two following methods using a Varian Pro Star 1200. Method
A: Chiracel AD column, 4.6 (I.D.) × 250 mm; mobile phase, A,
0.1% TFA in hexanes; B, 0.1% TFA in i-PrOH; isocratic, 95% A
(5% B), 20 min; flow rate, 1.5 mL/min; UV detection, 284 nm.
Method B: Chiracel AD column, 4.6 (I.D.) × 250 mm; mobile
phase, A, 0.1% TFA in hexanes; B, 0.1% TFA in i-PrOH; isocratic,
95% A (5% B), 25 min; flow rate, 1.0 mL/min; UV detection, 284
nm.
Electron impact mass spectra (EI-MS or GC-MS) were obtained
with a Hewlett-Packard 5989A mass spectrometer equipped with
a Hewlett-Packard 5890 Gas Chromatograph with a J & W DB-5
column (0.25 µM coating; 30 m × 0.25 mm). The ion source was
maintained at 250 °C, and spectra were scanned from 50 to 800
amu at 2 s per scan.
Two different methods were used to obtain HPLC electrospray
mass spectra (HPLC ES-MS). HPLC-MS method 1: An Agilent
1100 HPLC system was equipped with an Agilent 1100 autosam-
pler, quaternary pump, and a diode array. The HPLC column used
was a Waters Sunfire C-18 column (2.1 × 30 mm, 3.5 µM). The
HPLC eluent was directly coupled with a 1:4 split to a Finnigan
LTQ ion trap mass spectrometer with electrospray ionization.
Spectra were scanned from 50 to 800 amu using a variable ion
time according to the number of ions in the source using positive
ion mode. The eluents were A, water with 0.1% formic acid, and
B, acetonitrile with 0.1% formic acid. Gradient elution from 10%
B to 90% B over 3.0 min at a flow rate of 1.0 mL/min was used
with an initial hold of 2.0 min and a final hold at 95% B of 1.0
min. Total run time was 8.0 min.
HPLC-MS method 2: An Agilent 1100 HPLC system was
equipped with an Agilent 1100 autosampler, quaternary pump, a
variable wavelength detector set at 254 nm. The HPLC column
used was a Waters Sunfire C-18 column (2.1 × 30 mm, 3.5 µM).
The HPLC eluent was directly coupled without splitting to a
Finnigan LCQ DECA ion trap mass spectrometer with electrospray
ionization. Spectra were scanned from 140 to 1200 amu using a
variable ion time according to the number of ions in the source
using positive ion mode. The eluents were A, 2% acetonitrile in
water with 0.02% TFA, and B, 2% water in acetonitrile with 0.02%
TFA. Gradient elution from 10% B to 90% B over 3.0 min at a
flow rate of 1.0 mL/min was used with an initial hold of 1.0 min
and a final hold at 95% B of 1.0 min. Total run time was 7.0 min.
For consistency in characterization data, the retention time (RT) is
reported in min at the apex of the peak, as detected by the UV-
vis detector set at 254 nm.
1
g). H NMR (CDCl3) δ 7.5 (d, 1H), 6.8 (m, 2H), 6.2 (t, 1 H), 4.2
(q, 2H), 3.8 (s, 3H), 3.3 (m, 2H), 3.0 (t, 2H), 1.3 (t, 3H). MS (CI)
m/z 233 [M + H]+.
Ethyl (5-Methoxy-2,3-dihydro-1H-inden-1-yl)acetate (11). The
crude product 10 was dissolved in absolute ethanol (2.6 L) and
hydrogenated at 40 psi of hydrogen over 10% palladium on carbon
(21.6 g). Filtration through Celite and concentration of the filtrate
afforded the title compound: 433.3 g (99% yield for two steps) as
a brown oil. 1H NMR (CDCl3) δ 7.1 (dd, 1H), 6.8 (d, 1H), 6.7 (dd,
1H), 4.2 (q, 2H), 3.8 (s, 3H), 3.5 (m, 1H), 2.9 (m, 2H), 2.7 (dd,
1H), 2.4 (m, 2H), 1.7 (m, 1H), 1.3 (t, 3H). MS (CI) m/z 235 [M +
H]+.
[(1S)-5-Methoxy-2,3-dihydro-1H-inden-1-yl]acetic Acid (12).
A mixture of the crude ester 11 (500 g, 2.13 mol; 87% pure as
determined by analytical HPLC) in reagent grade acetone (1 L), a
phosphate buffer (2.5 L, pH 7.0, 0.05 M), and water (2.5 L) was
treated in one portion with Amano Lipase PS (150 g, Amano
Enzymes), and the mixture was stirred vigorously at rt for 12 h.
Chiral analytical HPLC analysis (method A) of an aliquot (homo-
geneous aliquot prepared by dissolving an aliquot in i-PrOH
followed by filtration) showed one peak corresponding to unreacted
R-ester and another peak corresponding to desired S-acid. Only trace
amounts of S-ester and R-acid were noted. Then HCl (500 mL, 2
N aqueous solution) was added in one portion to the reaction
mixture to ensure a pH ∼2, and the mixture was stirred for 20
min. The mixture was filtered and the solids were washed with
EtOAc (2 × 500 mL) and then water (500 mL). The combined
filtrates were further diluted with EtOAc (1 L), and the layers were
stirred together vigorously. Stirring was stopped, and the layers
were allowed to separate. The resulting emulsion was broken by
the addition of solid NaCl and stirring. The aqueous layer was
removed and then extracted with EtOAc (3 × 1 L) in the same
fashion. The combined organic extractions were washed with water
(4 × 500 mL) and brine and then extracted with Na2CO3 (8 × 500
mL, 5% aqueous solution). Chiral analytical HPLC (method A)
analysis of the organic layer showed that it contained none of the
S-enantiomer acid. The combined Na2CO3 extracts were washed
with EtOAc (2 × 1 L) and then acidified to pH ∼2 by the addition
of HCl (2 N aqueous solution). A white solid precipitated,
accompanied by CO2 evolution. The mixture was extracted with
EtOAc (3 × 1 L). The combined extracts were washed with water
(2 × 1 L) and brine and then dried over Na2SO4. Chiral analytical
1H NMR spectroscopy was performed on 300 or 400 MHz Varian
Mercury-plus as well as Bruker DRX500 spectrometers. The
samples were dissolved in deuterated solvents and transferred to 5
mm ID Wilmad NMR tubes. The spectra were acquired at 293 K.
The chemical shifts were recorded on the ppm scale and were
referenced to the appropriate residual solvent signals, such as 2.49

992 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5
Rudolph et al.
HPLC (method A) analysis of this solution showed that the material
had an ee of 98%. The solvent was evaporated under reduced
pressure, giving an oil that solidified upon standing. The title
product (172.9 g) was obtained as an off-white solid after vacuum
drying, and then this material was recrystallized from boiling
hexanes (8.8 L). After cooling for 12 h, light yellow needles were
collected via filtration, washed with hexanes (200 mL), and dried
under suction. The title product (146.9 g, 38% from crude starting
ester) was obtained as light yellow needles after vacuum drying.
1H NMR (CDCl3) δ 7.10 (d, 1H), 6.79 (d, 1H), 6.73 (dd, 1H), 3.79
(s, 3H), 3.55 (m, 1H), 2.89 (m, 2H), 2.79 (dd, 1H), 2.46 (dd, 1H),
2.43 (m, 1H), 1.80 (m, 1H). MS (ESI) m/z 207 [M + H]+. The
absolute configuration was indirectly determined by single-crystal
X-ray crystallography of a derivative containing Evans’ oxazoli-
dinone chiral auxiliary (see Supporting Information).
Ethyl [(1S)-5-Methoxy-2,3-dihydro-1H-inden-1-yl]acetate (13).
To a solution of the acid 12 (305 g, 1.48 mol) in 4.8 L of absolute
EtOH at rt under argon was added chlorotrimethylsilane (413 mL,
3.25 mol) dropwise. After stirring for 12 h, the EtOH was
evaporated under reduced pressure, giving a biphasic liquid mixture.
This mixture was diluted in ice-water (500 mL) and then extracted
with EtOAc (2 × 750 mL). The combined extracts were washed
with water (3 × 300 mL) and then with a saturated aqueous solution
of NaHCO3 (200 mL). The organic phase was washed once more
with water (300 mL) and then brine and dried over Na2SO4. The
title compound (354 g, quant.) was obtained as a light yellow oil
after solvent removal and vacuum drying. 1H NMR (CDCl3) δ 7.07
(d, 1H), 6.78 (d, 1H), 6.71 (dd, 1H), 4.18 (q, 2H), 3.78 (s, 3H),
3.52 (m, 1H), 2.89 (m, 2H), 2.72 (dd, 1H), 2.37 (o, 2H), 1.74 (m,
1H), 1.28 (t, 3H). MS (CI) m/z 235 [M + H]+.
Ethyl [(1S)-5-Hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (14).
To a cold solution (ice water bath) of 13 (346 g, 1.48 mol) in CH2-
Cl2 (4.2 L) was added AlCl3 (984.6 g, 7.38 mol) portionwise under
argon such that the reaction temperature was maintained below 10
°C. The light brown suspension was stirred for 10 min, and then
EtSH (546 mL, 7.38 mol) was added dropwise at such a rate that
the reaction temperature was maintained below 5 °C. After 2.5 h
of stirring below 10 °C, the reaction mixture was slowly poured
into 6 L of ice water with strong agitation. The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2 (3 ×
1 L). The combined CH2Cl2 layers were washed with water (2 ×
1 L) and then dried over Na2SO4. The solvent was removed under
reduced pressure, giving a brown oil that was filtered through a
pad of silica gel (eluted with 0-10% EtOAc/Hexanes). Fractions
were collected, and the title compound (314 g, 96%) was obtained
as a thick yellow oil after solvent removal and vacuum drying. 1H
NMR (CDCl3) δ 6.92 (d, 1H), 6.62 (d, 1H), 6.55 (dd, 1H), 4.10 (q,
2H), 3.43 (q, 1H), 2.75 (m, 2H), 2.64 (dd, 1H), 2.31 (dd, 1H), 2.29
(m, 1H), 1.67 (m, 1H), 1.20 (t, 3H). MS (CI) m/z 221 [M + H]+.
Ethyl [(1S)-5-(3-Bromopropoxy)-2,3-dihydro-1H-inden-1-yl]-
acetate (15). To a solution of ethyl [(1S)-5-hydroxy-2,3-dihydro-
1H-inden-1-yl]acetate (0.166 g, 0.754 mmol; 14) in DMF (0.5 mL,
containing 1% v/v of water) were added 1,3-dibromopropane (0.27
mL, 2.64 mmol) and Cs2CO3 (0.295 g, 0.905 mmol). The mixture
was stirred at rt for 13 h and then at 80 °C for 1 h. Upon cooling
to rt, the reaction mixture was concentrated under reduced pressure.
The residue was suspended in EtOAc and filtered, and the filter
cake was washed with EtOAc. The combined filtrate was dried,
concentrated, and purified by silica gel chromatography (100%
hexanes to EtOAc/hexane (v/v) 1:19 gradient) to give 153 mg (60%)
of the title compound containing minor impurities. This material
was used in later steps without further purification. 1H NMR (300
MHz, CDCl3) δ 7.08 (d, 1H), 6.78 (s, 1H), 6.70 (dd, 1H), 4.19 (q,
2H), 4.08 (t, 2H), 3.60 (t, 2), 3.58-3.44 (m, 1H), 2.96-2.64 (m,
3H), 2.50-2.21 (m, 4H), 1.93-1.68 (m, 1H), 1.28 (t, 3H).
1-(Allyloxy)-4-(trifluoromethyl)benzene (18). 4-(Trifluoro-
methyl)phenol (1.50 g, 9.25 mmol), allyl bromide (14.55 g, 12.03
mmol), Cs2CO3 (3.62 g, 11.10 mmol), and water (15 drops) were
combined in DMF (40 mL), and the mixture was stirred for 12 h.
The reaction mixture was then concentrated under reduced pressure,
diluted with water, and extracted with EtOAc (2×). The combined
organic phases were dried over Na2SO4, filtered, and concentrated
under reduced pressure to give 0.96 g (51%) of the title compound
as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.59 (d, 2H),
5.32 (d, 1H), 5.43 (d, 1H), 6.05 (m, 1H), 6.97 (d, 2H), 7.53 (d,
2H).
4-(Allyloxy)benzonitrile (19). 4-Hydroxybenzonitrile (30.0 g,
252 mmol), allyl bromide (39.6 g, 327 mmol), and Cs2CO3 (98.5
g, 302 mmol) were dissolved in DMF (900 mL), and water (1 mL)
was added. After stirring for 12 h at rt, the reaction mixture was
concentrated under reduced pressure, water was added, and the
mixture was extracted with EtOAc (2×). The combined organic
layers were washed with water and brine. The organic layer was
dried over Na2SO4, filtered, and concentrated under reduced
pressure, yielding 40 g (100%) of the title compound as a white
crystalline solid. 1H NMR (400 MHz, CDCl3) δ 4.60 (d, 2H), 5.34
(d, 1H), 5.43 (d, 1H), 6.03 (m, 1H), 6.96 (d, 2H), 7.58 (d, 2H).
2-Allyl-4-(trifluoromethyl)phenol (21). Under an atmosphere
of argon, 1-(allyloxy)-4-(trifluoromethyl)benzene (200 mg, 0.99
mmol; 18) was dissolved in CH2Cl2 (anhydrous, 5 mL) and cooled
to 15 °C. Then a solution of boron trichloride (1.04 mL, 1.04 mmol,
1 M in hexane) was added dropwise, and the reaction mixture was
stirred for 2 h during which time the reaction mixture was allowed
to warm to rt. The mixture was poured onto ice and extracted with
EtOAc (2×). The combined organic phases were washed with
NaHCO3 (saturated aqueous solution), dried over Na2SO4, filtered,
and concentrated under reduced pressure to afford the product as a
yellow oil. This was used in the next step without further
purification.
3-Allyl-4-hydroxybenzonitrile (22). 4-(Allyloxy)benzonitrile
(40.0 g, 251.3 mmol; 19) was heated under argon at 200 °C for 20
h. Upon cooling to rt, the product was purified via silica gel flash
chromatography (EtOAc/hexane (v/v) 1:10 f EtOAc/hexane (v/
v) 1:4), yielding 27.5 g (69%) of the title compound as a white
crystalline solid. 1H NMR (400 MHz, CDCl3) δ 3.44 (d, 2H), 5.18
(d, 1H), 5.24 (d, 1H), 5.99 (m, 1H), 6.05 (br, 1H), 6.89 (d, 1H),
7.46 (d, 2H).
2-Allyl-4-phenoxyphenol (23). 1-(Allyloxy)-4-phenoxybenzene
(20), prepared by using a similar procedure as described for the
synthesis of compound 18, was further converted into the title
compound using a similar procedure as described for the preparation
of compound 22. 1H NMR (400 MHz, CDCl3) δ 3.60 (d, 2H), 4.82
(s, 1H), 5.17 (d, 2H), 5.99 (m, 1H), 6.80 (m, 2H), 6.83 (s, 1H),
6.93 (d, 2H), 7.04 (t, 1H), 7.29 (m, 2H).
2-Propyl-4-(trifluoromethyl)phenol (24). The crude 2-allyl-4-
(trifluoromethyl)phenol (21) was dissolved in EtOH (5 mL), Pd/C
(20 mg, 10%, Fluka) was added, and the mixture was stirred under
an atmosphere of hydrogen at rt for 2 h. The catalyst was removed
by filtration. The filtrate was concentrated under reduced pressure,
and the residue was purified by silica gel flash chromatography
(EtOAc/hexane (v/v) 1:10). This gave 91 mg (45% over 2 steps)
of the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3)
δ 1.00 (t, 3H), 1.68 (m, 2H), 2.61 (t, 2H), 5.14 (br, 1H), 6.80 (d,
1H), 7.32 (d, 1H), 7.36 (s, 1H).
