(2R)-2-ethylchromane-2-carboxylic acids: Discovery of novel PPARα/γ dual agonists as antihyperglycemic and hypolipidemic agents

Article abstract of DOI:10.1021/jm030621d

A series of chromane-2-carboxylic acid derivatives was synthesized and evaluated for PPAR agonist activities. A structure-activity relationship was developed toward PPARα/γ dual agonism. As a result, (2R)-7-{3-[2-chloro-4-(4-fluorophenoxy)phenoxy]propoxy}

Full text of DOI:10.1021/jm030621d

J . Med. Chem. 2004, 47, 3255-3263
3255
(2R)-2-Eth ylch r om a n e-2-ca r boxylic Acid s: Discover y of Novel P P ARr/γ Du a l
Agon ists a s An tih yp er glycem ic a n d Hyp olip id em ic Agen ts
Hiroo Koyama,*,† Daniel J . Miller,† J ulia K. Boueres,† Ranjit C. Desai,† A. Brian J ones,† J oel P. Berger,‡
Karen L. MacNaul,‡ Linda J . Kelly,‡ Thomas W. Doebber,‡ Margaret S. Wu,‡ Gaochao Zhou,‡ Pei-ran Wang,§
Marc C. Ippolito,§ Yu-Sheng Chao,§ Arun K. Agrawal,| Ronald Franklin,| J ames V. Heck,† Samuel D. Wright,§
David E. Moller,‡ and Soumya P. Sahoo*,†
Departments of Medicinal Chemistry, Metabolic Disorders, Atherosclerosis and Endocrinology, and Drug Metabolism,
Merck Research Laboratories, P.O. Box 2000, Rahway, New J ersey 07065-0900
Received December 13, 2003
A series of chromane-2-carboxylic acid derivatives was synthesized and evaluated for PPAR
agonist activities. A structure-activity relationship was developed toward PPARR/γ dual
agonism. As a result, (2R)-7-{3-[2-chloro-4-(4-fluorophenoxy)phenoxy]propoxy}-2-ethylchromane-
2-carboxylic acid (48) was identified as a potent, structurally novel, selective PPARR/γ dual
agonist. Compound 48 exhibited substantial antihyperglycemic and hypolipidemic activities
when orally administered in three different animal models: the db/db mouse type 2 diabetes
model, a Syrian hamster lipid model, and a dog lipid model.
Ch a r t 1. Glitazone Class of Antidiabetic Drugs
In tr od u ction
Type 2 diabetes is a chronic disease characterized by
insulin resistance in the liver and peripheral tissues
accompanied by a defect in pancreatic â-cells.1-3 Insulin
resistance is a state in which the body fails to suf-
ficiently respond to normal circulating levels of insulin.
In the United States, diabetes is the fifth leading cause
of death and approximately 12 million people were
diagnosed with diabetes, over 90% with type 2. The cost
for lost productivity and medical treatment in 2002 was
estimated at $132 billion.4 In the late 1990s, a new class
of drugs called “glitazones” (or “thiazolidinediones”)5 was
approved by the FDA for the treatment of type 2
diabetes (Chart 1). These agents share a common partial
chemical structure: thiazolidine-2,4-dione (TZD). Gli-
tazones correct hyperglycemia by enhancing insulin
sensitivity of adipose, hepatic, and skeletal muscle
tissues.6 Because of this mode of action, glitazone
treatment is not associated with dangerous hypoglyce-
mic incidents that have been observed with conventional
sulfonylurea agents and insulin therapy. In the mid
1990s, the molecular target of glitazones was discovered
to be the peroxisome proliferator-activated receptor-γ
(PPARγ).7-9 The PPARs10-17 are a group of nuclear
receptors that act as transcriptional factors, which play
a major role in the regulation of lipid metabolism and
storage. To date, three isoforms (γ, δ(â), and R) have
been identified. PPARγ is predominantly expressed in
adipose tissue; its activation enhances adipocyte dif-
ferentiation and lipid uptake and storage by adipocytes.
Obesity, insulin resistance, and dyslipidemia are
generally found as a part of a complex mixture of
metabolic abnormalities collectively known as the meta-
Ch a r t 2. Fibrate Class of Hypolipidemic Drugs
bolic syndrome.18-20 The majority (∼80%) of type 2
diabetes patients are obese,21 and atherogenic lipid
abnormalities such as elevated triglyceride levels and
low high-density lipoprotein (HDL)-cholesterol (HDLc)
levels are frequently observed among patients with type
2 diabetes (diabetic dyslipidemia).21-25 Epidemiological
studies have shown that type 2 diabetes is associated
with a 2-4-fold increased risk of coronary heart disease
(CHD) and a 2-3-fold increased risk of ischemic
stroke.22,23 Approximately 75-80% of adult diabetic
patients die from CHD or cerebrovascular disease.23
These findings clearly indicate the unmet clinical needs
of lipid profile management among diabetics.
Fibric acid derivatives (fibrates) have been used
clinically to treat dyslipidemia for the past two decades
(Chart 2). Fibrates effectively lower the plasma triglyc-
eride level and modestly increase the HDLc concentra-
tion while lowering the low-density lipoprotein-choles-
terol level to a variable extent.22,26 While fibrates were
first identified as weak agonists of PPARR in the early
* To whom correspondence should be addressed. (H.K.) Tel: 732-
594-3004. Fax: 732-594-9556. E-mail: hiroo_koyama@merck.com,
(S.P.S.) Tel: 732-594-6058. Fax: 732-594-9556. E-mail: soumya_sahoo@
merck.com.
† Department of Medicinal Chemistry.
‡ Department of Metabolic Disorders.
§ Department of Atherosclerosis and Endocrinology.
| Department of Drug Metabolism.
10.1021/jm030621d CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/07/2004

3256 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
Koyama et al.
Sch em e 1a
F igu r e 1. Cyclized fibrate concept.
1990s,15 a recent study revealed that fibrates are rather
nonselective PPAR agonists.10 Their beneficial effect on
lipids is considered to be mainly driven by the activation
of PPARR. PPARR is predominantly expressed in the
liver, where its activation results in enhanced lipid
uptake and catabolic metabolism. In a recent large
clinical trial, gemfibrozil treatment resulted in a 22%
decrease in CHD death and nonfatal myocardial infarc-
tion incidents among patients with coronary disease and
low HDLc levels (VA-HIT study).27,28 Also, fenofibrate
has been shown to reduce the progression of athero-
sclerosis and coronary events among patients with
diabetes.29
a
i
Reagents: (i) Cs2CO3, DMF, 65 °C. (ii) 2N NaOH, PrOH, 70
°C.
Sch em e 2a
a
Reagents: (i) Bzl-Br, K2CO3, acetone refluxed. (ii) Na-
Considering the significantly increased risk of CHD
among patients with type 2 diabetes and the demon-
strated clinical beneficial effects of fibrates on lipid
profiles, we and others have postulated that a PPARR/γ
dual agonist might present a superior agent for the
HMDS, R-I, THF-HMPA, -78 °C. (iii) Pd/C, H2, EtOH.
moiety, it is interesting to note that the key functional
groups, namely, the acidic functional groups and the
phenyl group, are laid out in a very similar fashion in
both chromane-2-carboxylic acids and glitazones. On the
basis of this structural similarity, we assumed that it
would be possible to build PPARγ activity into the
chromane-2-carboxylic acid series. This “cyclized fibrate”
concept for generating chiral fibrates is not entirely new.