4-Hydroxy-3-propylbenzonitrile (25). 3-Allyl-4-hydroxyben-
zonitrile (20.0 g, 126 mmol; 22) was dissolved in EtOH (320 mL)
under argon. Pd/C (80 mg, 10%, Fluka) was added, and the reaction
mixture was stirred under a hydrogen atmosphere (1 atm) at rt for
20 h. The catalyst was filtered off and then the reaction mixture
was concentrated under reduced pressure, yielding 20.2 g (99%)
of the title compound as a slightly greenish oil. 1H NMR (400 MHz,
CDCl3) δ 0.95 (t, 3H), 1.63 (m, 2H), 2.56 (m, 2H), 6.86 (d, 1H),
7.30 (m, 2H).
4-Phenoxy-2-propylphenol (26). 2-Allyl-4-phenoxyphenol (23;
4.8 g, 21.3 mmol), Pd/C (480 mg, 10%) and ammonium formate
(8.03 g, 127.3 mmol) were combined in ethanol (100 mL) under
an argon atmosphere and heated to 40 °C. After 1.5 h, the catalyst
was filtered off, and the solution was concentrated under reduced
pressure and redissolved in EtOAc. The solution was passed through
a silica gel plug and concentrated to give the title compound as a
1
yellow oil (4.8 g, 99.9%). H NMR (400 MHz, CDCl3) δ 0.97 (t,

Indanylacetic Acid DeriVatiVes as PPAR Agonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5 993
3H), 1.63 (m, 2H), 2.56 (t, 2H), 4.69 (s, 1H), 6.72 (m, 2H), 6.83
(s, 1H), 6.91 (d, 2H), 7.01 (t, 1H), 7.26 (m, 2H).
2H), 1.58 (dd, J ) 12.51, 7.63 Hz, 1H). LC-MS: method 1, RT
(min) ) 5.38; [M + H]+ 410.9; method 2, RT (min) ) 4.06 (no
ionization).
((1S)-5-{3-[2-Propyl-4-(trifluoromethyl)phenoxy]propoxy}-
2,3-dihydro-1H-inden-1-yl)acetate (16n). Compounds 24 (91 mg,
0.45 mmol) and 15 (149 mg, 0.44 mmol) were dissolved in 6 mL
of DMF containing 1 vol % H2O. Cesium carbonate (171 mg, 0.52
mmol) was added, and the mixture was stirred at 40 °C for 16 h.
The DMF was removed under reduced pressure, water was added,
and it was extracted (2×) with EtOAc. The combined organic
phases were dried with Na2SO4, and the solvent was removed under
reduced pressure. Purification by silica gel column chromatography
using hexanes/EtOAc (20:1) furnished the product as a clear oil in
{(1S)-5-[3-(4-Methoxyphenoxy)propoxy]-2,3-dihydro-1H-in-
1
den-1-yl}acetic Acid (17e). H NMR (300 MHz, CDCl3) δ 7.09
(d, 1H), 6.84-6.70 (m, 6H), 4.17-4.05 (m, 4H), 3.76 (s, 3H), 3.51
(m, 1H), 2.90-2.77 (m, 2H), 2.50-2.35 (m, 2H), 2.25-2.17 (m,
2H), 1.85-1.70 (m, 1H). LC-MS: method 2, RT (min) ) 3.18;
[M + H]+ 356.9.
{(1S)-5-[3-(4-Ethoxyphenoxy)propoxy]-2,3-dihydro-1H-inden-
1-yl}acetic Acid (17f). 1H NMR (500 MHz, DMSO-d6) δ 7.04 (d,
J ) 8.24 Hz, 1H), 6.76-6.82 (m, 4H), 6.75 (s, 1H), 6.66 (d, J )
7.02 Hz, 1H), 4.01 (dt, J ) 16.78, 6.10 Hz, 4H), 3.89 (q, J ) 7.02
Hz, 2H), 3.26-3.33 (m, 1H), 2.74-2.81 (m, 1H), 2.69 (dt, J )
15.87, 7.93 Hz, 1H), 2.5 (m, 1H), 2.18-2.26 (m, 2H), 2.01-2.08
(m, J ) 6.10, 6.10, 6.10, 6.10 Hz, 2H), 1.55-1.63 (m, 1H), 1.18-
1.26 (m, 3H). LC-MS: method 1, RT (min) ) 5.17; [M + H]+
371.1; method 2, RT (min) ) 3.85; [M + H]+ 371.2.
1
143 mg (70%) yield. H NMR (400 MHz, CDCl3) δ 0.95 (t, 3H),
1.29 (t, 3H), 1.60 (m, 2H), 1.76 (m, 1H), 2.29 (m, 2H), 2.39 (m,
2H), 2.61 (m, 2H), 2.72 (dd, 1H), 2.86 (m, 2H), 4.17 (m, 6H),
6.69 (d, 1H), 6.78 (s, 1H), 6.88 (d, 1H), 7.07 (d, 1H), 7.07 (d, 1H),
7.34 (s, 1H), 7.40 (d, 1H). Compounds 16a-16m and compounds
16o-16x were made using the same procedure as for the prepara-
tion of compound 16n using appropriate starting materials.
{(1S)-5-[3-(4-Cyanophenoxy)propoxy]-2,3-dihydro-1H-inden-
1
1-yl}acetic Acid (17g). H NMR (500 MHz, DMSO-d6) δ 7.59
((1S)-5-{3-[2-Propyl-4-(trifluoromethyl)phenoxy]propoxy}-
2,3-dihydro-1H-inden-1-yl)acetic Acid (17n). To a solution of
compound 16n (132 mg, 0.28 mmol) in 4 mL of THF/water (3:1)
was added LiOH‚H2O (14 mg, 0.34 mmol), and the mixture was
stirred at rt for 16 h. The THF was evaporated and more water
was added. The aqueous layer was washed with a small amount of
ether. The aqueous layer was then acidified with 1 N HCl and
extracted (3×) with EtOAc. The combined organic layers were dried
(MgSO4) and concentrated to give 112 mg (90%) of the pure
(d, J ) 8.54 Hz, 1H), 7.50 (s, 1H), 7.02-7.10 (m, 2H), 6.74 (s,
1H), 6.65 (d, J ) 7.93 Hz, 1H), 4.16 (t, J ) 5.95 Hz, 2H), 4.06 (t,
J ) 6.10 Hz, 2H), 3.25-3.33 (m, 1H), 2.73-2.80 (m, 1H), 2.68
(dt, J ) 15.79, 7.82 Hz, 1H), 2.18-2.26 (m, 2H), 2.09-2.16 (m,
J ) 5.95, 5.95, 5.95, 5.95 Hz, 2H), 1.55-1.63 (m, 1H), 1.42-1.50
(m, J ) 7.32, 7.32, 7.32, 7.32, 7.32 Hz, 2H), 0.80 (t, J ) 7.32 Hz,
3H). LC-MS: method 1, RT (min) ) 5.30; [M + H]+ 393.9;
method 2, RT (min) ) 3.98; [M + H]+ 394.1.
1
{(1S)-5-[3-(Biphenyl-4-yloxy)propoxy]-2,3-dihydro-1H-inden-
product as a colorless oil. H NMR (500 MHz, DMSO-d6) δ 7.47
1
1-yl}acetic Acid (17h). H NMR (500 MHz, DMSO-d6) δ 7.54
(d, J ) 8.55 Hz, 1H), 7.39 (s, 1H), 7.01-7.10 (m, 2H), 6.74 (s,
1H), 6.66 (d, J ) 8.24 Hz, 1H), 4.15 (t, J ) 5.80 Hz, 2H), 4.02-
4.10 (m, 2H), 3.26-3.33 (m, 1H), 2.73-2.80 (m, 1H), 2.68 (ddd,
J ) 16.02, 7.93, 7.78 Hz, 2H), 2.18-2.26 (m, 2H), 2.11-2.16 (m,
J ) 5.87, 5.87, 5.87, 5.87 Hz, 2H), 1.55-1.63 (m, 1H), 1.44-1.52
(m, J ) 7.39, 7.39, 7.39, 7.39, 7.39 Hz, 4H), 0.81 (t, J ) 7.32 Hz,
3H). LC-MS: method 1, RT (min) ) 5.66 (no ionization); method
2, RT (min) ) 4.39 (no ionization).
(dd, J ) 7.63, 5.80 Hz, 4H), 7.38 (t, J ) 7.63 Hz, 2H), 7.26 (t, J
) 7.17 Hz, 1H), 7.05 (d, J ) 8.24 Hz, 1H), 6.99 (d, J ) 8.54 Hz,
2H), 6.77 (s, 1H), 6.64-6.72 (m, 1H), 4.12 (t, J ) 6.10 Hz, 2H),
4.06 (t, J ) 6.10 Hz, 2H), 3.26-3.33 (m, 1H), 2.74-2.81 (m, 1H),
2.69 (dt, J ) 15.79, 7.82 Hz, 1H), 2.5 (m, 1H), 2.17-2.26 (m,
2H), 2.06-2.14 (m, J ) 6.03, 6.03, 6.03, 6.03 Hz, 2H), 1.54-1.63
(m, 1H). LC-MS: method 1, RT (min) ) 5.44; [M + H]+ 403.1;
method 2, RT (min) ) 4.13 (no ionization).
Compounds 17a-17m and compounds 17o-17x were made
using the same procedure as for the preparation of compound 17n
using appropriate starting materials.
[(1S)-5-(3-Phenoxypropoxy)-2,3-dihydro-1H-inden-1-yl]ace-
tic Acid (17a). 1H NMR (300 MHz, CDCl3) δ 7.32-7.22 (m, 3H),
7.09 (d, 1H), 6.95-6.87 (m, 2H), 6.80 (s, 1H), 6.74 (d, 1H), 4.18-
4.08 (m, 4H), 3.51 (m, 1H), 2.88-2.79 (m, 2H), 2.73 (d, 1H), 2.48-
2.31 (m, 2H), 2.26-2.17 (m, 2H), 1.87-1.71 (m, 1H). LC-MS:
method 2, RT (min) ) 3.98 (no ionization).
{(1S)-5-[3-(3-Methylphenoxy)propoxy]-2,3-dihydro-1H-inden-
1-yl}acetic Acid (17i). 1H NMR (500 MHz, DMSO-d6) δ 7.10 (t,
J ) 7.78 Hz, 1H), 7.04 (d, J ) 8.24 Hz, 1H), 6.75 (s, 1H), 6.64-
6.71 (m, 4H), 4.00-4.06 (m, 4H), 3.27-3.33 (m, 1H), 2.74-2.81
(m, 1H), 2.69 (dt, J ) 15.87, 7.93 Hz, 1H), 2.5 (m, 1H), 2.18-
2.26 (m, 5H), 2.03-2.10 (m, J ) 6.03, 6.03, 6.03, 6.03 Hz, 2H),
1.55-1.63 (m, 1H). LC-MS: method 1, RT (min) ) 5.22; [M +
H]+ 341.1; method 2, RT (min) ) 3.91; [M + H]+ 341.3.
{(1S)-5-[3-(3,4-Dimethylphenoxy)propoxy]-2,3-dihydro-1H-
{(1S)-5-[3-(4-Ethylphenoxy)propoxy]-2,3-dihydro-1H-inden-
1
inden-1-yl}acetic Acid (17j). H NMR (500 MHz, DMSO-d6) δ
1
1-yl}acetic Acid (17b). H NMR (500 MHz, DMSO-d6) δ 7.05
7.04 (d, J ) 8.24 Hz, 1H), 6.96 (d, J ) 8.24 Hz, 1H), 6.75 (s, 1H),
6.64-6.69 (m, 2H), 6.60 (dd, J ) 8.09, 1.98 Hz, 1H), 4.01 (q, J )
6.71 Hz, 4H), 3.32 (s, 1H), 3.25-3.32 (m, 1H), 2.74-2.81 (m,
1H), 2.69 (dt, J ) 15.95, 8.05 Hz, 2H), 2.5 (m, 1H), 2.18-2.26
(m, 2H), 2.11 (s, 3H), 2.03-2.09 (m, 5H), 1.55-1.63 (m, 1H).
LC-MS: method 1, RT (min) ) 5.33; [M + H]+ 355.0; method 2,
RT (min) ) 4.01 (no ionization).
(dd, J ) 7.93, 4.27 Hz, 3H), 6.80 (d, J ) 8.24 Hz, 2H), 6.76 (s,
1H), 6.64-6.69 (m, 1H), 4.03 (t, J ) 5.49 Hz, 4H), 3.33 (m, 1H),
2.75-2.81 (m, 1H), 2.69 (dt, J ) 15.87, 7.93 Hz, 2H), 2.58 (d, J
) 5.80 Hz, 1H), 2.5 (m, 1H), 2.19-2.27 (m, 4H), 2.04-2.11 (m,
J ) 6.18, 6.18, 6.18, 6.18 Hz, 2H), 1.60 (dd, J ) 12.51, 7.63 Hz,
1H), 1.07-1.14 (m, 3H). LC-MS: method 1, RT (min) ) 5.37;
[M + H]+ 355.0; method 2, RT (min) ) 4.07 (no ionization).
{(1S)-5-[3-(3-Methoxyphenoxy)propoxy]-2,3-dihydro-1H-in-
den-1-yl}acetic Acid (17k). 1H NMR (500 MHz, DMSO-d6) δ 7.12
(t, J ) 8.09 Hz, 1H), 7.04 (d, J ) 8.24 Hz, 1H), 6.75 (s, 1H), 6.66
(d, J ) 7.93 Hz, 1H), 6.42-6.49 (m, 3H), 4.04 (q, J ) 6.31 Hz,
4H), 3.67 (s, 3H), 3.25-3.33 (m, 1H), 2.74-2.81 (m, 1H), 2.69
(dt, J ) 15.87, 7.93 Hz, 1H), 2.5 (m, 1H), 2.18-2.26 (m, 2H),
2.03-2.10 (m, J ) 6.10, 6.10, 6.10, 6.10 Hz, 2H), 1.55-1.63 (m,
1H). LC-MS: method 1, RT (min) ) 5.07; [M + H]+ 357.1;
method 2, RT (min) ) 3.75; [M + H]+ 357.2.
((1S)-5-{3-[4-(Trifluoromethyl)phenoxy]propoxy}-2,3-dihydro-
1
1H-inden-1-yl)acetic Acid (17c). H NMR (500 MHz, DMSO-
d6) δ 7.22 (d, J ) 8.54 Hz, 2H), 6.97-7.06 (m, 3H), 6.75 (s, 1H),
6.66 (d, J ) 8.24 Hz, 1H), 4.01-4.10 (m, 4H), 3.25-3.32 (m,
1H), 2.68 (ddd, J ) 16.02, 7.93, 7.78 Hz, 1H), 2.5 (m, 1H), 2.18-
2.26 (m, 2H), 2.05-2.12 (m, J ) 6.18, 6.18, 6.18, 6.18 Hz, 2H),
1.59 (ddd, J ) 19.99, 7.93, 7.78 Hz, 1H). LC-MS: method 1, RT
(min) ) 5.36 (no ionization); method 2, RT (min) ) 4.04 (no
ionization).
((1S)-5-{3-[4-(Trifluoromethoxy)phenoxy]propoxy}-2,3-dihy-
dro-1H-inden-1-yl)acetic Acid (17d). 1H NMR (500 MHz, DMSO-
d6) δ 7.21 (d, J ) 8.85 Hz, 2H), 6.90-7.07 (m, 3H), 6.74 (s, 1H),
6.65 (d, J ) 7.63 Hz, 1H), 3.70-4.10 (m, 4H), 3.28 (m, 1H), 2.62-
2.84 (m, 2H), 2.59 (m, 1H), 2.15-2.24 (m, 2H), 1.99-2.14 (m,
{(1S)-5-[3-(2,4-Dimethylphenoxy)propoxy]-2,3-dihydro-1H-
1
inden-1-yl}acetic Acid (17l). H NMR (500 MHz, DMSO-d6) δ
7.04 (d, J ) 7.93 Hz, 1H), 6.85-6.92 (m, 2H), 6.73-6.79 (m,
2H), 6.66 (d, J ) 7.63 Hz, 1H), 3.99-4.08 (m, 4H), 3.26-3.33
(m, 1H), 2.74-2.81 (m, 1H), 2.68 (dt, J ) 15.95, 8.05 Hz, 2H),
2.18-2.26 (m, 2H), 2.14 (s, 3H), 2.04-2.11 (m, 5H), 1.55-1.63

994 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5
Rudolph et al.
(m, 1H). LC-MS: method 1, RT (min) ) 5.39; [M + H]+ 355.0;
method 2, RT (min) ) 4.08 (no ionization).
2H), 4.06 (t, J ) 6.26 Hz, 2H), 3.30 (ddd, J ) 14.57, 7.63, 7.40
Hz, 1H), 2.74-2.81 (m, 1H), 2.69 (dt, J ) 15.87, 7.93 Hz, 1H),
2.5 (m, 1H), 2.18-2.27 (m, 3H), 2.07-2.15 (m, J ) 6.18, 6.18,
6.18, 6.18 Hz, 2H), 1.55-1.63 (m, 1H). LC-MS: method 1, RT
(min) ) 4.74; [M + H]+ 394.2; method 2, RT (min) ) 3.34; [M
+ H]+ 394.2.
((1S)-5-{3-[2-(Acetylamino)-4-(1H-1,2,3-triazol-1-yl)phenoxy]-
propoxy}-2,3-dihydro-1H-inden-1-yl)acetic Acid (17v). 1H NMR
(500 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.58 (s, 1H), 8.46 (s, 1H),
7.87 (s, 1H), 7.43-7.50 (m, 1H), 7.20 (d, J ) 8.85 Hz, 1H), 7.05
(d, J ) 8.24 Hz, 1H), 6.77 (s, 1H), 6.68 (d, J ) 8.24 Hz, 1H), 4.22
(t, J ) 5.95 Hz, 2H), 4.12 (t, J ) 6.10 Hz, 2H), 3.27-3.33 (m,
1H), 2.74-2.81 (m, 1H), 2.69 (ddd, J ) 15.72, 7.78, 7.63 Hz, 1H),
2.5 (m, 1H), 2.17-2.26 (m, 4H), 2.08 (s, 3H), 1.55-1.63 (m, 1H).
LC-MS: method 1, RT (min) ) 4.58; [M + H]+ 451.2; method 2,
RT (min) ) 3.19; [M + H]+ 451.2.
((1S)-5-{3-[2-Chloro-4-(4H-1,2,4-triazol-4-yl)phenoxy]propoxy-
2,3-dihydro-1H-inden-1-yl)acetic Acid (17w). 1H NMR (500
MHz, DMSO-d6) δ 9.08 (s, 1H), 7.55 (d, J ) 8.54 Hz, 1H), 7.46
(d, J ) 2.14 Hz, 2H), 7.24 (dd, J ) 8.54, 2.14 Hz, 1H), 7.04 (d, J
) 8.24 Hz, 1H), 6.76 (s, 1H), 6.66 (d, J ) 7.93 Hz, 1H), 4.28 (t,
J ) 5.95 Hz, 2H), 4.08 (t, J ) 6.10 Hz, 2H), 3.29 (dt, J ) 14.34,
7.17 Hz, 1H), 2.74-2.80 (m, 1H), 2.68 (dt, J ) 15.87, 7.93 Hz,
2H), 2.20-2.24 (m, 2H), 2.16 (dt, J ) 11.90, 5.95 Hz, 2H), 1.55-
1.63 (m, 1H). LC-MS: method 1, RT (min) ) 4.72; [M + H]+
428.2; method 2, RT (min) ) 3.31; [M + H]+ 428.3.
{(1S)-5-[3-(2-Propylphenoxy)propoxy]-2,3-dihydro-1H-inden-
1-yl}acetic Acid (17m). 1H NMR (500 MHz, DMSO-d6) δ 7.02-
7.11 (m, 3H), 6.89 (d, J ) 7.93 Hz, 1H), 6.80 (t, J ) 7.32 Hz,
1H), 6.74 (s, 1H), 6.66 (d, J ) 8.24 Hz, 1H), 4.06 (dt, J ) 11.67,
5.91 Hz, 4H), 3.26-3.33 (m, 1H), 2.73-2.80 (m, 2H), 2.65-2.72
(m, 2H), 2.5 (m, 1H), 2.18-2.26 (m, 3H), 2.07-2.13 (m, J ) 6.03,
6.03, 6.03, 6.03 Hz, 2H), 1.59 (dd, J ) 12.21, 7.63 Hz, 1H), 1.42-
1.50 (m, J ) 7.40, 7.40, 7.40, 7.40 Hz, 2H), 0.80 (t, J ) 7.32 Hz,
3H). LC-MS: method 1, RT (min) ) 5.50; [M + H]+ 369.0;
method 2, RT (min) ) 4.20 (no ionization).
{(1S)-5-[3-(4-Cyano-2-propylphenoxy)propoxy]-2,3-dihydro-
1
1H-inden-1-yl}acetic Acid (17o). H NMR (500 MHz, DMSO-
d6) δ 7.70 (d, J ) 8.85 Hz, 2H), 7.02-7.09 (m, 4H), 6.75 (s, 1H),
6.63-6.69 (m, 1H), 4.16 (t, J ) 6.10 Hz, 3H), 4.03 (t, J ) 6.10
Hz, 3H), 3.29 (dt, J ) 14.27, 7.06 Hz, 2H), 2.74-2.80 (m, 2H),
2.65-2.73 (m, 2H), 2.17-2.26 (m, 4H), 2.08-2.15 (m, J ) 6.03,
6.03, 6.03, 6.03 Hz, 3H), 1.54-1.63 (m, 2H). LC-MS: method 1,
RT (min) ) 4.97; [M + H]+ 351.9; method 2, RT (min) ) 3.62;
[M + H]+ 352.1.
{(1S)-5-[3-(4-Phenoxy-2-propylphenoxy)propoxy]-2,3-dihydro-
1
1H-inden-1-yl}acetic Acid (17p). H NMR (500 MHz, DMSO-
d6) δ 7.28 (t, J ) 7.78 Hz, 2H), 6.98-7.05 (m, 3H), 6.92 (d, J )
9.16 Hz, 1H), 6.84 (d, J ) 7.93 Hz, 1H), 6.73-6.78 (m, 3H), 6.65
(d, J ) 8.54 Hz, 1H), 4.02-4.09 (m, 4H), 2.98-3.40 (m, 1H),
2.75-2.85 (m, 4H), 2.50 (m, 1H), 2.59-2.72 (m, 2H), 2.17-2.24
(m, 2H), 2.08-2.12 (m, 2H), 1.58 (m, 1H), 1.40-1.48 (m, 2H),
0.78 (t, J ) 7.32 Hz, 3H). LC-MS: method 1, RT (min) ) 5.84;
[M + H]+ 460.9; method 2, RT (min) ) 4.54; [M + H]+ 461.5.
{(1S)-5-[3-(2-Methoxy-4-methylphenoxy)propoxy]-2,3-dihy-
dro-1H-inden-1-yl}acetic Acid (17q). 1H NMR (500 MHz,
DMSO-d6) δ 7.04 (d, J ) 8.24 Hz, 1H), 6.71-6.80 (m, 3H), 6.59-
6.67 (m, 2H), 4.01 (dt, J ) 19.23, 6.10 Hz, 4H), 3.67 (s, 3H), 3.26-
3.33 (m, J ) 7.48, 7.25, 7.13, 7.13 Hz, 1H), 2.74-2.81 (m, 1H),
2.69 (dt, J ) 15.79, 7.82 Hz, 1H), 2.5 (m, 1H), 2.16-2.25 (m,
5H), 2.00-2.08 (m, J ) 6.18, 6.18, 6.18, 6.18 Hz, 3H), 1.55-1.63
(m, 1H). LC-MS: method 1, RT (min) ) 5.09; [M + H]+ 371.1;
method 2, RT (min) ) 3.75; [M + H]+ 371.2.
[(1S)-5-(3-{2-Methyl-4-[3-(trifluoromethyl)-1,2,4-thiadiazol-
5-yl]phenoxy}propoxy)-2,3-dihydro-1H-inden-1-yl]acetic Acid
1
(17x). H NMR (500 MHz, DMSO-d6) δ 7.89 (d, J ) 8.54 Hz,
1H), 7.86 (s, 1H), 7.13 (d, J ) 8.54 Hz, 1H), 7.05 (d, J ) 8.24 Hz,
1H), 6.77 (s, 1H), 6.68 (d, J ) 7.93 Hz, 1H), 4.21 (t, J ) 5.80 Hz,
2H), 4.09 (t, J ) 6.10 Hz, 2H), 3.30 (dt, J ) 14.65, 7.32 Hz, 1H),
2.74-2.81 (m, 1H), 2.69 (ddd, J ) 16.02, 7.93, 7.78 Hz, 2H), 2.55-
2.63 (m, 1H), 2.15-2.24 (m, 7H), 1.55-1.63 (m, 1H). LC-MS:
method 1, RT (min) ) 5.62; [M + H]+ 493.1; method 2, RT (min)
) 4.32; [M + H]+ 493.0.
Ethyl {(1S)-5-[3-(4-Iodophenoxy)propoxy]-2,3-dihydro-1H-
inden-1-yl}acetate (27). To a mixture of 4-iodophenol (512 mg,
2.33 mmol) and intermediate 15 (794 mg, 2.33 mmol) in 40 mL of
DMF (containing 1% water) was added powdered Cs2CO3 (1137
mg, 3.49 mmol), and the mixture was stirred at rt for 16 h. EtOAc
was added to the mixture, and the solid residue was removed by
filtration. The filtrate was concentrated under reduced pressure, and
the residue was purified by silica gel column chromatography (5%
EtOAc in Hex) to give the pure product (248 mg, 22%) as a
{(1S)-5-[3-(4-Ethyl-2-methoxyphenoxy)propoxy]-2,3-dihydro-
1
1H-inden-1-yl}acetic Acid (17r). H NMR (500 MHz, DMSO-
d6) δ 7.04 (d, J ) 8.24 Hz, 1H), 6.81 (d, J ) 7.93 Hz, 1H), 6.75
(s, 2H), 6.65 (t, J ) 8.85 Hz, 2H), 4.02 (dt, J ) 16.40, 6.14 Hz,
4H), 3.68 (s, 3H), 3.30 (ddd, J ) 14.27, 7.48, 7.25 Hz, 1H), 2.74-
2.81 (m, 1H), 2.69 (dt, J ) 15.95, 8.05 Hz, 1H), 2.5 (m, 1H), 2.18-
2.26 (m, 2H), 2.01-2.08 (m, J ) 6.18, 6.18, 6.18, 6.18 Hz, 2H),
1.54-1.63 (m, 2H), 1.06-1.14 (m, 3H). LC-MS: method 1, RT
(min) ) 5.20; [M + H]+ 385.0; method 2, RT (min) ) 3.89; [M
+ H]+ 385.4.
1
colorless solid. H NMR (400 MHz, CDCl3) δ 7.54 (d, 2H), 7.06
(d, 1H), 6.80 (s, 1H), 6.72-6.64 (m, 3H), 4.23-4.06 (m, 6H),
3.58-3.46 (m, 1H), 2.94-2.78 (m, 2H), 2.72 (dd, 1H), 2.43-2.35
(m, 2H), 2.28-2.20 (m, 2H), 1.80-1.69 (m, 1H), 1.18 (t, 3H).
Ethyl ((1S)-5-{3-[4-(3-Thienyl)phenoxy]propoxy}-2,3-dihy-
dro-1H-inden-1-yl)acetate (28a; Approach A). To a solution of
thiophene-3-boronic acid (53 mg, 0.42 mmol), ethyl {(1S)-5-[3-
(4-iodophenoxy)propoxy]-2,3-dihydro-1H-inden-1-yl}acetate (27;
50 mg, 0.10 mmol) in toluene (1.8 mL) and 1,4-dioxane (0.45 mL)
was added PdCl2(dppf)‚CH2Cl2 (7.6 mg, 0.01 mmol), and argon
was passed through the mixture for 30 min. Then Na2CO3 (2 N
aqueous solution, 0.50 mL) was added, and the mixture was heated
to 75 °C for 48 h. The reaction was cooled to rt and extracted with
EtOAc (2×). The combined organic phases were washed with
NaHCO3 (saturated aqueous solution), dried, filtered, and concen-
trated under reduced pressure. The residue was purified by
preparative thin layer chromatography on silica gel to give 33 mg
(73%) of the title compound as a colorless oil. 1H NMR (400 MHz,
CDCl3) δ 7.51 (d, 2H), 7.40-7.31 (m, 3H), 7.06 (d, 1H), 6.97 (d,
2H), 6.80 (s, 1H), 6.72 (dd, 1H), 4.24-4.10 (m, 6H), 3.60-3.48
(m, 1H), 2.98-2.90 (m, 2H), 2.72 (dd, 1H), 2.46-2.36 (m, 2H),
2.36-2.23 (m, 2H), 1.85-1.70 (m, 1H), 1.30 (t, 3H). Compounds
28b-28g were synthesized using the same procedure as for the
preparation of compound 28a using appropriate starting materials.
Ethyl ((1S)-5-{3-[4-(6-Methyl-2-pyridinyl)phenoxy]propoxy}-
2,3-dihydro-1H-inden-1-yl)acetate (28h; Approach B). To a
{(1S)-5-[3-(4-Cyano-2-methoxyphenoxy)propoxy]-2,3-dihydro-
1
1H-inden-1-yl}acetic Acid (17s). H NMR (500 MHz, DMSO-
d6) δ 7.30-7.37 (m, 2H), 7.02-7.11 (m, 2H), 6.74 (s, 1H), 6.65
(d, J ) 7.93 Hz, 1H), 4.14 (t, J ) 5.80 Hz, 2H), 4.03 (t, J ) 5.95
Hz, 2H), 3.75 (s, 3H), 3.27-3.33 (m, 1H), 2.74-2.80 (m, 1H),
2.68 (dt, J ) 15.87, 7.93 Hz, 1H), 2.5 (m, 1H), 2.17-2.26 (m,
2H), 2.08-2.16 (m, J ) 6.03, 6.03, 6.03, 6.03 Hz, 2H), 1.55-1.63
(m, 1H). LC-MS: method 1, RT (min) ) 4.88; [M + H]+ 382.0;
method 2, RT (min) ) 3.44; [M + H]+ 382.2.
{(1S)-5-[3-(2-Ethoxy-4-methylphenoxy)propoxy]-2,3-dihydro-
1
1H-inden-1-yl}acetic Acid (17t). H NMR (500 MHz, DMSO-
d6) δ 7.04 (d, J ) 8.55 Hz, 1H), 6.80 (d, J ) 7.93 Hz, 1H), 6.74
(s, 1H), 6.72 (s, 1H), 6.59-6.67 (m, 2H), 3.98-4.06 (m, 4H), 3.92
(q, J ) 6.92 Hz, 2H), 3.26-3.34 (m, 1H), 2.74-2.81 (m, 1H),
2.69 (dt, J ) 15.87, 7.93 Hz, 1H), 2.5 (m, 1H), 2.20-2.26 (m,
2H), 2.17 (s, 3H), 2.04 (qd, J ) 6.15, 5.95 Hz, 2H), 1.55-1.63
(m, 1H), 1.18-1.25 (m, 3H). LC-MS: method 1, RT (min) ) 5.21;
[M + H]+ 385.1; method 2, RT (min) ) 3.88; [M + H]+ 385.4.