A few attempts have been reported since the 1970s, but
almost no improvement in the hypolipidemic activity
was observed.43,44 The scope of our structure-activity
relationship (SAR) studies is summarized in the struc-
ture in Table 1.
treatment of type 2 diabetes and dyslipidemia.30-40
A
number of new chemical entities with PPARR/γ dual
activity are currently in preclinical and clinical studies.
A successful launch of the first agent of this class would
ultimately validate the concept of PPARR/γ dual activa-
tion for the treatment of hyperglycemia and dyslipi-
demia in type 2 diabetes.
Design Con cep t for th e P P ARr/γ Du a l Agon ists
As a class, glitazones have a chiral center at the
5-positon of the TZD ring. In the case of rosiglitazone,
it has been recently reported that only the (S)-enantio-
mer carries the PPAR activity and that the enantiomers
quickly racemize under physiological conditions.41,42 To
date, all glitazones have been developed as racemates.
Glitazones are generally PPARγ selective agonists.
Fibric acid (2-phenoxyisobutyric acid) is a common
substructure of fibrates. Gemfibrozil has a tris-homo
fibric acid moiety instead of fibric acid. Currently,
marketed fibrates are all achiral entities.
With this background, we set out to discover a potent
PPARR/γ dual agonist, which is chiral and structurally
distinct from glitazones. For the structural design, we
started from fibric acid. Thus, by forming a ring between
the phenyl group and the alkyl substituent R to the
carboxylate moiety, we conceived chromane-2-carboxylic
acid with a chiral center at the 2-position of the
chromane ring (Figure 1). We hoped that the PPARR
activities from the fibric acid moiety would be preserved
even after forming an extra ring. Given that TZD can
be viewed as a replacement of the carboxylic acid
Ch em istr y
Compounds 3-10 were synthesized as described in
Scheme 1. An ether bond was formed between the 6- or
the 7-hydroxy-chromane-2-carboxylates (1a -d ) shown
in Scheme 1 and the bromides (2a ,b) using cesium
carbonate in dimethyl formamide (DMF) at 65 °C. The
resulting ester products were hydrolyzed to give the
desired carboxylic acids (3-10). Ethyl 6-hydroxychro-
mane-2-carboxylate (1a ),45 ethyl 6-hydroxy-2-methyl-
chromane-2-carboxylate (1b),46 and ethyl 7-hydroxy-
chromane-2-carboxylate (1c)47 were prepared according
to the procedures reported in the literature. Compounds
1d and 11-13 were prepared from 1c through a
sequence of reactions: (i) protection of the phenol by a
benzyl group; (ii) standard ester enolate alkylation using
alkyl iodide and HMPA as a cosolvent; and (iii) depro-
tection of the benzyl group (Scheme 2).
Compounds 14-16 were prepared as described in
general Scheme 1 employing phenols 11-13. Com-
pounds 25-28 in Scheme 1 were synthesized from

PPARR/ γ Antihyperglycemic and Hypolipidemic Agents
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3257
Ta ble 1. In Vitro Human PPAR Activities of Chromane-2-carboxylic Acids
SPA IC50 (µM)a
TA EC50 (µM)a
phenol
position
compd
n
R1
R2
R3
(R/S)b
R
δ
γ
R
γ
3
6
6
6
6
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
1
1
2
2
1
1
2
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
H
Me
H
Me
H
Me
H
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
H
H
H
H
H
H
H
H
H
H
H
H
F
racemicc
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
(R)
>15
>15
>50
>50
>50
0.17
>50
>15
>50
>50
>50
5.0
>50
>50
>50
>50
>50
>50
>15
>15
>15
>50
>15
>50
>50
2.9
NAd
NA
NA
NA
2.8
6.8
2.5
1.2
7.3
1.0
1.6
3.6
1.0
0.83
4
3.3
1.7
5
5.8
2.0
1.5
1.9
3.0
2.3
6
7
0.98
0.75
1.8
3.0
8
0.1
9
>15
>15
6.3
10
14
15
16
25
26
27
28
37
38
39
40
46
47
48
49
Me
Et
5.1
5.2
0.36
2.1
3.0
0.97
4.0
0.44
0.37
1.2
0.03
0.12
n-Pr
i-Bu
Et
NTe
NT
1.2
1.4
0.63
0.37
0.01
0.21
4.6
0.75
0.67
0.89
2.8
10
1.0
0.16
0.36
0.08
7.6
0.17
5.0
0.02
Et
Cl
Et
OMe
SO2Me
>15
>15
1.7
Et
NA
Et
H
H
H
H
H
H
F
>15
0.22
0.05
0.03
0.08
0.01
4.2
Et
F
0.37
0.12
0.12
0.06
4.7
0.69
1.4
0.25
1.4
0.26
4.4
0.2
Et
Cl
Me
Et
Cl
Cl
Et
Cl
(S)
>15
0.06
>15
>15
Et
Cl
(R)
(S)
0.04
6.1
NA
Et
Cl
F
rosiglitazone
a
Mean values are shown (n ) 3); SD ( 15%; SPA (scintillation proximity assay);51 TA (chimeric GAL4-hPPAR transactivation assay).52
Absolute stereochemistry of the chiral center at the 2-position of the chromane ring. c Racemic mixture. Not active: <20% activation
b
d
at 10 µM. e Not tested.
Sch em e 3a
Sch em e 4a
a
Reagents: (i) Br(CH)3Br, Cs2CO3, DMF, 65 °C.
chromane carboxylate 11 and the bromides 21-24
(Scheme 3). Bromides 21-24 were prepared from known
phenols 17-20 by forming an ether bond with 1,3-
dibromopropane employing cesium carbonate (Scheme
3).48-50
Compounds 37-40 were synthesized from appropri-
ately substituted chromanes 1d and 11 and the bro-
mides 33-36 (Scheme 4), followed by ester hydrolysis.
Introduction of a halogen atom at the ortho position of
the phenols 29a ,b was performed by electrophilic aro-
matic substitution reactions (Scheme 4). Upon treat-
ment with sulfuryl chloride in toluene at 70 °C, phe-
noxyphenol derivatives 29a,b gave the chloro-substituted
phenols 30 and 31. Introduction of a fluoro group to
phenol 29a was performed using 3,5-dichloro-1-fluoro-
pyridinium triflate, giving 32. These ortho halogen-
substituted phenols were reacted with 1,3-dibromopro-
pane, giving bromides 34-36. Bromide 33 was synthe-
sized from 29a reacting with 1,3-dibromopropane.
a
Reagents: (i) SO2Cl2, diisobutylamine, toluene, 70 °C, or 3,5-
dichloro-1-fluoropyridinium triflate, CH2Cl2-CH3CN (9:1), 0 °C
to room temperature. (ii) Br(CH2)3Br, Cs2CO3, DMF, 65 °C. (iii)
Compounds 1d or 11, Cs2CO3, DMF, 65 °C. (iv) 2N NaOH, iPrOH,
70 °C.
Chiral resolution of the intermediate 41 was ac-
complished by forming a covalent bond with the chiral

3258 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
Koyama et al.