((1S)-5-{3-[4-(1H-1,2,4-Triazol-1-yl)phenoxy]propoxy}-2,3-di-
hydro-1H-inden-1-yl)acetic Acid (17u). 1H NMR (500 MHz,
DMSO-d6) δ 9.07 (s, 1H), 7.69 (d, J ) 8.85 Hz, 2H), 7.02-7.09
(m, 3H), 6.76 (s, 1H), 6.64-6.71 (m, 1H), 4.13 (t, J ) 6.26 Hz,

Indanylacetic Acid DeriVatiVes as PPAR Agonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5 995
solution of ethyl{(1S)-5-[3-(4-iodophenoxy)propoxy]-2,3-dihydro-
1H-inden-1-yl}acetate (27; 70 mg, 0.15 mmol) in DMF (1 mL)
was added bis(pinacolato)diboron (41 mg, 0.16 mmol), PdCl2(dppf)‚
CH2Cl2 (11 mg, 0.01 mmol), and KOAc (43 mg, 0.44 mmol). Argon
was passed through the solution, and the reaction mixture was
heated at 80 °C for 2 h and then cooled to rt. More PdCl2(dppf)‚CH2-
Cl2 (5 mg, 0.005 mmol) was added, followed by the addition of
2-bromo-6-methylpyridine (50 mg, 0.29 mmol) and Na2CO3 (2 M
aqueous solution, 0.37 mL). The reaction mixture was heated to
80 °C for 12 h and then cooled to rt, diluted with HCl (1 N aqueous
solution), and extracted with EtOAc. The combined organic phases
were dried, filtered, and concentrated under reduced pressure.
Purification by preparative thin layer chromatography (EtOAc/
hexanes 2:3) gave 286 mg (40%) of the title compound. 1H NMR
(400 MHz, CDCl3) δ 8.00 (d, 2H), 7.73-7.62 (m, 1H), 7.62-7.52
(m, 1H), 7.16-6.96 (m, 4H), 6.83 (s, 1H), 6.52 (d, 1H), 4.28-
4.04 (m, 6H), 3.52-3.38 (m, 1H), 2.96-2.63 (m, 3H), 2.54 (s,
3H), 2.48-2.12 (m, 4H), 1.82-1.62 (m, 1H), 1.23 (t, 3H).
Compound 28i was synthesized using the same procedure as for
the preparation of compound 28h using appropriate starting
materials.
RT (min) ) 4.43; [M + H]+ 404.2; method 2, RT (min) ) 2.98;
[M + H]+ 404.3.
((1S)-5-{3-[4-(4-Methoxypyridin-3-yl)phenoxy]propoxy}-2,3-
1
dihydro-1H-inden-1-yl)acetic Acid (29e). H NMR (500 MHz,
DMSO-d6) δ 8.35 (d, J ) 2.14 Hz, 1H), 7.89 (dd, J ) 8.54, 2.44
Hz, 1H), 7.52 (d, J ) 8.54 Hz, 2H), 7.05 (d, J ) 8.24 Hz, 1H),
6.99 (d, J ) 8.54 Hz, 2H), 6.83 (d, J ) 8.54 Hz, 1H), 6.76 (s, 1H),
6.67 (d, J ) 8.24 Hz, 1H), 4.03-4.13 (m, 4H), 3.83 (s, 3H), 3.26-
3.33 (m, 1H), 2.94 (s, 1H), 2.74-2.81 (m, 1H), 2.69 (dt, J ) 16.10,
7.97 Hz, 2H), 2.17-2.26 (m, 3H), 2.07-2.15 (m, 2H), 1.54-1.63
(m, 1H). LC-MS: method 1, RT (min) ) 5.28; [M + H]+ 434.2;
method 2, RT (min) ) 3.84; [M + H]+ 434.4.
{(1S)-5-[3-(4-Pyrimidin-5-ylphenoxy)propoxy]-2,3-dihydro-
1
1H-inden-1-yl}acetic Acid (29f). H NMR (500 MHz, DMSO-
d6) δ 9.08 (s, 1H), 9.03 (s, 2H), 7.70 (d, J ) 8.55 Hz, 2H), 7.06 (t,
J ) 8.09 Hz, 3H), 6.77 (s, 1H), 6.67 (d, J ) 7.93 Hz, 1H), 4.11-
4.17 (m, 2H), 4.06 (t, J ) 6.10 Hz, 2H), 3.30 (dt, J ) 14.42, 7.29
Hz, 1H), 2.75-2.81 (m, 1H), 2.69 (dt, J ) 15.95, 8.05 Hz, 1H),
2.5 (m, 1H), 2.18-2.27 (m, 2H), 2.09-2.16 (m, J ) 6.10, 6.10,
6.10, 6.10 Hz, 2H), 1.55-1.63 (m, 1H). LC-MS: method 1, RT
(min) ) 4.82; [M + H]+ 405.2; method 2, RT (min) ) 3.43; [M
+ H]+ 405.2.
((1S)-5-{3-[4-(3-Thienyl)phenoxy]propoxy}-2,3-dihydro-1H-
inden-1-yl)acetic Acid (29a). To a solution of compound 28a (24
mg, 0.05 mmol) in 1.6 mL of THF/water (3:1) was added LiOH‚
H2O (3 mg, 0.07 mmol), and the mixture was stirred at rt for 16 h.
The THF was evaporated and more water was added. The aqueous
layer was washed with a small amount of ether. The aqueous layer
was then acidified with 1 N HCl and extracted 3× with EtOAc.
The combined organic layers were dried (MgSO4), concentrated,
and subjected to preparative HPLC purification to give 6.5 mg
(29%) of the pure product. 1H NMR (500 MHz, DMSO-d6) δ 7.66
(s, 1H), 7.53-7.61 (m, 3H), 7.44 (d, J ) 4.88 Hz, 1H), 7.06 (d, J
) 8.24 Hz, 1H), 6.94 (d, J ) 8.55 Hz, 2H), 6.77 (s, 1H), 6.68 (d,
J ) 7.32 Hz, 1H), 4.04-4.12 (m, 4H), 3.32 (d, J ) 3.05 Hz, 1H),
2.78 (d, J ) 4.27 Hz, 1H), 2.66-2.75 (m, 1H), 2.5 (m, 1H), 2.19-
2.27 (m, 2H), 2.08-2.14 (m, 2H), 1.60 (d, J ) 4.88 Hz, 1H). LC-
MS: method 1, RT (min) ) 5.40; [M + H]+ 409.0; method 2, RT
(min) ) 3.97 (no ionization). Compounds 29b-29i were synthe-
sized using the same procedure as for the preparation of compound
29a using appropriate starting materials.
((1S)-5-{3-[4-(3-Furyl)phenoxy]propoxy}-2,3-dihydro-1H-in-
den-1-yl)acetic acid (29b). 1H NMR (500 MHz, DMSO-d6) δ 7.46
(d, J ) 8.55 Hz, 1H), 7.04 (d, J ) 8.24 Hz, 1H), 6.99 (td, J )
8.47, 3.51 Hz, 1H), 6.91 (d, J ) 8.54 Hz, 1H), 6.81-6.87 (m, 1H),
6.73-6.80 (m, 1H), 6.67 (d, J ) 8.24 Hz, 1H), 4.13 (d, J ) 15.87
Hz, 1H), 4.06 (dt, J ) 18.84, 5.99 Hz, 4H), 3.26-3.33 (m, 2H),
2.90-2.97 (m, 1H), 2.74-2.81 (m, 2H), 2.69 (dt, J ) 16.10, 7.97
Hz, 1H), 2.18-2.27 (m, 2H), 2.06-2.14 (m, 2H), 1.72 (s, 1H),
1.59 (ddd, J ) 19.99, 7.93, 7.78 Hz, 1H). LC-MS: method 1, RT
(min) ) 5.24; [M + H]+ 393.1; method 2, RT (min) ) 3.88 (no
ionization).
((1S)-5-{3-[4-(2,4-Dimethoxypyrimidin-5-yl)phenoxy]propoxy-
2,3-dihydro-1H-inden-1-yl)acetic Acid (29g). 1H NMR (500 MHz,
DMSO-d6) δ 8.25 (s, 1H), 7.39 (d, J ) 8.54 Hz, 2H), 7.05 (d, J )
8.24 Hz, 1H), 6.96 (d, J ) 8.54 Hz, 2H), 6.76 (s, 1H), 6.67 (d, J
) 8.24 Hz, 1H), 4.11 (t, J ) 6.10 Hz, 2H), 4.05 (t, J ) 5.95 Hz,
2H), 3.88 (s, 6H), 3.26-3.33 (m, 1H), 2.74-2.81 (m, 1H), 2.65-
2.73 (m, 1H), 2.5 (m, 1H), 2.18-2.26 (m, 2H), 2.07-2.14 (m, J )
6.03, 6.03, 6.03, 6.03 Hz, 2H), 1.59 (dd, J ) 12.36, 7.78 Hz, 1H).
LC-MS: method 1, RT (min) ) 5.12; [M + H]+ 465.2; method 2,
RT (min) ) 3.55; [M + H]+ 465.3.
((1S)-5-{3-[4-(6-Methyl-2-pyridinyl)phenoxy]propoxy}-2,3-di-
hydro-1H-inden-1-yl)acetic Acid (29h). 1H NMR (500 MHz,
DMSO-d6) δ 7.94 (d, J ) 8.54 Hz, 2H), 7.76 (s, 1H), 7.66 (d, J )
7.63 Hz, 1H), 7.18 (d, J ) 7.02 Hz, 1H), 7.00-7.08 (m, 3H), 6.77
(s, 1H), 6.68 (d, J ) 8.24 Hz, 1H), 4.14 (t, J ) 6.10 Hz, 2H),
4.03-4.11 (m, 3H), 3.26-3.33 (m, 1H), 2.94 (s, 1H), 2.77 (d, J )
3.66 Hz, 2H), 2.65-2.74 (m, 2H), 2.18-2.26 (m, 2H), 2.07-2.15
(m, 2H), 1.55-1.63 (m, 1H), 1.18 (s, 1H), 1.12 (t, J ) 7.48 Hz,
1H). LC-MS: method 1, RT (min) ) 4.32; [M + H]+ 418.2;
method 2, RT (min) ) 2.91; [M + H]+ 418.3.
[(1S)-5-(3-{4-[5-(Trifluoromethyl)pyridin-2-yl]phenoxy}pro-
poxy)-2,3-dihydro-1H-inden-1-yl]acetic acid (29i). 1H NMR (500
MHz, DMSO-d6) δ 8.91 (s, 1H), 8.15 (d, J ) 8.54 Hz, 1H), 8.03-
8.10 (m, 3H), 7.06 (d, J ) 8.54 Hz, 2H), 7.04 (s, 1H), 6.77 (s,
1H), 6.68 (d, J ) 7.02 Hz, 1H), 4.16 (t, J ) 6.10 Hz, 2H), 4.02-
4.12 (m, 3H), 3.30 (dt, J ) 14.42, 7.29 Hz, 1H), 2.74-2.81 (m,
1H), 2.69 (ddd, J ) 16.02, 7.93, 7.78 Hz, 1H), 2.5 (m, 1H), 2.18-
2.26 (m, 2H), 2.07-2.16 (m, 2H), 1.55-1.63 (m, 1H), 1.18 (s,
1H). LC-MS: method 1, RT (min) ) 5.49; [M + H]+ 472.2;
method 2, RT (min) ) 4.16; [M + H]+ 472.3.
Ethyl ((1S)-5-{3-[4-(Aminocarbonothioyl)-2-propylphenoxy]-
propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (31). To a solution
of ethyl {(1S)-5-[3-(4-cyano-2-propylphenoxy) propoxy]-2,3-dihy-
dro-1H-inden-1-yl}acetate (17o, 1.2 g, 2.9 mmol) in anhydrous
DMF (15 mL) under argon at rt was passed H2S gas at a moderate
rate for 20 min. Then a solution of diethylamine (0.3 g, 4.3 mmol)
in DMF (3 mL) was added in one portion, and the reaction mixture
was stirred at 60 °C for 3 h. Upon completion, the reaction was
cooled to rt and argon was passed through the reaction mixture for
1 h to remove residual H2S. The reaction mixture was concentrated
under reduced pressure, and the residue was purified by silica gel
flash chromatography (EtOAc/hexane (v/v) ) 1:1) to give 0.9 g
(76%) of the title compound as a yellow solid. 1H NMR (300 MHz,
CD3OD) δ 0.94 (t, 3H), 1.31 (t, 3H), 1.52-1.64 (m, 2H), 1.65-
1.80 (m, 1H), 2.20-2.44 (m, 4H), 2.58-2.95 (m, 5H), 3.38-3.61
(m, 1H), 4.16-4.21 (m, 4H), 4.26 (t, 2H), 6.69 (d, 1H), 6.80 (s,
1H), 6.95 (d, 1H), 7.09 (d, 1H), 7.79 (d, 1H), 7.84 (s, 1H).
Ethyl ((1S)-5-{3-[4-(Aminocarbonothioyl)-2-methoxyphen-
oxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (32). Into a
((1S)-5-{3-[4-(1H-Indol-6-yl)phenoxy]propoxy}-2,3-dihydro-
1
1H-inden-1-yl)acetic Acid (29c). H NMR (500 MHz, DMSO-
d6) δ 11.01 (s, 1H), 7.69 (s, 1H), 7.52 (d, J ) 8.54 Hz, 2H), 7.39
(d, J ) 8.24 Hz, 1H), 7.26-7.34 (m, 2H), 7.06 (d, J ) 8.54 Hz,
1H), 6.97 (d, J ) 8.54 Hz, 2H), 6.78 (s, 1H), 6.69 (d, J ) 6.71 Hz,
1H), 6.41 (s, 1H), 4.05-4.14 (m, 4H), 3.33 (d, J ) 2.75 Hz, 1H),
2.76-2.82 (m, 1H), 2.70 (dt, J ) 15.79, 7.82 Hz, 1H), 2.60 (dd, J
) 15.41, 5.65 Hz, 1H), 2.19-2.28 (m, 2H), 2.09-2.16 (m, J )
6.03, 6.03, 6.03, 6.03 Hz, 2H), 1.60 (dd, J ) 12.21, 7.63 Hz, 1H).
LC-MS: method 1, RT (min) ) 5.26; [M + H]+ 442.1; method 2,
RT (min) ) 3.93; [M + H]+ 442.5.
{(1S)-5-[3-(4-Pyridin-3-ylphenoxy)propoxy]-2,3-dihydro-1H-
1
inden-1-yl}acetic Acid (29d). H NMR (500 MHz, DMSO-d6) δ
8.78 (s, 1H), 7.98 (d, J ) 7.93 Hz, 1H), 7.61 (d, J ) 8.54 Hz, 2H),
7.41 (dd, J ) 7.78, 4.73 Hz, 1H), 7.01-7.07 (m, 3H), 6.76 (s,
1H), 6.63-6.71 (m, 1H), 4.13 (t, J ) 6.10 Hz, 2H), 4.06 (t, J )
6.10 Hz, 2H), 3.26-3.33 (m, 1H), 2.74-2.81 (m, 1H), 2.69 (dt, J
) 15.95, 8.05 Hz, 1H), 2.5 (m, 1H), 2.18-2.27 (m, 3H), 2.12 (qd,
J ) 6.00, 5.80 Hz, 3H), 1.54-1.63 (m, 1H). LC-MS: method 1,

996 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5
Rudolph et al.
solution of ethyl {(1S)-5-[3-(4-cyano-2-methoxyphenoxy) propoxy]-
2,3-dihydro-1H-inden-1-yl}acetate (2.2 g, 5.4 mmol; 17s) in DMF
(anhydrous, 20 mL) under argon at rt was passed H2S gas at a
moderate rate for 30 min. A solution of diethylamine (0.8 g, 8.1
mmol) in DMF (5 mL) was added in one portion, and the reaction
was stirred at 60 °C for 3 h. Then the reaction was cooled to rt and
argon was passed through the reaction mixture for 1 h to remove
residual H2S. The reaction mixture was then concentrated under
reduced pressure and the residue was purified by silica gel flash
chromatography (EtOAc/hexane (v/v) ) 1:1) to afford 1.9 g (81%)
of the title compound as a yellow solid. 1H NMR (400 MHz,
DMSO-d6) δ 1.21 (t, 3H), 1.60-1.68 (m, 1H), 2.15-2.22 (m, 2H),
2.23-2.34 (m, 1H), 2.38 (q, 1H), 2.70-2.86 (m, 3H), 3.38-3.44
(m, 1H), 3.80 (s, 3H), 4.05-4.16 (m, 4H), 4.19 (t, 2H), 6.70 (d,
1H), 6.80 (s, 1H), 6.97 (d, 1H), 7.06 (d, 1H), 7.56-7.64 (m, 2H),
9.33-9.40 (s, 1H), 9.65 (s, 1H).
The reaction was cooled to rt and concentrated under reduced
pressure. Purification by silica gel flash chromatography (EtOAc/
hexane (v/v) ) 1:2) gave 292 mg (49%) of the title compound as
a yellow oil. LC-MS (method 2): RT (min) ) 4.27; [M + H]+
526.1.
Compound 33a was synthesized using a similar procedure as
described for the preparation of compound 33b. Compounds 33c,
33d, 33f-33s, and 33u-33ad were made using a similar procedure
as described for the preparation of compound 33e. Among those,
compounds 33z-33ad were prepared as derivatives having R1 or
R2 ) COOMe or COOEt. Compounds 33ae-33aj and 33al-33an
were synthesized using a similar procedure as described for
compound 33ak.
Compounds 34a-34an were synthesized using the ester hy-
drolysis procedure described for the preparation of compound 17n.
[(1S)-5-{3-[2-Propyl-4-(1,3-thiazol-2-yl)phenoxy]propoxy}-
2,3-dihydro-1H-inden-1-yl]acetic Acid (34a). 1H NMR (500 MHz,
DMSO-d6) δ 7.78 (d, J ) 3.36 Hz, 1H), 7.69 (d, J ) 8.54 Hz,
1H), 7.66 (s, 1H), 7.59 (s, 1H), 7.04 (t, J ) 8.39 Hz, 2H), 6.75 (s,
1H), 6.67 (d, J ) 7.32 Hz, 1H), 4.14 (t, J ) 5.80 Hz, 2H), 4.08 (t,
J ) 6.10 Hz, 2H), 3.30 (dt, J ) 14.27, 7.06 Hz, 1H), 2.74-2.81
(m, 1H), 2.69 (ddd, J ) 16.02, 7.93, 7.78 Hz, 1H), 2.5 (m, 1H),
2.18-2.26 (m, 4H), 2.11-2.16 (m, J ) 5.87, 5.87, 5.87, 5.87 Hz,
2H), 1.59 (dd, J ) 12.36, 7.48 Hz, 1H), 1.47-1.55 (m, J ) 7.32,
7.32, 7.32, 7.32 Hz, 2H), 0.83 (t, J ) 7.32 Hz, 3H). LC-MS:
method 1, RT (min) ) 5.50; [M + H]+ 452.2; method 2, RT (min)
) 4.12; [M + H]+ 452.3.
Ethyl ((1S)-5-{3-[4-(Aminocarbonothioyl)phenoxy]propoxy-
2,3-dihydro-1H-inden-1-yl)acetate (30). The title product was
synthesized using the same procedure as for the preparation of
1
compound 31 using appropriate starting materials. H NMR (400
MHz, CD3OD) δ 7.92 (dd, 2H), 7.14 (d, 1H), 6.96 (dd, 2H), 6.82
(m, 1H), 6.76 (m, 1H), 4.20-4.28 (m, 2H), 4.11-4.19 (m, 4H),
3.40-3.57 (m, 1H), 2.69-2.96 (m, 3H), 2.28-2.44 (m, 2H), 2.20-
2.27 (q, 2H), 1.72-1.80 (m, 1H), 1.21-1.30 (t, 3H).
Ethyl ((1S)-5-{3-[2-methoxy-4-(1,3-thiazol-2-yl)phenoxy]pro-
poxy}-2,3-dihydro-1H-inden-1-yl)acetate (33b). Ethyl ((1S)-5-
{3-[4-(aminocarbonothioyl)-2-methoxyphenoxy]propoxy}-2,3-dihydro-
1H-inden-1-yl)acetate (1.00 g, 2.3 mmol; 32) and bromoacetaldehyde
diethyl acetal (1.78 g, 9.2 mmol) were dissolved in EtOH (30 mL)
and water (2 drops) was added. The mixture was heated at 70 °C
for 18 h, and then the reaction mixture was cooled to rt and
concentrated under reduced pressure. Purification by silica gel flash
chromatography (EtOAc/hexane (v/v) ) 1:1) gave 610 mg (58%)
of the title compound as a clear oil. LC-MS (method 2): RT (min)
) 3.81; [M + H]+ 468.1.
Ethyl ((1S)-5-{3-[4-(4-Ethyl-1,3-thiazol-2-yl)-2-propylphe-
noxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (33e). A solu-
tion of ethyl ((1S)-5-{3-[4-(aminocarbonothioyl)-2-propylphenoxy]-
propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (90 mg, 0.2 mmol; 31)
and 1-bromo-2-butanone (35.8 mg, 0.24 mmol) in EtOH (anhy-
drous, 8 mL) was heated at 70 °C for 6 h. The reaction mixture
was cooled to rt and then concentrated under reduced pressure.
Purification by silica gel flash chromatography (EtOAc/hexane (v/
v) 1:2) gave 42 mg (42%) of the title compound as a clear oil.
LC-MS (method 2): RT (min) ) 4.85; [M + H]+ 508.2.
[(1S)-5-{3-[2-Methoxy-4-(1,3-thiazol-2-yl)phenoxy]propoxy}-
2,3-dihydro-1H-inden-1-yl]acetic Acid (34b). 1H NMR (500 MHz,
DMSO-d6) δ 7.79 (s, 1H), 7.61 (d, J ) 3.05 Hz, 1H), 7.45 (s, 1H),
7.04 (d, J ) 8.24 Hz, 2H), 6.76 (s, 1H), 6.67 (s, 1H), 4.12 (t, J )
6.10 Hz, 2H), 4.05 (t, J ) 5.95 Hz, 2H), 3.79 (s, 3H), 3.29 (m,
1H), 2.80 (m, 1H), 2.70 (m, 1H), 2.50 (m, 1H), 2.24 (m, 2H), 2.08-
2.16 (m, 2H), 1.59 (s, 1H). LC-MS: method 1, RT (min) ) 4.98;
[M + H]+ 440.2; method 2, RT (min) ) 3.64; [M + H]+ 440.2.
[(1S)-5-{3-[2-Methoxy-4-(4-methyl-1,3-thiazol-2-yl)phenoxy]-
propoxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid (34c). 1H NMR
(500 MHz, DMSO-d6) δ 7.40 (s, 1H), 7.37 (d, J ) 8.54 Hz, 1H),
7.16 (s, 1H), 7.03 (t, J ) 9.31 Hz, 2H), 6.76 (s, 1H), 6.67 (d, J )
8.24 Hz, 1H), 4.12 (t, J ) 6.10 Hz, 2H), 4.05 (t, J ) 5.95 Hz, 2H),
3.78 (s, 4H), 3.26-3.33 (m, 1H), 2.74-2.81 (m, 1H), 2.69 (dt, J
) 15.79, 7.82 Hz, 1H), 2.5 (m, 1H), 2.35 (s, 2H), 2.18-2.26 (m,
2H), 2.08-2.15 (m, J ) 6.03, 6.03, 6.03, 6.03 Hz, 2H), 1.55-1.63
(m, 1H). LC-MS: method 1, RT (min) ) 5.09; [M + H]+ 454.2;
method 2, RT (min) ) 3.68; [M + H]+ 454.3.
Ethyl ((1S)-5-{3-[4-(1,3-Benzothiazol-2-yl)-2-methoxyphe-
noxy] propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (33t). A slurry
of 2-aminothiophenol (357 mg, 2.85 mmol) in polyphosphoric acid
(14.0 g) was heated to 110 °C and 4-hydroxy-3-methoxybenzoic
acid (480 mg, 2.85 mmol) was added. After 2 h, the reaction mixture
was cooled to rt. The mixture was poured carefully into ice cold
water, and the solution was neutralized with KOH (3 M aqueous
solution). The aqueous phase was extracted with EtOAc (2×). The
combined organic layers were washed with Na2CO3 (1 M aqueous
solution), HCl (1 M aqueous solution), and water, dried, and
concentrated under reduced pressure. Purification by silica gel
chromatography gave 22 mg of the intermediate 4-(1,3-benzothia-
zol-2-yl)-2-methoxyphenol as an oil. This intermediate was coupled
with compound 15 as described for the preparation of compound
[(1S)-5-{3-[4-(4-Ethyl-1,3-thiazol-2-yl)phenoxy]propoxy}-2,3-
1
dihydro-1H-inden-1-yl]acetic Acid (34d). H NMR (500 MHz,
DMSO-d6) δ 7.79 (d, J ) 8.54 Hz, 2H), 7.15 (s, 1H), 6.98-7.06
(m, 3H), 6.76 (s, 1H), 6.67 (d, J ) 7.32 Hz, 1H), 4.13 (t, J ) 6.10
Hz, 3H), 4.05 (t, J ) 6.10 Hz, 2H), 3.30 (dt, J ) 14.34, 7.17 Hz,
1H), 2.74-2.81 (m, 1H), 2.66-2.73 (m, 3H), 2.5 (m, 1H), 2.18-
2.26 (m, 2H), 2.08-2.15 (m, J ) 6.03, 6.03, 6.03, 6.03 Hz, 2H),
1.55-1.63 (m, 1H), 1.20 (t, J ) 7.63 Hz, 3H). LC-MS: method 1,
RT (min) ) 5.41; [M + H]+ 438.2; method 2, RT (min) ) 4.01;
[M + H]+ 438.3.
[(1S)-5-{3-[4-(4-Ethyl-1,3-thiazol-2-yl)-2-propylphenoxy]pro-
poxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid (34e). 1H NMR
(500 MHz, DMSO-d6) δ 7.65 (d, J ) 8.55 Hz, 1H), 7.62 (s, 1H),
7.05 (d, J ) 8.39 Hz, 1H), 7.02 (d, J ) 8.39 Hz, 1H), 6.75 (s, 1H),
6.64-6.69 (m, 1H), 4.06-4.15 (m, 4H), 3.26-3.33 (m, 1H), 2.74-
2.81 (m, 1H), 2.65-2.72 (m, 3H), 2.5 (m, 1H), 2.18-2.26 (m, 2H),
2.13 (qd, J ) 6.00, 5.80 Hz, 2H), 1.55-1.63 (m, 1H), 1.50 (qt, J
) 7.40, 7.21 Hz, 3H), 1.20 (t, J ) 7.48 Hz, 3H), 0.83 (t, J ) 7.32
Hz, 3H). LC-MS: method 1, RT (min) ) 5.84; [M + H]+ 480.3;
method 2, RT (min) ) 4.20; [M + H]+ 480.3.
1
16n to give the title compound as an oil. H NMR (400 MHz,
CDCl3) δ 8.03 (d, 1H), 7.86 (d, 1H), 7.70 (s, 1H), 7.58 (m, 1H),
7.48 (m, 1H), 7.37 (m, 1H), 7.06 (d, 1H), 6.96 (d, 1H), 6.81 (s,
1H), 6.72 (d, 1H), 4.34-4.24 (m, 2H), 4.24-4.12 (m, 4H), 4.00
(s, 3H), 3.58-3.48 (m, 1H), 2.95-2.80 (m, 2H), 2.72 (dd, 1H),
2.44-2.28 (m, 4H), 1.84-1.68 (m, 1H), 1.28 (t, 3H).
Ethyl ((1S)-5-{3-[4-(4-Isopropoxy-1,3-thiazol-2-yl)-2-meth-
oxyphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (33ak).
A solution of ethyl ((1S)-5-{3-[4-(aminocarbonothioyl)-2-meth-
oxyphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (500 mg,
1.1 mmol; 32) and 2-chloro-N,N-dimethylacetamide (800 mg, 6.6
mmol) in i-PrOH (anhydrous, 15 mL) was stirred at 70 °C for 8 h.
[(1S)-5-{3-[4-(4-Ethyl-1,3-thiazol-2-yl)-2-methoxyphenoxy]pro-
poxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid (34f). 1H NMR (500
MHz, DMSO-d6) δ 7.40 (s, 1H), 7.38 (d, J ) 8.55 Hz, 1H), 7.18
(s, 1H), 7.04 (t, J ) 8.55 Hz, 2H), 6.76 (s, 1H), 6.64-6.71 (m,
1H), 4.12 (t, J ) 5.95 Hz, 2H), 4.05 (t, J ) 5.95 Hz, 2H), 3.78 (s,
3H), 3.37 (s, 1H), 3.27-3.33 (m, 2H), 2.75-2.84 (m, 1H), 2.67-

Indanylacetic Acid DeriVatiVes as PPAR Agonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5 997
2.75 (m, 4H), 2.5 (m, 1H), 2.18-2.26 (m, 2H), 2.08-2.16 (m, 2H),
1.59 (dd, J ) 12.21, 7.63 Hz, 1H), 1.21 (t, J ) 7.48 Hz, 3H). LC-
MS: method 1, RT (min) ) 5.24; [M + H]+ 468.2; method 2, RT
(min) ) 3.60; [M + H]+ 468.3.
[(1S)-5-{3-[4-(4-tert-Butyl-1,3-thiazol-2-yl)-2-propylphenoxy]-
propoxy}-2,3-dihydro-1H-1-inden-1-yl]acetic Acid (34g). 1H
NMR (500 MHz, DMSO-d6) δ 7.60 (d, J ) 1.83 Hz, 1H), 7.05 (d,
J ) 8.39 Hz, 1H), 7.02 (d, J ) 8.39 Hz, 1H), 6.75 (s, 1H), 6.63-
6.69 (m, 1H), 4.06-4.15 (m, 4H), 3.30 (s, 1H), 2.73-2.81 (m,
1H), 2.69 (d, J ) 7.93 Hz, 1H), 2.5 (m, 1H), 2.18-2.26 (m, 2H),
2.10-2.18 (m, 2H), 1.59 (d, J ) 4.58 Hz, 1H), 1.46-1.55 (m,
2H), 1.28 (s, 10H), 1.09-1.15 (m, 1H), 1.06 (s, 3H), 0.81-0.89
(m, 4H). LC-MS: method 1, RT (min) ) 6.17; [M + H]+ 508.3;
method 2, RT (min) ) 4.81; [M + H]+ 508.4.
[(1S)-5-(3-{2-Propyl-4-[4-(trifluoromethyl)-1,3-thiazol-2-
yl]phenoxy}propoxy)-2,3-dihydro-1H-inden-1-yl]acetic Acid (34h).
1H NMR (500 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.74 (d, J ) 8.55
Hz, 1H), 7.68 (d, J ) 1.53 Hz, 1H), 7.02-7.09 (m, 2H), 6.75 (s,
1H), 6.67 (d, J ) 7.93 Hz, 1H), 4.16 (t, J ) 5.80 Hz, 2H), 4.09 (t,
J ) 6.10 Hz, 2H), 3.26-3.33 (m, 1H), 2.74-2.81 (m, 1H), 2.69
(dt, J ) 16.10, 7.97 Hz, 1H), 2.5 (m, 1H), 2.18-2.26 (m, 4H),
2.12-2.17 (m, J ) 5.95, 5.95, 5.95, 5.95 Hz, 2H), 1.59 (dd, J )
12.21, 7.63 Hz, 1H), 1.48-1.55 (m, 2H), 0.83 (t, J ) 7.32 Hz,
3H). LC-MS: method 1, RT (min) ) 5.83; [M + H]+ 520.2;
method 2, RT (min) ) 4.51; [M + H]+ 520.4.
[(1S)-5-(3-{2-Methoxy-4-[4-(trifluoromethyl)-1,3-thiazol-2-
yl]phenoxy}propoxy)-2,3-dihydro-1H-inden-1-yl]acetic Acid (34i).
1H NMR (500 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.48 (d, J ) 8.24
Hz, 1H), 7.42 (s, 1H), 7.07 (d, J ) 8.24 Hz, 1H), 7.05 (d, J ) 8.24
Hz, 1H), 6.76 (s, 1H), 6.68 (s, 1H), 4.15 (t, J ) 5.95 Hz, 2H), 4.05
(t, J ) 5.95 Hz, 2H), 3.81 (s, 3H), 3.27-3.33 (m, 1H), 2.74-2.81
(m, 1H), 2.69 (dt, J ) 15.87, 7.93 Hz, 1H), 2.5 (m, 1H), 2.18-
2.26 (m, 2H), 2.10-2.16 (m, 2H), 1.55-1.63 (m, 1H). LC-MS:
method 1, RT (min) ) 5.34; [M + H]+ 508.1; method 2, RT (min)
) 3.98; [M + H]+ 508.3.