Sch em e 5a
a
i
Reagents: (i) 2N NaOH, PrOH, 70 °C. (ii) (R)-Pantolactone, EDCI, CH2Cl2. (iii) Chromatographic separation. (iv) CH2N2. (v) 10%
Pd/C, H2, EtOH. (vi) Bromide 34 or 35, Cs2CO3, DMF, 65 °C. (vii) (S)-Pantolactone, EDCI, CH2Cl2.
auxiliary (R)-pantolactone, which generated a pair of
chromatographically separable diastereomers (Scheme
5). The ethyl ester group of 41 was hydrolyzed to give
the corresponding carboxylic acid, which was esterified
with (R)-pantolactone using EDCI in dichloromethane
to give a mixture of the (R,R)-isomer 42 and the (R,S)-
isomer 43. These diastereomers were easily separated
by flash chromatography. We decided to determine the
absolute stereochemistry of the pantolactone-ester that
gave the more active final compounds. While this isomer
(which turned out to be 42 afterward) tended to remain
as an oil, replacement of its pantolactone moiety (R-
isomer) with the other enantiomer (S-pantolactone) gave
50 that was found to be highly crystalline (Scheme 5).
By using X-ray crystal analysis, the absolute stereo-
chemistry of the 2-position of the chromane ring of 50
was determined to be (R) relative to the known chiral
center of (S)-pantolactone. On the basis of this finding,
the absolute stereochemistries of 42-49 were assigned
as shown in Scheme 5. After the chiral resolution,
isomers 42 and 43 were individually hydrolyzed, esteri-
fied with diazomethane, and debenzylated to give
compounds 44 and 45, respectively. Chiral intermedi-
ates 44 and 45 were separately recrystallized from
dichloromethane/hexanes to yield prisms, which have
the same rotation value in opposite directions. Chiral
compounds 46-49 were synthesized starting from the
chiral intermediates 44 and 45 as described in Scheme
5.
tors.52 All results were produced in triplicate, and mean
values are reported. Generally, the SAR was directed
based on the results of these two in vitro assays.
Because the high binding affinity for the receptor did
not necessarily translate into significant functional
activity, the binding assay was mainly used as a
primary screen to exclude inactive compounds.
In Vivo. d b/d b Mou se Stu d ies. db/db (leprdb-3J
/
leprdb-3J ) mice were used as a type 2 diabetic animal
model. Male db/db mice at 12-13 weeks of age and
nondiabetic db/+ (lean) mice from J ackson Laboratories
were housed seven mice per cage and fed a rodent chow
(Purina no. 5001) ad libitum with free access to water.
Mice (seven per group) received a once daily oral dosing
of test compounds with vehicle (0.25% methylcellulose)
by oral gavage for 11 days. The blood was collected from
the tail immediately prior to the next dosing at days 0,
4, 7, and 11 for measurement of the plasma glucose
levels.
Ha m ster Lip id Stu d ies. Golden Syrian hamsters
weighing between 120 and 150 g were purchased from
Charles River Laboratories and used for the experi-
ments. Hamsters were housed in boxes (five per box)
and fed a normal rodent chow ad libitum with free
access to water. Hamsters (ten for each group) were
orally dosed with compounds (suspended in 0.5% me-
thylcellulose) for 9 days. On the morning of the 10th
day, hamsters were euthanized with carbon dioxide, and
blood samples were obtained via heart puncture. Serum
cholesterol and triglyceride levels were determined from
the samples.
Biology
In Vitr o. Activities of compounds were evaluated for
both binding affinity and functional activity. First,
binding affinities for the PPARs were measured in a
scintillation proximity assay (SPA).51 Second, potencies
of PPAR gene activation were evaluated in cell-based
transcription assays using GAL4-PPAR chimeric recep-
Dog Lip id Stu d ies. Mature male Beagle dogs weigh-
ing between 12 and 18 kg were purchased from Mar-
shall Farm, PA. They were housed individually and fed
a cholesterol-free chow diet ad libitum with free access
to water. Prior to starting experiments, the dogs (five
for each group) were bled weekly from the jugular vein

PPARR/ γ Antihyperglycemic and Hypolipidemic Agents
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3259
Ta ble 2. Pharmacokinetic Profiles of 46 and 48
and their serum cholesterol levels were determined.
Test compounds were suspended in 0.5% methylcellu-
lose and gavaged daily to the dogs for 2 weeks. Blood
samples were taken during and after the dosing periods,
and serum cholesterol levels were determined.
dose nAUCa,b
Clpa
t1/2
F
a
compd species route (mpk) (µM h) (mL/min/kg)
(h)
(%)
46
48
rat
rat
dog
iv
po
iv
po
iv
po
0.5 5.6 ( 0.2
2.0 2.6 ( 1.4
5.8 ( 0.2
3.4 ( 0.6
3.5 ( 1.2
8.6 ( 1.2
1.2 ( 0.3
43
0.5
10 ( 1.9
4.6 ( 0.8
P h a r m a cok in etic Stu d ies. Male Sprague-Dawley
rats (n ) 3), male adult Beagle dogs (n ) 4), and male
adult Rhesus monkeys (n ) 3) that had been fasted
overnight received an oral gavage dose of 2 mg/kg, or
an intravenous dose of 0.5 mg/kg by bolus injection.
Blood samples were obtained from the femoral arterial
cannula for rat, the jugular vein for dog, and the
saphenous vein for monkey at designated time points
into heparin-containing tubes. The plasma was prepared
immediately by centrifugation, acidified by the addition
of 0.5 M formate buffer, pH 3.0, and stored at -70 °C.
Quantitative analysis was carried out with LC-MS/MS
using the PE Sciex API 3000 triplex quadruple mass
spectrometer.
2.0 4.8 ( 0.6
0.5
2.0 9.2 ( 4.3
0.5
2.0 1.7 ( 0.6
3.7 ( 0.7 48
10 ( 2.0
92
monkey iv
po
3.5 ( 1.7
43
a
b
Mean ( SD (n ) 3 for rat and monkey; n ) 4 for dog). Dose-
normalized AUC.
Ta ble 3. In Vitro Activity of 48 on PPARR and PPARγ of
Human and Preclinical Species
TA EC50 (µM)a
species
R
γ
mouse
hamster
dog
>3
0.15
0.2
0.14
0.17
0.02
0.11
0.04
human
Resu lts a n d Discu ssion
a
Mean values (n ) 3) are shown; SD ( 15%.
Activities of compounds with human PPARs are
summarized in Table 1. Compounds 3-10 belong to the
initial set of compounds synthesized. The effects of
phenol linkage position, tether length, and R-substituent
were investigated. As for the effect of the phenol linkage
position, compounds with a 6-phenol linkage (3-6)
clearly lack in PPARR functional activity as seen in the
transactivation assay results. On the contrary, com-
pounds with a 7-phenol linkage (7-10) have both
PPARγ and PPARR activities, albeit not really potent.
For the tether length, the three-methylene tether (n )
1) seemed to give superior results as compared with the
four-methylene tether (n ) 2) on both PPARγ and
PPARR binding affinities (comparing compounds 7 and
9, 8 and 10). The effect of the R-substituent was not
clear from these data. It was quite encouraging that we
were able to see PPARR/γ dual activity from the very
first set of the compounds prepared. On the basis of
these findings, we decided to take compound 8 as a lead
and continue SAR studies with the 7-phenol linkage and
the three-methylene tether.
We then decided to investigate the effect of the
R-substituent more carefully. From the results of com-
pounds 7, 8, and 14-16, it became clear from the
binding affinity results that there is a desirable range
of size for the R-substituent. While methyl and ethyl
groups showed comparable levels of PPARγ activation,
the ethyl group gave superior PPARR activation. There-
fore, we decided to continue SAR studies primarily with
the ethyl group as the R-substituent.
be significant. In our previous series of PPAR agonists,
the propyl substituent at the R2 position has been
essential for the PPARγ activity.38,50-52 The effect of the
R2 group can be seen when compounds 14 and 37-39
and compounds 8 and 40 are compared. As the size of
the substituent increased, the PPARγ binding affinity
seemed to improve. However, as for the functional
activities, there seemed to be a desirable range of size
for the R2 group. The chlorine substituent at the R2
position gave consistently superior functional activity
for PPARγ as compared with the ones with the propyl
group at the R2 position (14 and 39 and 8 and 40). From
this study, it became clear that the chloro substituent
at the R2 position is optimal for both PPARγ and PPARR
functional activities.