[(1S)-5-{3-[4-(4,5-Dimethyl-1,3-thiazol-2-yl)phenoxy]propoxy}-
2,3-dihydro-1H-inden-1-yl]acetic Acid (34j). 1H NMR (500 MHz,
DMSO-d6) δ 7.71 (d, J ) 8.85 Hz, 2H), 7.06 (d, J ) 8.24 Hz,
1H), 6.98 (d, J ) 8.85 Hz, 2H), 6.77 (s, 1H), 6.68 (d, J ) 6.71 Hz,
1H), 4.13 (t, J ) 6.10 Hz, 2H), 4.06 (t, J ) 6.10 Hz, 2H), 3.28 (d,
J ) 3.97 Hz, 2H), 2.77 (d, J ) 8.24 Hz, 1H), 2.65-2.74 (m, 1H),
2.31 (s, 3H), 2.19-2.27 (m, 5H), 2.07-2.15 (m, 3H), 1.60 (dd, J
) 12.51, 7.32 Hz, 1H). LC-MS: method 1, RT (min) ) 5.28; [M
+ H]+ 438.2; method 2, RT (min) ) 3.80; [M + H]+ 438.3.
[(1S)-5-{3-[4-(4,5-Dimethyl-1,3-thiazol-2-yl)-2-methoxyphe-
noxy]propoxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid (34k). 1H
NMR (500 MHz, DMSO-d6) δ 7.34 (s, 1H), 7.28 (d, J ) 8.24 Hz,
1H), 6.98-7.06 (m, 2H), 6.76 (s, 1H), 6.64-6.71 (m, 1H), 4.11 (t,
J ) 6.10 Hz, 2H), 4.05 (t, J ) 6.10 Hz, 2H), 3.77 (s, 3H), 3.30
(ddd, J ) 14.27, 7.48, 7.25 Hz, 1H), 2.74-2.81 (m, 1H), 2.69 (dt,
J ) 15.79, 7.82 Hz, 1H), 2.5 (m, 1H), 2.30 (s, 3H), 2.18-2.27 (m,
5H), 2.07-2.15 (m, J ) 6.14, 6.14, 6.03, 5.80 Hz, 2H), 1.54-1.63
(m, 1H). LC-MS: method 1, RT (min) ) 5.17; [M + H]+ 468.2;
method 2, RT (min) ) 3.68; [M + H]+ 468.3.
MS: method 1, RT (min) ) 5.87; [M + H]+ 492.3; method 2, RT
(min) ) 4.47; [M + H]+ 492.4.
[(1S)-5-{3-[4-(5,6-Dihydro-4H-cyclopenta[d]1,3thiazol-2-yl)-2-
methoxyphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid
1
(34n). H NMR (500 MHz, DMSO-d6) δ 7.38 (s, 1H), 7.33 (d, J
) 8.24 Hz, 1H), 7.04 (d, J ) 8.24 Hz, 1H), 7.02 (d, J ) 8.24 Hz,
1H), 6.76 (s, 1H), 6.67 (d, J ) 7.63 Hz, 1H), 4.11 (t, J ) 6.10 Hz,
3H), 4.05 (t, J ) 6.10 Hz, 3H), 3.78 (s, 4H), 2.85 (t, J ) 6.87 Hz,
2H), 2.69-2.78 (m, 5H), 2.18-2.26 (m, 2H), 2.11 (dq, J ) 6.41,
6.21 Hz, 3H), 1.54-1.63 (m, 1H). LC-MS: method 1, RT (min)
) 5.32; [M + H]+ 480.2; method 2, RT (min) ) 3.97; [M + H]+
480.4.
[(1S)-5-{3-[4-(4,5,6,7-Tetrahydro-1,3-benzothiazol-2-yl)phe-
noxy]propoxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid (34o). 1H
NMR (500 MHz, DMSO-d6) δ 7.72 (d, J ) 8.54 Hz, 2H), 7.04 (d,
J ) 8.24 Hz, 1H), 6.98 (d, J ) 8.85 Hz, 2H), 6.76 (s, 1H), 6.67 (d,
J ) 7.32 Hz, 1H), 4.09-4.17 (m, 2H), 4.05 (t, J ) 6.10 Hz, 2H),
3.30 (ddd, J ) 14.27, 7.48, 7.25 Hz, 1H), 2.74-2.80 (m, 1H), 2.65-
2.73 (m, 5H), 2.5 (s, 1H), 2.18-2.26 (m, 2H), 2.08-2.15 (m, J )
6.03, 6.03, 6.03, 6.03 Hz, 2H), 1.76 (m, 4H), 1.55-1.63 (m, 1H).
LC-MS: method 1, RT (min) ) 5.52; [M + H]+ 464.2; method 2,
RT (min) ) 4.01; [M + H]+ 464.4.
[(1S)-5-{3-[2-Propyl-4-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-
yl)phenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid (34p).
1H NMR (500 MHz, DMSO-d6) δ 7.56-7.63 (m, 2H), 7.06 (d, J
) 8.24 Hz, 1H), 6.99 (d, J ) 8.55 Hz, 1H), 6.76 (s, 1H), 6.67 (d,
J ) 7.02 Hz, 1H), 4.06-4.15 (m, 4H), 3.31 (d, J ) 3.36 Hz, 1H),
2.73-2.81 (m, 2H), 2.65-2.73 (m, 5H), 2.60 (dd, J ) 15.41, 5.95
Hz, 1H), 2.5 (m, 1H), 2.19-2.27 (m, 2H), 2.10-2.17 (m, 2H),
1.77 (s, 4H), 1.60 (dd, J ) 12.51, 7.63 Hz, 1H), 1.46-1.55 (m, J
) 7.32, 7.32, 7.32, 7.32 Hz, 2H), 0.84 (t, J ) 7.32 Hz, 3H). LC-
MS: method 1, RT (min) ) 5.94; [M + H]+ 506.3; method 2, RT
(min) ) 4.34; [M + H]+ 506.4.
[(1S)-5-{3-[2-Methoxy-4-(4,5,6,7-tetrahydro-1,3-benzothiazol-
2-yl)phenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid
1
(34q). H NMR (500 MHz, DMSO-d6) δ 7.36 (s, 1H), 7.30 (d, J
) 8.24 Hz, 1H), 7.06 (d, J ) 8.24 Hz, 1H), 7.1 (d, J ) 8.24 Hz,
1H), 6.76 (s, 1H), 6.68 (d, J ) 8.24 Hz, 1H), 4.12 (t, J ) 6.10 Hz,
2H), 4.06 (t, J ) 6.10 Hz, 2H), 3.78 (s, 3H), 3.33 (d, J ) 3.05 Hz,
1H), 2.77 (dd, J ) 8.24, 4.88 Hz, 1H), 2.70 (dd, J ) 16.17, 6.10
Hz, 5H), 2.5 (m, 1H), 2.19-2.26 (m, 2H), 2.08-2.15 (m, J ) 6.03,
6.03, 6.03, 6.03 Hz, 2H), 1.77 (s, 5H), 1.60 (dd, J ) 12.36, 7.78
Hz, 1H). LC-MS: method 1, RT (min) ) 5.36; [M + H]+ 494.2;
method 2, RT (min) ) 3.94; [M + H]+ 494.3.
[(1S)-5-{3-[4-(6,7-Dihydro-5H-pyrano[2,3-d]1,3thiazol-2-yl)-2-
propylphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid
1
(34r). H NMR (500 MHz, DMSO-d6) δ 7.55 (d, J ) 8.54 Hz,
1H), 7.51 (s, 1H), 6.97-7.06 (m, 2H), 6.74 (s, 1H), 6.66 (d, J )
7.93 Hz, 1H), 4.15-4.21 (m, 2H), 4.05-4.14 (m, 4H), 3.26-3.33
(m, 1H), 2.75 (dd, J ) 8.39, 5.04 Hz, 2H), 2.68 (t, J ) 6.10 Hz,
3H), 2.5 (s, 1H), 2.18-2.26 (m, 4H), 2.09-2.16 (m, 2H), 1.89-
1.96 (m, 2H), 1.58 (s, 1H), 1.45-1.53 (m, 2H), 0.82 (t, J ) 7.32
Hz, 3H). LC-MS: method 1, RT (min) ) 5.67; [M + H]+ 508.3;
method 2, RT (min) ) 4.30; [M + H]+ 508.6. Anal. (C29H33NO5S)
C, H, N.
[(1S)-5-{3-[4-(5,6-Dihydro-4H-cyclopenta[d]1,3thiazol-2-yl)phe-
noxy]propoxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid (34l). 1H
NMR (500 MHz, DMSO-d6) δ 7.74 (d, J ) 8.55 Hz, 2H), 7.05 (d,
J ) 8.24 Hz, 1H), 6.99 (d, J ) 8.85 Hz, 2H), 6.77 (s, 1H), 6.67 (d,
J ) 8.24 Hz, 1H), 4.13 (t, J ) 6.10 Hz, 2H), 4.05 (t, J ) 6.10 Hz,
2H), 3.36 (m, 1H), 2.85 (t, J ) 6.87 Hz, 4H), 2.69-2.78 (m, 5H),
2.19-2.27 (m, 2H), 2.12 (qd, J ) 6.00, 5.80 Hz, 2H), 1.59 (dd, J
) 12.21, 7.63 Hz, 1H). LC-MS: method 1, RT (min) ) 5.44; [M
+ H]+ 450.2; method 2, RT (min) ) 4.06; [M + H]+ 450.3.
[(1S)-5-{3-[4-(5,6-Dihydro-4H-cyclopenta[d]1,3thiazol-2-yl)-2-
propylphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid
[(1S)-5-{3-[4-(6,7-Dihydro-5H-pyrano[2,3-d]1,3thiazol-2-yl)-2-
methoxyphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid
(34s). 1H NMR (500 MHz, DMSO-d6) δ 7.27-7.34 (m, 1H), 7.05
(d, J ) 8.24 Hz, 1H), 7.03 (d, J ) 8.24 Hz, 1H), 6.76 (s, 1H), 6.67
(d, J ) 7.93 Hz, 1H), 4.15-4.22 (m, 2H), 4.11 (t, J ) 6.10 Hz,
2H), 4.04 (t, J ) 5.95 Hz, 2H), 3.73-3.80 (m, 3H), 3.37 (s, 1H),
3.26-3.33 (m, 1H), 2.74-2.81 (m, 1H), 2.65-2.72 (m, 3H), 2.5
(s, 1H), 2.18-2.26 (m, 2H), 2.07-2.15 (m, 2H), 1.89-1.96 (m,
2H), 1.55-1.63 (m, 1H). LC-MS: method 1, RT (min) ) 5.16;
[M + H]+ 496.2; method 2, RT (min) ) 3.83; [M + H]+ 496.6.
[(1S)-5-{3-[4-(1,3-Benzothiazol-2-yl)-2-methoxyphenoxy]pro-
poxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid (34t). 1H NMR (500
MHz, DMSO-d6) δ 7.65-7.71 (m, 2H), 7.53 (d, J ) 8.54 Hz, 1H),
7.07 (d, J ) 8.24 Hz, 1H), 6.75 (s, 1H), 6.66 (d, J ) 7.93 Hz, 1H),
4.15-4.20 (m, 2H), 4.11 (t, J ) 5.80 Hz, 2H), 3.35 (s, 3H), 3.17
(t, J ) 5.65 Hz, 2H), 2.95 (s, 1H), 2.77 (dd, J ) 8.24, 4.88 Hz,
1
(34m). H NMR (500 MHz, DMSO-d6) δ 7.56-7.63 (m, 2H),
6.98-7.07 (m, 2H), 6.76 (s, 1H), 6.67 (d, J ) 7.93 Hz, 1H), 4.06-
4.15 (m, 4H), 3.35 (d, J ) 3.05 Hz, 1H), 2.85 (t, J ) 6.87 Hz,
3H), 2.69-2.78 (m, 5H), 2.5 (m, 1H), 2.19-2.26 (m, 4H), 2.10-
2.17 (m, J ) 5.99, 5.99, 5.87, 5.65 Hz, 2H), 1.59 (dd, J ) 12.21,
7.63 Hz, 1H), 1.47-1.55 (m, 2H), 0.84 (t, J ) 7.32 Hz, 3H). LC-

998 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5
Rudolph et al.
1H), 2.64-2.73 (m, 2H), 2.59 (s, 1H), 2.39 (s, 1H), 2.20-2.29
(m, 4H), 1.60 (s, 1H), 1.20 (t, J ) 7.17 Hz, 3H). LC-MS: method
1, RT (min) ) 4.20 (no ionization); method 2, RT (min) ) 2.96
(no ionization).
4H), 2.18-2.26 (m, 2H), 2.11-2.17 (m, 2H), 1.54-1.63 (m, 1H),
1.46-1.54 (m, 2H), 1.12 (t, J ) 7.48 Hz, 1H), 0.83 (t, J ) 7.32
Hz, 4H). LC-MS: method 1, RT (min) ) 5.28; [M + H]+ 510.2;
method 2, RT (min) ) 3.90; [M + H]+ 510.3.
[(1S)-5-{3-[4-(5-Acetyl-4-methyl-1,3-thiazol-2-yl)phenoxy]pro-
poxy}-2,3-dihydro-1H-inden-1-yl)acetic Acid (34u). 1H NMR
(500 MHz, DMSO-d6) δ 7.89 (d, J ) 8.85 Hz, 2H), 7.04 (d, J )
8.55 Hz, 3H), 6.76 (s, 1H), 6.68 (s, 1H), 6.66 (d, J ) 1.53 Hz,
1H), 4.16 (t, J ) 6.10 Hz, 2H), 4.05 (t, J ) 6.10 Hz, 2H), 3.26-
3.33 (m, J ) 7.17, 7.17, 7.17, 7.17 Hz, 1H), 2.74-2.81 (m, 1H),
2.68 (td, J ) 16.40, 8.70 Hz, 4H), 2.5 (m, 1H), 2.18-2.26 (m,
2H), 2.09-2.15 (m, J ) 6.14, 6.14, 6.03, 5.80 Hz, 5H), 1.55-1.63
(m, 1H). LC-MS: method 1, RT (min) ) 5.24; [M + H]+ 466.2;
method 2, RT (min) ) 3.79; [M + H]+ 466.4.
[(1S)-5-{3-[4-(5-Acetyl-4-methyl-1,3-thiazol-2-yl)-2-propyl-
phenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetic Acid (34v).
1H NMR (500 MHz, DMSO-d6) δ 7.73-7.79 (m, 1H), 7.71 (d, J
) 1.83 Hz, 1H), 7.05 (dd, J ) 8.39, 5.04 Hz, 2H), 6.75 (s, 1H),
6.64-6.69 (m, 1H), 4.16 (t, J ) 5.80 Hz, 2H), 4.08 (t, J ) 6.10
Hz, 2H), 3.37 (s, 1H), 3.30 (d, J ) 7.02 Hz, 2H), 2.74-2.80 (m,
2H), 2.62-2.72 (m, 3H), 2.5 (m, 4H), 2.18-2.26 (m, 2H), 2.11-
2.17 (m, 2H), 1.55-1.63 (m, 1H), 1.46-1.55 (m, 3H), 0.83 (t, J )
7.32 Hz, 3H). LC-MS: method 1, RT (min) ) 5.64; [M + H]+
508.3; method 2, RT (min) ) 4.26; [M + H]+ 508.3.
2-[4-(3-{[(1S)-1-(Carboxymethyl)-2,3-dihydro-1H-inden-5-yl]-
oxy}propoxy)-3-methoxyphenyl]-4-methyl-1,3-thiazole-5-car-
boxylic Acid (34ab). 1H NMR (500 MHz, DMSO-d6) δ 7.47 (d, J
) 8.24 Hz, 1H), 7.44 (s, 1H), 7.01-7.08 (m, 2H), 6.76 (s, 1H),
6.67 (d, J ) 8.24 Hz, 1H), 4.14 (t, J ) 6.10 Hz, 2H), 4.05 (t, J )
6.10 Hz, 2H), 3.80 (s, 3H), 3.26-3.34 (m, 1H), 2.74-2.81 (m,
1H), 2.69 (ddd, J ) 16.02, 7.93, 7.78 Hz, 1H), 2.60 (s, 3H), 2.18-
2.26 (m, 3H), 2.12 (qd, J ) 6.00, 5.80 Hz, 2H), 1.59 (ddd, J )
19.99, 7.93, 7.78 Hz, 1H). LC-MS: method 1, RT (min) ) 4.89;
[M + H]+ 498.2; method 2, RT (min) ) 3.46; [M + H]+ 498.2.
2-[4-(3-{[(1S)-1-(Carboxymethyl)-2,3-dihydro-1H-inden-5-yl]-
oxy}propoxy)-3-propylphenyl]-4-(hydroxymethyl)-1,3-thiazole-
5-carboxylic Acid (34ac). 1H NMR (500 MHz, DMSO-d6) δ 7.73
(d, J ) 8.54 Hz, 1H), 7.64 (s, 1H), 6.98-7.06 (m, 2H), 6.75 (s,
1H), 6.66 (d, J ) 7.93 Hz, 1H), 4.14 (t, J ) 5.65 Hz, 2H), 4.07 (t,
J ) 6.10 Hz, 2H), 3.5 (m, 2H), 3.30 (dt, J ) 14.42, 7.29 Hz, 2H),
2.74-2.80 (m, 1H), 2.68 (dt, J ) 15.87, 7.93 Hz, 1H), 2.5 (m,
1H), 2.18-2.26 (m, 4H), 2.10-2.16 (m, J ) 5.87, 5.87, 5.87, 5.87
Hz, 2H), 1.54-1.63 (m, 1H), 1.44-1.52 (m, J ) 7.63, 7.48, 7.48,
7.48, 7.48 Hz, 2H), 0.78-0.85 (m, 3H). LC-MS: method 1, RT
(min) ) 5.01 (no ionization); method 2, RT (min) ) 3.69; [M +
H]+ 526.4.
[(1S)-5-{3-[4-(5-Acetyl-4-methyl-1,3-thiazol-2-yl)-2-methoxy-
phenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetic Acid (34w).
1H NMR (500 MHz, DMSO-d6) δ 7.51 (d, J ) 8.24 Hz, 1H), 7.46
(s, 1H), 7.07 (d, J ) 8.39 Hz, 1H), 7.05 (d, J ) 8.39 Hz, 2H), 6.76
(s, 1H), 6.66 (s, 1H), 4.15 (t, J ) 6.10 Hz, 3H), 4.05 (t, J ) 6.10
Hz, 2H), 3.80 (s, 3H), 3.27-3.33 (m, 1H), 2.74-2.81 (m, 1H),
2.63-2.72 (m, 4H), 2.5 (m, 1H), 2.18-2.26 (m, 2H), 2.09-2.16
(m, 2H), 1.55-1.63 (m, 1H). LC-MS: method 1, RT (min) ) 5.10;
[M + H]+ 496.2; method 2, RT (min) ) 3.59; [M + H]+ 496.3.
[(1S)-5-(3-{4-[5-(Dimethylcarbamoyl)-4-methyl-1,3-thiazol-2-
yl]-2-propylphenoxy}propoxy)-2,3-dihydro-1H-inden-1-yl]ace-
{2-[4-(3-{[(1S)-1-(Carboxymethyl)-2,3-dihydro-1H-inden-5-
yl]oxy}propoxy)-3-propylphenyl]-1,3-thiazol-4-yl}acetic Acid
1
(34ad). H NMR (500 MHz, DMSO-d6) δ 7.65 (d, J ) 8.54 Hz,
1H), 7.61 (s, 1H), 7.33 (s, 1H), 7.05 (d, J ) 8.39 Hz, 1H), 7.02 (d,
J ) 8.39 Hz, 1H), 6.75 (s, 1H), 6.67 (d, J ) 7.93 Hz, 1H), 4.06-
4.15 (m, 4H), 3.70 (s, 2H), 3.26-3.33 (m, 1H), 2.74-2.81 (m,
1H), 2.69 (dt, J ) 15.87, 7.93 Hz, 1H), 2.5 (m, 1H), 2.18-2.26
(m, 4H), 2.10-2.16 (m, 2H), 1.55-1.63 (m, 1H), 1.46-1.54 (m,
J ) 7.36, 7.36, 7.36, 7.36, 7.17 Hz, 2H), 0.83 (t, J ) 7.17 Hz,
3H). LC-MS: method 1, RT (min) ) 5.17; [M + H]+ 510.2;
method 2, RT (min) ) 3.76; [M + H]+ 510.3.
1
tic Acid (34x). H NMR (500 MHz, DMSO-d6) δ 7.66 (d, J )
8.54 Hz, 1H), 7.63 (s, 1H), 7.03 (t, J ) 8.54 Hz, 2H), 6.75 (s, 1H),
6.66 (d, J ) 8.24 Hz, 1H), 4.14 (t, J ) 5.80 Hz, 2H), 4.08 (t, J )
6.10 Hz, 2H), 3.26-3.34 (m, 1H), 2.95 (s, 6H), 2.74-2.80 (m,
1H), 2.65-2.72 (m, 1H), 2.5 (m, 1H), 2.30 (s, 3H), 2.18-2.26 (m,
4H), 2.10-2.16 (m, 2H), 1.59 (dd, J ) 12.21, 7.63 Hz, 1H), 1.46-
1.54 (m, 2H), 0.82 (t, J ) 7.17 Hz, 3H). LC-MS: method 1, RT
(min) ) 5.27; [M + H]+ 537.3; method 2, RT (min) ) 3.92; [M
+ H]+ 537.4.
[(1S)-5-{3-[4-(4-Methoxy-1,3-thiazol-2-yl)phenoxy]propoxy}-
2,3-dihydro-1H-inden-1-yl]acetic Acid (34ae). 1H NMR (500
MHz, DMSO-d6) δ 7.69-7.78 (m, 1H), 6.97-7.06 (m, 3H), 6.76
(s, 1H), 6.67 (d, J ) 8.24 Hz, 1H), 4.13 (t, J ) 6.10 Hz, 3H),
3.99-4.07 (m, 3H), 3.79 (s, 2H), 3.26-3.33 (m, 1H), 2.74-2.81
(m, 1H), 2.69 (ddd, J ) 15.95, 7.86, 7.63 Hz, 1H), 2.18-2.26 (m,
3H), 2.08-2.15 (m, 2H), 1.59 (dt, J ) 19.91, 7.74 Hz, 1H). LC-
MS: method 1, RT (min) ) 5.21; [M + H]+ 440.2; method 2, RT
(min) ) 3.86; [M + H]+ 440.4.
[(1S)-5-{3-[2-Methoxy-4-(4-methoxy-1,3-thiazol-2-yl)phenoxy]-
propoxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid (34af). 1H NMR
(500 MHz, DMSO-d6) δ 7.33-7.38 (m, 2H), 7.04 (t, J ) 9.46 Hz,
2H), 6.77 (s, 1H), 6.68 (d, J ) 8.24 Hz, 1H), 6.46 (s, 1H), 4.09-
4.17 (m, 2H), 4.06 (t, J ) 5.95 Hz, 2H), 3.75-3.82 (m, 6H), 3.32
(m, 1H), 2.75-2.82 (m, 1H), 2.70 (dt, J ) 15.87, 7.93 Hz, 1H),
2.5 (m, 1H), 2.19-2.27 (m, 2H), 2.08-2.16 (m, J ) 5.99, 5.99,
5.87, 5.65 Hz, 2H), 1.56-1.64 (m, 1H). LC-MS: method 1, RT
(min) ) 5.07; [M + H]+ 470.2; method 2, RT (min) ) 3.77; [M
+ H]+ 470.2.
[(1S)-5-{3-[4-(4-Ethoxy-1,3-thiazol-2-yl)phenoxy]propoxy}-
2,3-dihydro-1H-inden-1-yl]acetic Acid (34ag). 1H NMR (500
MHz, DMSO-d6) δ 7.75 (d, J ) 8.54 Hz, 2H), 6.98-7.06 (m, 3H),
6.76 (s, 1H), 6.64-6.71 (m, 1H), 6.41 (s, 1H), 4.14 (t, J ) 6.10
Hz, 2H), 4.03-4.10 (m, 4H), 3.30 (ddd, J ) 14.19, 7.32, 7.17 Hz,
1H), 2.74-2.81 (m, 1H), 2.69 (ddd, J ) 15.95, 7.86, 7.63 Hz, 1H),
2.5 (m, 1H), 2.18-2.26 (m, 2H), 2.08-2.15 (m, 2H), 1.55-1.63
(m, 1H), 1.30 (t, J ) 6.87 Hz, 3H). LC-MS: method 1, RT (min)
) 5.32; [M + H]+ 454.2; method 2, RT (min) ) 4.05; [M + H]+
454.6.
[(1S)-5-{3-[4-(4-Ethoxy-1,3-thiazol-2-yl)-2-propylphenoxy]-
propoxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid (34ah). 1H NMR
(500 MHz, DMSO-d6) δ 7.61 (d, J ) 8.54 Hz, 1H), 7.57 (s, 1H),
7.04 (d, J ) 8.39 Hz, 1H), 7.01 (d, J ) 8.39 Hz, 1H), 6.75 (s, 1H),
6.66 (d, J ) 6.41 Hz, 1H), 6.39 (s, 1H), 4.13 (t, J ) 5.80 Hz, 2H),
[(1S)-5-(3-{4-[5-(Dimethylcarbamoyl)-4-methyl-1,3-thiazol-2-
yl]-2-methoxyphenoxy}propoxy)-2,3-dihydro-1H-inden-1-yl]ace-
1
tic Acid (34y). H NMR (500 MHz, DMSO-d6) δ 7.37-7.43 (m,
2H), 7.04 (d, J ) 8.24 Hz, 2H), 6.75 (s, 1H), 6.64-6.70 (m, 1H),
4.13 (t, J ) 5.95 Hz, 2H), 4.05 (t, J ) 5.95 Hz, 2H), 3.78 (s, 3H),
3.26-3.33 (m, 1H), 2.95 (s, 6H), 2.74-2.81 (m, 1H), 2.65-2.72
(m, 1H), 2.5 (m, 1H), 2.31 (s, 3H), 2.17-2.26 (m, 2H), 2.08-2.15
(m, 2H), 1.58 (dd, J ) 12.36, 7.48 Hz, 1H). LC-MS: method 1,
RT (min) ) 4.81; [M + H]+ 525.2; method 2, RT (min) ) 3.44;
[M + H]+ 525.4.
2-[4-(3-{[(1S)-1-(Carboxymethyl)-2,3-dihydro-1H-inden-5-yl]-
oxy}propoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylic Acid
1
(34z). H NMR (500 MHz, DMSO-d6) δ 7.86 (d, J ) 8.85 Hz,
2H), 7.04 (t, J ) 8.39 Hz, 3H), 6.77 (s, 1H), 6.68 (dd, J ) 8.24,
1.22 Hz, 1H), 4.16 (t, J ) 5.95 Hz, 2H), 4.06 (t, J ) 6.10 Hz, 2H),
3.36 (s, 1H), 2.75-2.82 (m, 1H), 2.69 (dt, J ) 16.10, 7.97 Hz,
1H), 2.55-2.63 (m, 3H), 2.5 (m, 1H), 2.19-2.27 (m, 2H), 2.09-
2.16 (m, J ) 6.03, 6.03, 6.03, 6.03 Hz, 2H), 1.56-1.63 (m, 1H).
LC-MS: method 1, RT (min) ) 5.00; [M + H]+ 468.2; method 2,
RT (min) ) 3.64; [M + H]+ 468.3.
2-[4-(3-{[(1S)-1-(Carboxymethyl)-2,3-dihydro-1H-inden-5-yl]-
oxy}propoxy)-3-propylphenyl]-4-methyl-1,3-thiazole-5-carbox-
1
ylic Acid (34aa). H NMR (500 MHz, DMSO-d6) δ 7.73 (d, J )
8.85 Hz, 1H), 7.68 (d, J ) 1.53 Hz, 1H), 7.04 (d, J ) 6.41 Hz,
2H), 7.03 (s, 1H), 6.75 (s, 1H), 6.67 (s, 1H), 4.15 (t, J ) 5.65 Hz,
2H), 4.08 (t, J ) 5.95 Hz, 2H), 3.27-3.33 (m, 1H), 2.86-2.96
(m, 1H), 2.74-2.81 (m, 2H), 2.65-2.72 (m, 2H), 2.55-2.63 (m,

Indanylacetic Acid DeriVatiVes as PPAR Agonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5 999
4.03-4.10 (m, 4H), 3.29 (m, 1H), 2.84 (m, 1H), 2.73-2.82 (m,
2H), 2.63-2.72 (m, 3H), 2.57 (m, 1H), 2.20-2.26 (m, 2H), 2.09-
2.16 (m, 2H), 1.61 (m, 1H), 1.45-1.53 (m, 2H), 1.30 (t, J ) 6.87
Hz, 3H), 0.83 (t, J ) 7.32 Hz, 3H). LC-MS: method 1, RT (min)
) 5.74; [M + H]+ 496.3; method 2, RT (min) ) 4.41; [M + H]+
496.5.
[(1S)-5-{3-[4-(4-Ethoxy-1,3-thiazol-2-yl)-2-methoxyphenoxy]-
propoxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid (34ai). 1H NMR
(500 MHz, DMSO-d6) δ 7.32-7.40 (m, 2H), 7.03 (t, J ) 9.16 Hz,
2H), 6.76 (s, 1H), 6.64-6.71 (m, 1H), 6.42 (s, 1H), 4.12 (t, J )
6.10 Hz, 2H), 4.03-4.08 (m, 4H), 3.74-3.81 (m, 3H), 3.30 (dt, J
) 14.27, 7.06 Hz, 1H), 2.74-2.81 (m, 1H), 2.69 (dt, J ) 15.79,
7.82 Hz, 1H), 2.5 (m, 1H), 2.18-2.26 (m, 2H), 2.11 (qd, J ) 6.00,
5.80 Hz, 2H), 1.59 (ddd, J ) 19.99, 7.93, 7.78 Hz, 1H), 1.30 (t, J
) 7.02 Hz, 3H). LC-MS: method 1, RT (min) ) 5.23; [M + H]+
484.2; method 2, RT (min) ) 3.73; [M + H]+ 484.2.
[(1S)-5-{3-[4-(4-Isopropoxy-1,3-thiazol-2-yl)-2-propylphenoxy]-
propoxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid (34aj). 1H NMR
(500 MHz, DMSO-d6) δ 7.64-7.71 (m, 1H), 6.98-7.06 (m, 2H),
6.74 (s, 1H), 6.66 (d, J ) 5.80 Hz, 1H), 4.09-4.18 (m, 3H), 4.07
(s, 2H), 3.37 (s, 1H), 3.30 (d, J ) 7.32 Hz, 2H), 2.89-2.96 (m,
1H), 2.77 (s, 1H), 2.75 (d, J ) 4.27 Hz, 1H), 2.64-2.72 (m, 2H),
2.18-2.26 (m, 2H), 2.09-2.17 (m, 2H), 1.54-1.63 (m, 1H), 1.48
(d, J ) 7.32 Hz, 2H), 1.26 (d, J ) 5.80 Hz, 1H), 1.21 (dd, J )
9.92, 6.26 Hz, 1H), 1.12 (t, J ) 7.48 Hz, 1H), 0.76-0.84 (m, 4H).
LC-MS: method 1, RT (min) ) 4.81; [M + H]+ 412.1; method 2,
RT (min) ) 3.44; [M + H]+ 412.3.