Finally, we decided to examine the effect of chirality.
Chiral resolution was performed on our most potent
compound 39. Compounds 46 and 47 are the (R)- and
(S)-enantiomers of compound 39, respectively. Clearly,
the (R)-enantiomer carries far superior activity. Com-
pounds 48 and 49 were prepared as fluoro-substituted
analogues of 46 and 47 because of the potential me-
tabolism concern that was described earlier. Again, the
more active enantiomer has the (R)-stereochemistry.
Compound 48 showed no appreciable level of activity
in the human PPARδ transactivation assay (25% acti-
vation at 10 µM). Table 2 summarizes the pharmaco-
kinetic profiles of 46 and 48. In rat, compound 48 has a
significantly higher exposure (nAUC ) dose-normalized
AUC), lower clearance (Clp), and longer half-life (t1/2
)
Having optimized structural features for the left side
of the molecule, we then turned our attention to the
right side of the molecule and synthesized compounds
(25-28). We anticipated that the R3 position, para to
the oxygen substituent, might be metabolically vulner-
able. We assumed that it was prudent to block this
position with a substituent that is resistant to metabolic
oxidation. When compounds 14 and 25-28 were com-
pared, it appeared that the spacial requirement for this
position was rather critical; only hydrogen and fluoro
substituents seemed to be tolerated in order to maintain
potent PPARR activity. With respect to the PPARγ
activity, the effect of the R3 substituent did not seem to
than compound 46. Although compound 46 has slightly
better in vitro activities than 48, we opted for 48 because
of its superior pharmacokinetic profile. Pharmacokinetic
profiles and in vitro PPAR activities of compound 48 in
other experimental animal species are listed in Tables
2 and 3. We were pleased to find that compound 48 has
desirable pharmacokinetic profiles and in vitro activities
also in dogs and rhesus monkeys.
Having optimized the in vitro activities, we then
decided to test our most potent compound in the db/db
mouse type 2 diabetes model. The db/db mouse is an
obese animal model of type 2 diabetes and is character-
ized by severe insulin resistance and marked hyper-

3260 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
Koyama et al.
PPARR and PPARγ activities into one structure. Sys-
tematic SAR studies directed toward selective PPARR/γ
dual agonism culminated in the discovery of compound
48, which exhibited comparable antihyperglycemic ac-
tivities to rosiglitazone in the db/db mouse type 2
diabetes animal model studies. In addition, the lipid-
lowering activities of compound 48 were amply demon-
strated in a Syrian hamster model and a dog model.
Unlike the currently marketed glitazone class of an-
tidiabetic drugs, compound 48 is a single enantiomer
that is not vulnerable to racemization. To date, the
clinical utility of PPARγ and PPARR agonists has been
proven separately by the glitazones and the fibrates,
respectively. However, the general strategy of treating
type 2 diabetes and dyslipidemia through the use of
PPARR/γ dual agonists and the ideal balance of PPARR
and PPARγ activities have yet to be validated in the
clinic. Compound 48 is one such PPARR/γ dual agonist
that could demonstrate the viability of this approach.
It is hoped that the PPARR/γ dual activation strategy
will provide a comprehensive treatment for type 2
diabetes and dyslipidemia.
F igu r e 2. In vivo activity of PPARR/γ dual agonist 48 in db/
db mice. Time course of antihyperglycemic activity. Lean mice
(n ) 7) and db/db mice (n ) 7) received a once daily dosing of
48 or rosiglitazone by oral gavage with vehicle. Blood glucose
levels were measured 24 h after dosing on the preceding day.
The figure plots the mean value ( SD.
Ta ble 4. Effects of 48 on Serum Cholesterol and Triglyceride
in Hamster
dose cholesterola change triglyceridea change
treatment (mpk)
(mg/dL)
(%)
(mg/dL)
(%)
vehicle
fenofibrate 100
48
48
108 ( 5
67 ( 3
85 ( 3
65 ( 2
305 ( 17
161 ( 4
222 ( 18
159 ( 9
Exp er im en ta l Section
-38b
-21b
-40b
-44b
-27b
-48b
Gen er a l. All commercial chemicals and solvents are reagent
grade and were used without further purification unless
otherwise specified. All reactions except those in aqueous
media were carried out under nitrogen atmosphere. Chro-
matographic purification was performed using flash chroma-
tography techniques and silica gel (E. Merck 230-400 mesh).
The following solvents were abbreviated: tetrahydrofuran
(THF), ethyl acetate (AcOEt), and methyl-tert-butyl-ether
(MTBE). 1H NMR spectra were measured using Varian Unity
INOVA 500 MHz instrument. Chemical shifts were reported
in parts per million (ppm, δ units) using tetramethylsilane as
an internal standard. The mass spectrum was measured in
the positive ion mode using HP1100 and micromass ZMD
instruments (LC-MS system). Elemental analyses were ob-
tained from Robertson Microlit Laboratories (Madison, NJ ).
Gen er a l P r oced u r e for th e Syn th esis of 3-10, 14-16,
25-28, a n d 37-40. To a DMF solution of ethyl-6 (or -7)-
hydroxy-chromane-carboxylate (1a -d or 11-13) (1.0 equiv)
and the bromide (2a ,b, 21-24, or 33-36) (1.1 equiv) was
added cesium carbonate (1.2 equiv). The resulting suspension
was heated to 65 °C for 5 h. The reaction mixture was diluted
with MTBE and water. The organic layer was separated. The
aqueous layer was extracted twice with MTBE. The combined
organic layers were dried over anhydrous sodium sulfate,
filtered, concentrated under reduced pressure, and chromato-
graphed on silica gel eluting with a gradient mixture of AcOEt/
hexanes to give the corresponding ether product. This product
was dissolved in 2-propanol-2 N NaOH(aq) (3:1 v/v) and
heated to 70 °C overnight. After most of the solvent was
removed under reduced pressure, the residue was diluted with
AcOEt and 2 N HCl(aq). The organic layer was separated. The
aqueous layer was extracted twice with AcOEt. The combined
organic layers were dried over anhydrous sodium sulfate,
filtered, and concentrated to give the title compound (70-95%
yield).
3
10
a
b
Mean ( SD (n ) 10). p < 0.01 vs vehicle control.
Ta ble 5. Effect of 48 on Serum Cholesterol in Doga
treatment
dose (mpk)
change (%)
fenofibrate
48
48
50
1
3
-16.3b
-23.3b
-31.6b
a
b
Mean values are shown (n ) 5). p < 0.05 vs vehicle control.
triglyceridemia. The in vivo antihyperglycemic activity
of 48 is depicted in Figure 2. Compound 48 exhibited
robust serum glucose level lowering in a dose-dependent
manner that was comparable to rosiglitazone. Antihy-
perglycemic activity of 48 in the db/db mouse is mainly
driven by its PPARγ activity because 48 does not have
significant activity on mouse PPARR. In addition, the
lipid-lowering activity of 48 was assessed in two animal
models: a Syrian hamster model and a dog model. The
results are summarized in Tables 4 and 5. In the
hamster model, compound 48 at 10 mpk caused com-
parable levels of cholesterol and triglyceride lowering
with fenofibrate treatment at 100 mpk. In the dog
studies, compound 48 achieved superior cholesterol
lowering to fenofibrate even at significantly lower doses.
Importantly, compound 48 was tested against other
nuclear receptors and was found to be inactive in GAL4
assays for the following receptors: no activation of
hLXRR, hLXRâ, RXR, or PXR at concentrations up to
10 µM. In addition, no binding to hERR, hERâ, FXR,
hTRâ, and hGR at concentrations up to 10 µM was
observed.
6-{3-[2-P r opyl-4-ph en oxyph en oxy]p r opoxy}ch r om a n e-
1
2-ca r boxylic Acid (3). H NMR (500 MHz, CD3OD): δ 7.27
(m, 2H), 7.01 (t, 1H, J ) 7.4 Hz), 6.89 (m, 3H), 6.77 (m, 3H),
6.69 (dd, 1H, J ) 2.8, J ) 8.8 Hz), 6.63 (d, 1H, J ) 2.8 Hz),
4.62 (m, 1H), 4.13 (m, 4H), 2.82 (m, 1H), 2.72 (m, 1H), 2.55
(m, 2H), 2.25 (m, 1H), 2.22 (p, 2H, J ) 6 Hz), 2.01 (m, 1H),
1.55 (sext, 2H, J ) 7.5), 0.89 (t, 3H, J ) 7.3). MS: m/e ) 463
(M + 1). Anal. (C28H30O6) C, H.
Con clu sion
We have identified a series of structurally novel
antidiabetic (2R)-chromane-2-carboxylic acids as potent
PPARR/γ dual agonists. By combining the cyclized
fibrate concept and the side chains from our previous
studies, we were able to successfully incorporate both
Gen er a l P r oced u r e of th e Ester -En ola te Alk yla tion for
th e Syn th esis of (1d a n d 11-13). The synthesis of 11 is
described below. Compounds 1d , 12, and 13 were synthesized

PPARR/ γ Antihyperglycemic and Hypolipidemic Agents
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3261
following a similar procedure that employs the appropriate
alkyliodide instead of iodoethane in step B.
small amount (5%) of an elimination product (3-[2-propyl-4-
phenoxyphenoxy]-1-propene).
3-[2-P r op yl-4-(4-flu or op h en oxy)p h en oxy]-1-br om op r o-
p a n e (21). H NMR (500 MHz, CDCl3): δ 7.03-6.99 (m, 2H),
Eth yl 2-Eth yl-7-h yd r oxych r om a n e-2-ca r boxyla te (11).
Step A: Eth yl 7-Ben zyloxych r om a n e-2-ca r boxyla te. To
a 5 L acetone solution of ethyl 7-hydroxy-chromane-2-carboxy-
late (630.1 g, 2.84 mol) were added potassium carbonate
powder (785 g, 5.68 mol) and benzyl bromide (405 mL, 3.41
mol). The resulting suspension was heated to reflux for 16 h.
The reaction mixture was filtered through a pad of Celite. The
filtrate was concentrated to give solid material, which was
redissolved in AcOEt, washed with water to remove residual
salt, dried over anhydrous magnesium sulfate, filtered, and
concentrated to a small volume. The addition of hexanes
caused precipitation of the title compound, which was collected
by suction-filtration. The filtrate was triturated from dichloro-
methane/hexanes to give more precipitates. Finally, the filtrate
was concentrated and then chromatographed on silica gel,
eluting with a gradient mixture of 20-80% dichloromethane/
hexanes. The combination of all of the crops yielded the title
1
6.95-6.92 (m, 2H), 6.86-6.79 (m, 3H), 4.11 (t, 2H, J ) 5.8
Hz), 3.66 (t, 2H, J ) 5.8 Hz), 2.58 (t, 2H, J ) 7.8 Hz), 2.37 (q,
2H, J ) 5.8 Hz), 1.60 (m, 2H), 0.96 (t, 3H, J ) 7.3 Hz).
2-Ch lor o-4-p h en oxyp h en ol (30). A 54 mL toluene solu-
tion of 4-phenoxyphenol (2.0 g, 107 mmol) and diisobutylamine
(0.15 mL, 0.86 mmol) was heated to 70 °C. To it was added
sulfuryl chloride (0.69 mL, 8.6 mmol) over 2 h. The reaction
mixture was stirred for 1 h after the addition was complete.
Then, the reaction mixture was concentrated and diluted in
AcOEt and saturated aqueous sodium bicarbonate solution.
The organic layer was separated. The aqueous layer was
extracted twice with AcOEt. The combined organic layer was
dried over anhydrous sodium sulfate, filtered, concentrated,
and chromatographed on silica gel. Elution with 15% AcOEt/
hexanes gave the title compound as a pale yellow syrup (2.3
1
1
compound 760.2 g as an off-white solid (86%). H NMR (500
g, 97%). H NMR (500 MHz, CDCl3): δ 7.35 (m, 2H), 7.12 (m,
MHz, CDCl3): δ 7.33-7.46 (m, 5H), 6.96 (d, 1H), 6.621 (d, 1H),
6.58 (dd, 1H), 5.05 (s, 2H), 4.72 (q, 1H), 4.29 (q, 2H), 2.69-
2.84 (m, 2H), 2.29 (m, 1H), 2.21 (m, 1H), 1.33 (t, 3H).
1H), 7.06 (d, 1H), 7.02 (d, 1H), 6.99 (d, 2H), 6.92 (dd, 1H), 5.69
(s, 1H). Anal. (C12H9O2Cl1) C, H, Cl.
2-Ch lor o-4-(4-flu or op h en oxy)p h en ol (31). This com-
pound was prepared from 4-(4-fluorophenoxy)phenol according
to a procedure similar to the one used for the synthesis of
compound 30. 1H NMR (500 MHz, CDCl3): δ 7.06-7.00 (m,
4H), 6.98-6.94 (m, 2H), 6.88 (app. q. 1H), 5.40 (s, 1H).
2-F lu or o-4-p h en oxyp h en ol (32). To a 250 mL dichlo-
romethane solution of 4-phenoxyphenol (2.0 g, 10.7 mmol) was
added 3,5-dichloro-1-fluoro-pyridinium triflate (4.14 g, 13.1
mmol). After the mixture was heated to reflux for 1 h, the
solvent was removed. The residue was diluted with AcOEt and
saturated aqueous sodium bicarbonate solution. The organic
layer was separated, dried over anhydrous sodium sulfate,
filtered, concentrated, and chromatographed on silica gel.
Elution with 10% MTBE/hexanes gave 312 mg of the title
Step B: Eth yl 7-Ben zyloxy-2-eth ylch r om a n e-2-ca r -
boxyla te. To a 320 mL anhydrous THF solution of ethyl
7-benzyloxychromane-2-carboxyate (14.6 g, 46.6 mmol) was
added hexamethylphosphoramide (distitilled from CaH2) (10.5
mL, 60.4 mmol). After the mixture was cooled in a dry ice-
acetone bath, sodium bis(trimethylsilyl)amide (1.0 M/THF)
(60.5 mL, 60.5 mmol) was added via syringe over a 15 min
period. The resulting orange solution was stirred at that
temperature for 30 min before iodoethane (18.6 mL, 233 mmol)
was added via syringe. The reaction was slowly warmed to
room temperature and stirred overnight. The solvent was
removed under reduced pressure, and the residue was diluted
with AcOEt and aqueous ammonium chloride (NH4Cl 7.2 g/200
mL water). The organic layer was separated, and the aqueous
layer was extracted with AcOEt twice. The combined organic
layers were dried over anhydrous sodium sulfate, filtered,
concentrated, and chromatographed on silica gel eluting with
7.5% AcOEt/hexanes to give the title compound 15.2 g (96%).