[(1S)-5-{3-[4-(4-Isopropoxy-1,3-thiazol-2-yl)-2-methoxyphe-
noxy]propoxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid (34ak). 1H
NMR (500 MHz, DMSO-d6) δ 7.31-7.36 (m, 2H), 7.04 (d, J )
8.85 Hz, 1H), 7.02 (d, J ) 8.85 Hz, 1H), 6.76 (s, 1H), 6.67 (d, J
) 8.24 Hz, 1H), 6.43 (s, 1H), 4.62 (dt, J ) 11.98, 6.07 Hz, 1H),
4.12 (t, J ) 6.10 Hz, 2H), 4.05 (t, J ) 5.95 Hz, 2H), 3.78 (s, 3H),
3.26-3.33 (m, 1H), 2.74-2.81 (m, 1H), 2.69 (dt, J ) 15.87, 7.93
Hz, 1H), 2.5 (m, 1H), 2.18-2.26 (m, 2H), 2.08-2.15 (m, J ) 6.03,
6.03, 6.03, 6.03 Hz, 2H), 1.55-1.64 (m, 1H), 1.26 (d, J ) 6.10
Hz, 6H). LC-MS: method 1, RT (min) ) 5.33; [M + H]+ 498.2;
method 2, RT (min) ) 4.04; [M + H]+ 498.3.
[(1S)-5-{3-[4-(4-Ethoxy-5-methyl-1,3-thiazol-2-yl)-2-propyl-
phenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid (34al).
1H NMR (500 MHz, DMSO-d6) δ 7.56 (d, J ) 8.54 Hz, 1H), 7.51
(d, J ) 1.53 Hz, 1H), 6.98-7.06 (m, 2H), 6.75 (s, 1H), 6.66 (d, J
) 8.24 Hz, 1H), 4.25 (q, J ) 6.82 Hz, 2H), 4.05-4.14 (m, 4H),
3.26-3.33 (m, 1H), 2.74-2.80 (m, 2H), 2.68 (ddd, J ) 15.72, 7.78,
7.63 Hz, 2H), 2.5 (m, 1H), 2.19-2.26 (m, 2H), 2.10-2.17 (m, 5H),
1.55-1.63 (m, 1H), 1.45-1.53 (m, 2H), 1.21-1.27 (m, 3H), 0.78-
0.85 (m, 3H). LC-MS: method 1, RT (min) ) 6.14; [M + H]+
510.3; method 2, RT (min) ) 4.72; [M + H]+ 510.4.
[(1S)-5-{3-[4-(4-Ethoxy-5-methyl-1,3-thiazol-2-yl)-2-methoxy-
phenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid (34am).
1H NMR (500 MHz, DMSO-d6) δ 7.30 (m, 2H), 7.04 (d, J ) 8.54
Hz, 1H), 7.02 (d, J ) 8.54 Hz, 1H), 6.71 (s, 1H), 6.62 (d, J ) 9.46
Hz, 1H), 4.26 (d, J ) 6.71 Hz, 2H), 4.11 (m, 2H), 4.03 (m, 2H),
3.77 (m, 3H), 3.35 (m, 1H), 2.7 (m, 1H), 2.6 (m, 1H), 2.5 (m, 1H),
2.26 (m, 2H), 2.17 (s, 3H), 2.10 (m, 2H), 1.54 (m, 1H), 1.25 (t, J
) 7.02 Hz, 3H). LC-MS: method 1, RT (min) ) 5.51; [M + H]+
498.2; method 2, RT (min) ) 4.23 (no ionization).
[(1S)-5-{3-[4-(4-Ethoxy-5-ethyl-1,3-thiazol-2-yl)-2-methoxyphe-
noxy]propoxy}-2,3-dihydro-1H-inden-1-yl]acetic Acid (34an). 1H
NMR (500 MHz, DMSO-d6) δ 7.28-7.34 (m, 2H), 7.05 (d, J )
8.24 Hz, 1H), 7.03 (d, J ) 8.24 Hz, 1H), 6.76 (s, 1H), 6.67 (d, J
) 7.93 Hz, 1H), 4.26 (q, J ) 7.02 Hz, 2H), 4.11 (t, J ) 5.95 Hz,
2H), 4.05 (t, J ) 6.10 Hz, 2H), 3.74-3.80 (m, 3H), 3.30 (dt, J )
14.34, 7.17 Hz, 1H), 2.74-2.81 (m, 1H), 2.69 (ddd, J ) 15.95,
7.86, 7.63 Hz, 1H), 2.5 (m, 1H), 2.18-2.26 (m, 3H), 2.07-2.15
(m, J ) 5.99, 5.99, 5.87, 5.65 Hz, 3H), 1.55-1.63 (m, 1H), 1.21-
1.28 (m, 3H), 1.13 (t, J ) 7.32 Hz, 3H). LC-MS: method 1, RT
(min) ) 5.65; [M + H]+ 512.3; method 2, RT (min) ) 4.21; [M
+ H]+ 512.3.
Acknowledgment. We thank Jordi Benet-Buchholz, David
Cantin, Jefferson Chin, Martin Hentemann, Derek Lowe, Laszlo
Musza, Anthony Paiva, and Philip Wickens for their contribu-
tions to this work.
Supporting Information Available: Determination of the
absolute configuration of compound 12. In vitro activities of fused
ring tail group derivatives. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) Eckel, R. H.; Grundy, S. M.; Zimmet, P. Z. The metabolic syndrome.
Lancet 2005, 365, 1415-1428.
(2) Akiyama, T. E.; Meinke, P. T.; Berger, J. P. PPAR ligands: Potential
therapies for metabolic syndrome. Curr. Diabetes Rep. 2005, 5, 45-
52.
(3) 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.
(4) Verges, B. Clinical interest of PPARs ligands: Particular benefit in
type 2 diabetes and metabolic syndrome. Diabetes Metab. 2004, 30,
7-12.
(5) Shearer, B. G.; Hoekstra, W. J. Recent advances in peroxisome
proliferator-activated receptor science. Curr. Med. Chem. 2003, 10,
267-280.
(6) Campbell, I. W. The clinical significance of PPAR gamma agonism.
Curr. Mol. Med. 2005, 5, 349-363.
(7) In addition, benefits of PPARgamma agonists in conditions not
directly linked to glucose homeostasis, particularly on modulation
of lipid metabolism, have later become apparent: (a) Zhang, L.;
Chawla, A. Role of PPAR gamma in macrophage biology and
atherosclerosis. Trends Endocrinol. Metab. 2004, 15, 500-505. (b)
Walczak, R.; Tontonoz, P. PPARadigms and PPARadoxes: Expand-
ing roles for PPAR gamma in the control of lipid metabolism. J.
Lipid Res. 2002, 43, 177-186.
(8) Pegorier, J. P. PPAR receptors and insulin sensitivity: New agonists
in development. Ann. Endocrinol. 2005, 66, 1S10-11S17.
(9) Henke, B. R. Peroxisome proliferator-activated receptor alpha/gamma
dual agonists for the treatment of type 2 diabetes. J. Med. Chem.
2004, 47, 4118-4127.
(10) Gervois, P.; Fruchart, J. C.; Staels, B. Inflammation, dyslipidaemia,
diabetes and PPARs: Pharmacological interest of dual PPAR alpha
and PPAR gamma agonists. Int. J. Clin. Pract., Suppl. 2004, 143,
22-29.
(11) Moller, D. E.; Wright, S. D. (Merck & Co., Inc., U.S.A.). Combina-
tion therapy including a PPAR alpha/gamma dual agonist, and use
in the treatment of hyperglycemia, lipid disorders, and obesity in
patients with type 2 diabetes or related disorders. WO 2003088962,
2003.
(12) Barlocco, D. Muraglitazar Bristol-Myers Squibb/Merck. Curr. Opin.
InVest. Drugs 2005, 6, 427-434.
(13) Cox, S. L. Muraglitazar: An agent for the treatment of type 2 diabetes
and associated dyslipidemia. Drugs Today 2005, 41, 579-587.
(14) Fagerberg, B.; Edwards, S.; Halmos, T.; Lopatynski, J.; Schuster,
H.; et al. Tesaglitazar, a novel dual peroxisome proliferator-activated
receptor alpha/gamma agonist, dose-dependently improves the meta-
bolic abnormalities associated with insulin resistance in a non-diabetic
population. Diabetologia 2005, 48, 1716-1725.
(15) Kamber, N.; Davis, T. M. E. Tesaglitazar AstraZeneca. IDrugs 2005,
8, 927-935.
(16) Oakes, N. D.; Thalen, P.; Hultstrand, T.; Jacinto, S.; Camejo, G.; et
al. Tesaglitazar, a dual PPAR alpha/gamma agonist, ameliorates
glucose and lipid intolerance in obese Zucker rats. Am. J. Physiol.
2005, 289, R938-R946.
(17) Lee, C.-H.; Kang, K.; Mehl, Isaac, R.; Nofsinger, R.; Alaynick,
William, A.; et al. Peroxisome proliferator-activated receptor delta
promotes very low-density lipoprotein-derived fatty acid catabolism
in the macrophage. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 2434-
2439.
(18) Luquet, S.; Gaudel, C.; Holst, D.; Lopez-Soriano, J.; Jehl-Pietri, C.;
et al. Roles of PPAR delta in lipid absorption and metabolism: a
new target for the treatment of type 2 diabetes. Biochim. Biophys.
Acta 2005, 1740, 313-317.
(19) Barish, G. D.; Narkar, V. A.; Evans, R. M. PPAR delta: A dagger
in the heart of the metabolic syndrome. J. Clin. InVest. 2006, 116,
590-597.
(20) Takahashi, S.; Tanaka, T.; Kodama, T.; Sakai, J. Peroxisome
proliferator-activated receptor delta, a novel target site for drug
discovery in metabolic syndrome. Pharmacol. Res. 2006, 53, 501-
507.

1000 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5
Rudolph et al.
(21) Oliver, W. R., Jr.; Shenk, J. L.; Snaith, M. R.; Russell, C. S.; Plunket,
K. D.; et al. A selective peroxisome proliferator-activated receptor
delta agonist promotes reverse cholesterol transport. Proc. Natl. Acad.
Sci. U.S.A. 2001, 98, 5306-5311.
(22) Evans, J. L.; Lin, J. J.; Goldfine, I. D. Novel approach to treat insulin
resistance, type 2 diabetes, and the metabolic syndrome: Simulta-
neous activation of PPAR alpha, PPAR gamma, and PPAR delta.
Curr. Diabetes ReV. 2005, 1, 299-307.
(23) Jones, A. B. Peroxisome proliferator-activated receptor (PPAR)
modulators: Diabetes and beyond. Med. Res. ReV. 2001, 21, 540-
552.
(33) Cantin, L.-D.; Choi, S.; Clark, R. B.; Hentemann, M. F.; Ma, X.;
Rudolph, J.; et al. (Bayer Pharmaceuticals Corporation, U.S.A.).
Preparation of indaneacetic acid derivatives and their use as
pharmaceutical agents. WO 2004058174, 2004.
(34) Santini, C.; Berger, G. D.; Han, W.; Mosley, R.; MacNaul, K.; et al.
Phenylacetic acid derivatives as hPPAR agonists. Bioorg. Med. Chem.
Lett. 2003, 13, 1277-1280.
(35) Gupta, R. R.; Kumar, M.; Gupta, V. In Heterocyclic chemistry; Gupta,
R. R., Kumar, M., Gupta, V., Eds.; Springer: Berlin, Heidelberg,
New York, 1999.
(36) R-Bromo/chloro carbonyl derivatives were commercially available,
except 3-bromotetrahydro-2H-pyran-2-one, which was synthesized
according to a literature procedure: Wolff, J. J.; Frenking, G.; Harms,
K. The conformational behavior of 10-substituted spiro[4.5]decanes.
Chem. Ber. 1991, 124, 551-561.
(37) The benzothiazole derivative 33t/34t was the only compound that
was not prepared through Hantzsch thiazole synthesis but instead
through condensation of 2-aminothiophenol with 4-hydroxy-3-
methoxybenzoic acid. Its synthesis is described in the Experimental
Section.
(38) Grunfeld, C. Insulin receptor in 3T3-L1 cultured adipose cells. Recept.
Biochem. Methodol. 1988, 12A, 235-248.
(39) Connor, S. C.; Hughes, M. G.; Moore, G.; Lister, C. A.; Smith, S.
A. Antidiabetic efficacy of BRL 49653, a potent orally active insulin-
sensitizing agent, assessed in the C57BL/KsJ db/db diabetic mouse
by noninvasive [1H]NMR studies of urine. J. Pharm. Pharmacol.
1997, 49, 336-344.
(24) Adams, A. D.; Yuen, W.; Hu, Z.; Santini, C.; Jones, A. B.; et al.
Amphipathic 3-phenyl-7-propylbenzisoxazoles; human PPAR gamma,
delta, and alpha agonists. Bioorg. Med. Chem. Lett. 2003, 13, 931-
935.
(25) Mogensen, J. P.; Jeppesen, L.; Bury, P. S.; Pettersson, I.; Fleckner,
J.; et al. Design and synthesis of novel PPAR alpha/gamma/delta
triple activators using a known PPAR alpha/gamma dual activator
as structural template. Bioorg. Med. Chem. Lett. 2003, 13, 257-
260.
(26) Miller, D. J.; Koyama, H.; Berger, J. P.; MacNaul, K. L.; Doebber,
T. W.; et al. DiscoVery of PPAR alpha/gamma/delta pan-agonists:
Ligand conformational constraint and selectiVity, 37th Middle
Atlantic Regional Meeting of the American Chemical Society, New
Brunswick, NJ, May 22-25, 2005; GENE-363.
(27) Mahindroo, N.; Huang, C.-F.; Peng, Y.-H.; Wang, C.-C.; Liao, C.-
C.; et al. Novel indole-based peroxisome proliferator-activated
receptor agonists: Design, SAR, structural biology, and biological
activities. J. Med. Chem. 2005, 48, 8194-8208.
(28) Mahindroo, N.; Wang, C.-C.; Liao, C.-C.; Huang, C.-F.; Lu, I. L.;
et al. Indol-1-yl acetic acids as peroxisome proliferator-activated
receptor agonists: Design, synthesis, structural biology, and molecular
docking studies. J. Med. Chem. 2006, 49, 1212-1216.
(29) Ramachandran, U.; Kumar, R.; Mittal, A. Fine tuning of PPAR
ligands for type 2 diabetes and metabolic syndrome. Mini-ReV. Med.
Chem. 2006, 6, 563-573.
(40) Wolffenbuttel, B. H. R.; Sels, J.-P.; Huijberts, M. S. P. Rosiglitazone.
Exp. Opin. Pharmacother. 2001, 2, 467-478.
(41) Peterson, R. G.; Shaw, W. N.; Neel, M. A.; Little, L. A.; Eichberg,
J. Zucker diabetic fatty rat as a model for non-insulin-dependent
diabetes mellitus. ILAR News 1990, 32, 16-19.
(42) Wang, P. R.; Guo, Q.; Ippolito, M.; Wu, M.; Milot, D.; et al. High
fat fed hamster, a unique animal model for treatment of diabetic
dyslipidemia with peroxisome proliferator activated receptor alpha
selective agonists. Eur. J. Pharmacol. 2001, 427, 285-293.
(43) Garber, D. W.; Kulkarni, K. R.; Anantharamaiah, G. M. A sensitive
and convenient method for lipoprotein profile analysis of individual
mouse plasma samples. J. Lipid Res. 2000, 41, 1020-1026.
(30) Lowe, D. B.; Bifulco, N.; Bullock, W. H.; Claus, T.; Coish, P.; et al.
Substituted indanylacetic acids as PPAR alpha/gamma activators.
Bioorg. Med. Chem. Lett. 2006, 16, 297-301.
(31) Bayer Pharmaceuticals, unpublished results.
(32) Lowe, D. B.; Wickens, P. L.; Ma, X.; Zhang, M.; Bullock, W. H.;
Coish, P. D. G.; et al. (Bayer Corporation, U.S.A.). Preparation of
indaneacetic acid derivatives for treating diabetes, obesity, hyper-
lipidemia, and atherosclerotic diseases. WO 2003011842, 2003.
JM061299K