1H NMR (500 MHz, CDCl3): δ 7.35 (m, 4H), 7.30 (m, 1H), 6.89
(d, 1H, J ) 8.3 Hz), 6.53 (d, 1H, J ) 2.6 Hz), 6.45 (dd, 1H, J
) 2.5 Hz, 8.2 Hz), 4.54 (s, 2H), 4.19 (m, 2H), 4.07 (m, 2H),
3.67 (t, 2H, J ) 6.3 Hz), 2.66-2.61 (m, 2H), 2.33 (m, 1H), 2.09
(p, 2H, J ) 6.2 Hz), 2.00 (m, 1H), 1.91 (m, 2H), 1.23 (t, 3H J
) 7.1 Hz), 1.04 (t, 3H, J ) 7.4 Hz). MS m/e ) 341 (M + 1).
1
compound as a pale yellow oil. H NMR (500 MHz, CDCl3): δ
7.34 (m, 2H), 7.11 (m, 1H), 6.98 (m, 3H), 6.82 (dd, 1H), 6.76
(m, 1H), 5.00 (s, 1H).
Op tica l Resolu tion of Eth yl 7-Ben zyloxy-2-eth ylch r o-
m a n e-2-ca r boxyla te (41). (2R)-Meth yl 2-Eth yl-7-h yd r oxy-
ch r om a n e-2-ca r boxyla te (44). Step A: 7-Ben zyloxy-2-
eth ylch r om a n e-2-ca r boxylic Acid . To a 2 L 2-propanol
solution of ethyl 7-benzyloxy-2-ethylchromane-2-carboxylate
(41) (155 g, 0.455 mol) was added 1 L of aqueous 5 N sodium
hydroxide. This solution was heated to 70 °C overnight.
2-Propanol was removed under reduced pressure. The residue
was acidified with 300 mL of concentrated hydrochloric acid
and 2 N hydrochloric acid to pH 1. The acidic solution was
extracted three times with AcOEt. The combined organic
layers were dried over anhydrous sodium sulfate, filtered, and
concentrated to give a yellow oil, which crystallized upon
standing (130 g, 91%).
Step B: Resolu tion of th e Ra cem a te. (1) Ester F or m a -
tion w ith (R)-P a n tola cton e. To a 1.1 L dichloromethane
solution of 7-benzyloxy-2-ethylchromane-2-carboxylic acid (75
g, 0.24 mol) and (R)-pantolactone (100 g, 0.768 mol) were added
EDCI (55.5 g, 0.289 mol) and 4-(dimethylamino)pyridine (6.4
g, 0.054 mol). This solution was stirred at room temperature
overnight. The solvent was removed under reduced pressure.
The residue was diluted with AcOEt, washed with water and
brine, dried over anhydrous magnesium sulfate, filtered, and
concentrated to give a yellow oil (137 g, crude).
Step C: Eth yl 7-Hyd r oxy-2-eth ylch r om a n e-2-ca r boxy-
la te (11). To a 5 mL ethanol solution of ethyl 7-benzyloxy-2-
ethylchromane-2-carboxylate (228 mg, 0.67 mmol) were added
0.25 mL of water and 10 mg of 10% Pd/C. The resulting
suspension was placed in a Parr shaker and hydrogenated
under hydrogen atmosphere at 50 psi overnight. The reaction
suspension was then filtered through a pad of Celite, concen-
trated, and chromatographed on silica gel. Elution with a
gradient mixture of 20-30% AcOEt/hexanes gave the title
1
compound (166 mg, quant.) as a clear oil. H NMR (500 MHz,
CDCl3): δ 6.87 (d, 1H, J ) 8 Hz), 6.47 (d, 1H, J ) 2.8 Hz),
6.38 (dd, 1H, J ) 2.8 Hz, 8 Hz), 4.99 (brs, 1H), 4.20 (m, 2H),
2.65 (m, 2H), 2.32 (m, 1H), 2.05-1.85 (m, 4H), 1.24 (t, 3H, J
) 7 Hz), 1.04 (t, 3H, J ) 7 Hz). MS m/e ) 251 (M + 1). Anal.
(C14H18O4) C, H.
Gen er a l P r oced u r e for th e Syn th esis of 21-24 a n d 33-
36. To a DMF solution (0.2 M based on the phenol) of the
phenol (17-20 and 30-32) (1.0 equiv) and 1,3-dibromopropane
(5.0 equiv) was added cesium carbonate (1.3 equiv). The
resulting suspension was heated to 65 °C overnight. The
reaction mixture was diluted with AcOEt and water. The
organic layer was separated. The aqueous layer was extracted
twice with AcOEt. The combined organic layers were dried
over anhydrous sodium sulfate, filtered, concentrated, and
chromatographed on silica gel. Elution with a gradient mixture
of AcOEt/hexanes or MTBE/hexanes yielded the title com-
pounds (yield 70-90%). Generally, the product contained a
(2) Ch r om a togr a p h ic Sep a r a tion of th e Dia ster eo-
m er s. The crude ester obtained as described above was
dissolved in hexanes and a small amount of dichloromethane
and then charged on a silica gel column. Elution with 10%
THF/hexanes (48 Ls), 12.5% THF/hexanes (64 Ls), and 25%
AcOEt/hexanes (4 Ls) gave the faster eluting 42 (R,R)-isomer
(30.4 g, 30%) as a thick colorless oil, the more slowly eluting
43 (R,S)-isomer (34.5 g, 34%) as a white solid, and a mixture
of the diastereomers (7 g, 7%) as a yellow oil.
Com p ou n d 42. (R,R)-Isom er . 1H NMR (500 MHz,
CDCl3): δ 7.49 (m, 2H), 7.44 (m, 2H), 7.33 (m, 1H), 6.93 (d,

3262 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
Koyama et al.
1H, J ) 8.5 Hz), 6.61 (d, 1H, J ) 2.5 Hz), 6.55 (dd, 1H, J )
2.6, 8.4 Hz), 5.35 (s, 1H), 5.05 (s, 2H), 4.00 (s, 2H), 2.75 (m,
2H), 2.45 (m, 1H), 2.10 (m, 1H), 1.95 (m, 2H), 1.31 (t, 3H, J )
7.5 Hz), 1.03 (s, 3H), 0.87 (s, 3H).
Com p ou n d 43. (R,S)-Isom er . 1H NMR (500 MHz,
CDCl3): δ 7.44 (m, 2H), 7.39 (m, 2H), 7.33 (m, 1H), 6.93 (d,
1H, J ) 8.5 Hz), 6.59 (1H, J ) 2.5 Hz), 6.54 (dd, 1H, J ) 2.6,
8.4 Hz), 5.35 (s, 1H), 5.05 (s, 2H), 4.0 (s, 2H), 2.75 (m, 2H),
2.35 (m, 1H), 2.10 (m, 1H), 2.00 (m, 2H), 1.20 (s, 3H), 1.12 (t,
3H, J ) 7.5 Hz), 1.03 (s, 3H).
(aq). The organic layer was separated. The aqueous layer was
extracted twice with AcOEt. The combined organic layers were
dried over anhydrous sodium sulfate, filtered, and concen-
trated to give the title compound as a pale yellow oil (4.48 g).
1H NMR (500 MHz, CDCl3): δ 7.34 (m, 2H), 7.09 (m, 2H),
6.99-6.89 (m, 5H), 6.54 (d, 1H, J ) 2 Hz), 6.51 (dd, 1H, J )
1.6, 8.2 Hz), 4.20 (t, 2H, J ) 6 Hz), 4.19 (t, 2H, J ) 5.9 Hz),
2.71 (m, 2H), 2.30 (m, 1H), 2.30 (p, 2H, J ) 6 Hz), 2.05-1.90
(m, 3H), 1.06 (t, 3H, J ) 7.4 Hz). MS: m/e ) 483 (M + 1).
Anal. (C27H27O6Cl1) C, H, Cl.
(2S)-7-[3-(2-Ch lor o-4-p h en oxyp h en oxy)p r op oxy]-2-eth -
ylch r om a n e-2-ca r b oxylic Acid (47). 1H NMR (500 MHz,
CDCl3): δ 7.34 (m, 2H), 7.09 (m, 2H), 6.99-6.89 (m, 5H), 6.54
(d, 1H, J ) 2 Hz), 6.51 (dd, 1H, J ) 1.6, 8.2 Hz), 4.20 (t, 2H,
J ) 6 Hz), 4.19 (t, 2H, J ) 5.9 Hz), 2.71 (m, 2H), 2.3 (m, 1H),
2.30 (p, 2H, J ) 6 Hz), 2.05-1.90 (m, 3H), 1.06 (t, 3H, J ) 7.4
Hz). MS: m/e ) 483 (M + 1). Anal. (C27H27O6Cl1) C, H, Cl.
Step C: (2R)-Meth yl 2-Eth yl-7-h yd r oxych r om a n e-2-
ca r boxyla te (44). To a 250 mL round-bottomed flask were
added the 42 (R,R) ester (5.07 g, 11.9 mmol) obtained as
described in step B, 50 mL of 2-propanol, and 50 mL of aqueous
2.5 N sodium hydroxide. This solution was heated to 65 °C
overnight. 2-Propanol was removed under reduced pressure.
The residue was acidified to pH 1 with 2 N hydrochloric acid
and then extracted with AcOEt three times. The combined
organic layers were dried over anhydrous sodium sulfate,
filtered, and concentrated to give a thick oil. This crude product
was dissolved in dichloromethane and treated with diazo-
methane ethereal solution. After the gas evolution ceased, the
solution was concentrated and the resulting oil was chromato-
graphed on silica gel. Elution with a gradient mixture of 10-
12.5% AcOEt/hexanes gave the corresponding methyl ester.
Then, the methyl ester was dissolved in 200 mL of ethanol
and 6 mL of water, combined with 200 mg of 10% Pd/C, placed
in a Parr shaker, and hydrogenated (H2, 50 psi) overnight. The
catalyst was removed by suction-filtration through a pad of
Celite. The filtrate was concentrated and chromatographed on
silica gel using gradient elution 20-30% AcOEt/hexanes to
give 2.75 g of the title compound (97%). Recrystallization from
dichloromethane/hexanes gave prisms; mp 98.0-98.5 °C. 1H
NMR (500 MHz, CDCl3): δ 6.8 (d, 1H, J ) 8.2 Hz), 6.45 (d,
1H, J ) 2.6), 6.38 (dd, 1H, J ) 2.5, J ) 8.0 Hz), 3.73 (s, 3H),
2.59-2.66 (m, 2H), 2.33 (m, 1H), 1.99 (sext, 1H), 1.91 (m, 2H),
(2R)-7-{3-(2-Ch lor o-4-(4-flu or op h en oxy)p h en oxy]p r o-
1
p oxy}-2-eth ylch r om a n e-2-ca r boxylic Acid (48). H NMR
(500 MHz, CDCl3): δ 7.05-7.01 (m, 2H), 6.97-6.9 (m, 5H),
6.86 (dd, 1H J ) 3, J ) 8.9 Hz), 6.55-6.51 (m, 2H), 4.20 (m,
4H), 2.70 (m, 2H), 2.32 (m, 1H), 2.30 (p, 2H, J ) 6 Hz), 2.00
(m, 2H), 1.93 (m, 1H), 1.06 (t, 3H, J ) 7.3 Hz). MS: m/e ) 501
20
(M + 1). [R]D +59.3 (c ) 1, MeOH) Anal. (C27H26O6F1Cl1) C,
H, F, Cl.
(2S)-7-{3-(2-Ch lor o-4-(4-flu or op h en oxy)p h en oxy]p r o-
1
p oxy}-2-eth ylch r om a n e-2-ca r boxylic Acid (49). H NMR
(500 MHz, CDCl3): δ 7.05-7.01 (m, 2H), 6.97-6.90 (m, 5H),
6.86 (dd, 1H J ) 3, J ) 8.9 Hz), 6.55-6.51 (m, 2H), 4.20 (m,
4H), 2.70 (m, 2H), 2.32 (m, 1H), 2.30 (p, 2H, J ) 6 Hz), 2.00
(m, 2H), 1.93 (m, 1H), 1.06 (t, 3H, J ) 7.3 Hz). MS: m/e ) 501
(M + 1). Anal. (C27H26O6F1Cl1) C, H, F, Cl.
Ack n ow led gm en t. We gratefully acknowledge Mr.
J oseph F. Leone and Drs. Gerard R. Kiecykowski and
Philip Eskola of Synthetic Services Group for large scale
synthetic support. We also thank Dr. Richard G. Ball
and Mrs. Nancy Tsou for the X-ray crystallographic
analysis, and Drs. J ohn G. Menke, Monica Einstein,
William P. Feeney, and Susan A. Iliff for biological
evaluation of compounds.
20
1.04 (t, 3H). MS: m/e ) 237 (M + 1). [R]D +106.6 (c ) 1,
MeOH). Anal. (C13H16O4) C, H.
(2S)-Met h yl 2-E t h yl-7-h yd r oxych r om a n e-2-ca r b oxy-
la te (45). Following the same procedure as compound 44, the
title compound was synthesized from the 43 (R,S)-isomer.
Recrystallization from dichloromethane/hexanes gave prisms;
1
mp 98.0-98.5 °C. H NMR (500 MHz, CDCl3): δ 6.8 (d, 1H, J
) 8.2 Hz), 6.45 (d, 1H, J ) 2.6), 6.38 (dd, 1H, J ) 2.5, J ) 8.0
Hz), 3.73 (s, 3H), 2.59-2.66 (m, 2H), 2.33 (m, 1H), 1.99 (sext,
Su p p or tin g In for m a tion Ava ila ble: NMR spectral data
and results of elemental analysis for all final compounds not
included in the Experimental Section and the X-ray crystal-
lographic data of compound 50. This material is available free
of charge via the Internet at http://pubs.acs.org.
20
1H), 1.91 (m, 2H), 1.04 (t, 3H). MS: m/e ) 237 (M + 1). [R]D
-108.6 (c ) 1, MeOH). Anal. (C13H16O4) C, H.
Deter m in a tion of Absolu te Ster eoch em istr y. Com -
p ou n d 50. (S,R)-Isom er . Com p ou n d 42. The (R,R)-isomer
was treated as described in steps A and C in the procedure as
described above and yielded 50 (S,R)-isomer. Compound 50
was recrystalized from 2-propanol-water to give crystals
suitable from single X-ray crystallographic analysis. The
absolute stereochemistry of 50 was determined to be (R)
relative to the known chiral center of (S)-pantolactone. An
ORTEP structure drawing and coordinates are included in the
Supporting Information.
(2R)-7-[3-(2-Ch lor o-4-ph en oxyph en oxy)p r op oxy]-2-eth -
ylch r om a n e-2-ca r boxylic Acid (46). To an 80 mL DMF
solution of (2R)-methyl 2-ethyl-7-hydroxychromane-2-carboxy-
late (44) (2.71 g, 11.5 mmol) and 3-(2-chloro-4-phenoxyphe-
noxy)-1-bromopropane (34) (4.4 g, 13.0 mmol) was added
cesium carbonate (4.1 g, 12.6 mmol). The resulting suspension
was stirred at 65 °C for 5 h. The reaction mixture was diluted
in MTBE and water. The organic layer was separated. The
aqueous layer was extracted twice with MTBE. The combined
organic layers were dried over anhydrous sodium sulfate,
filtered, concentrated, and chromatographed on silica gel.
Elution with 15% AcOEt/hexanes yielded the methyl ester of
the title compound as a pale yellow oil (5.1 g). This material
was dissolved in 175 mL of 2-propanol and 94 mL of 1 N
NaOH(aq). The resulting solution was heated to 70 °C for
overnight. Then, the solvent was removed under reduced
pressure. The residue was dissolved in AcOEt and 2 N HCl-
Refer en ces
(1) Moller, D. E. New drug targets for type 2 diabetes and the
metabolic syndrome. Nature 2001, 414, 821-827.
(2) Saltiel, A. R. New perspective into the molecular pathogenesis
and treatment of type 2 Diabetes. Cell 2001, 104, 517-529.
(3) Cobb, J .; Dukes, L. Recent advances in the development of agents
for the treatment of type 2 diabetes. Annu. Rep. Med. Chem.
1998, 33, 213-222.
(4) American Diabetes Association. Economic cost of diabetes in the
U.S. in 2002. Diabetes Care 2003, 26, 917-932.
(5) Hulin, B.; McCarthy, P. A.; Gibbs, E. M. The glitazone family of
antidiabetic agents. Curr. Pharm. Des. 1996, 2, 85-102.
(6) Combs, T. P.; Wagner, J . A.; Berger, J . P.; Doebber, T. W.; Wang,
W. J .; Zhang, B. B.; Tanem, M.; Berg, A. H.; O’Rahilly, S.;
Savage, D. B.; Chatterjee, K.; Weiss, S.; Larson, P. J .; Gottes-
diener, K. M.; Gertz, B. J .; Charron, M. J .; Scherer, P. E.; Moller,
D. E. Induction of adipocyte complement-related protein of 30
kDa by PPARgamma agonists: A potential mechanism of insulin
sensitization. Endocrinology 2002, 143, 998-1007.
(7) Ibrahimi, A.; Teboul, L.; Gaillard, D.; Amri, E. Z.; Ailhaud, G.;
Young, P.; Cawthorne, M. A.; Grimaldi, P. A. Evidence for a
common mechanism of action for fatty acids and thiazolidinedi-
one antidiabetic agents on gene expression in preadipose cells.
Mol. Pharmacol. 1994, 46, 1070-1070.
(8) Tontonoz, P.; Hu, E.; Spiegelman, B. M. Stimulation of adipo-
genesis in fibroblasts by PPARγ2, a lipid activated transcription
factor. Cell 1994, 79, 1147-1156.

PPARR/ γ Antihyperglycemic and Hypolipidemic Agents
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3263
(9) Lehmann, J . M.; Moore, L. B.; Smith-Oliver, T. A.; Wilkinson,
W. O.; Willson, T. M.; Kliewer, S. A. An antidiabetic thiazo-
lidinedione is a high affinity ligand for peroxisome proliferator-
activated receptor γ (PPARγ). J . Biol. Chem. 1995, 270, 12953-
12956.
(10) Willson, T. M.; Brown, P. T.; Sternbach, D. D.; Henke, B. R. The
PPARs: From orphan receptors to drug discovery. J . Med. Chem.
2000, 43, 527-550.
(11) Berger, J . P.; Moller, D. E. The mechanisms of action of PPARs.
Annu. Rev. Med. 2002, 53, 409-435.
(12) Francis, G. A.; Fayard, E.; Picard, F.; Auwerx, J . Nuclear
receptors and the control of metabolism. Annu. Rev. Physiol.
2003, 65, 261-311.
(13) Kersten, S.; Desvergne, B.; Wahli, W. Roles of PPARs in health
and disease. Nature 2000, 405, 421-424.
(14) Desvergne, B.; Wahli, W. Peroxisome Proliferator-Activated
Receptors: Nuclear control of metabolism. Endocr. Rev. 1999,
20, 649-688.
(15) Issemann, I.; Green, S. Activation of a member of the steroid
hormone receptor superfamily by peroxisome proliferators.
Nature 1990, 347, 645-650.
(16) Auwerx, J . PPARγ, the ultimate thrifty gene. Diabetolotgia 1999,
42, 1033-1049.
(17) Martin, G.; Schoonjans, K.; Staels, B.; Auwerx, J . PPAR activa-
tors improve glucose homeostasis by stimulating fatty acid
uptake in the adipocytes. Atherosclerosis 1998, 137 (Suppl.),
S75-S80.
(34) Cheng, P. T.; Chandrasena, G.; Chen, S. BMS-298585 is a novel,
uniquely balanced dual activator of peroxisome proliferator-
activated receptors (PPAR) alpha and gamma, with an excellent
ADME profile. Diabetes 2002, 51 (Suppl. 2), A94.
(35) Lohray, B. B.; Lohray, V. B.; Bajji, A. C.; Kalchar, S.; Poondra,
R. R.; Padakanti, S.; Chakrabarti, R.; Vikramadithyan, R. K.;
Misra, P.; J uluri, S.; Mamidi, N. V. S. R.; Rajagopalan, R. (-)3-
[4-[2-Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic Acid-
[(-)DRF2725]: A dual PPAR agonist with potent antihyperg-
lycemic and lipid modulating activity. J . Med. Chem. 2001, 44,
2675-2678.
(36) Brooks, D. A.; Etgen, G. J .; Rito, C. J .; Shuker, A. J .; Dominianni,
S. J .; Warshawsky, A. W.; Ardecky, R.; Paterniti, J . R.; Tyhonas,
J .; Broderick, C. L.; Oldham, B. A.; Montrose-Rafizadeh, C.;
Winneroski, L. L.; Faul, M. M.; McCarthy, J . R. Design and
synthesis of 2-methyl-2-{4-[2-(5-methyl-2-aryloxazol-4-yl)ethoxy]-
phenoxy}propionic acids: A new class of dual PPARR/γ agonists.
J . Med. Chem. 2001, 44, 2061-2064.
(37) Sauerberg, P.; Pettersson, I.; J eppesen, L.; Bury, P. S.; Mor-
gensen, J . P.; Wassermann, K.; Brand, C. L.; Sturis, J .; Woldike,
H. F.; Fleckner, J .; Andersen, A. T.; Mortensen, S. B.; Svensson,
l. A.; Rasmussen, H. B.; Lehmann, S. V.; Polivka, Z.; Sindelar,
K.; Panajotova, V.; Ynddal, L.; Wulff, E. M. Novel tricyclic-R-
alkoxyphenylpropionic acids: Dual PPARR/γ agonists with
hypolipidemic and antidiabetic Activity. J . Med. Chem. 2002,
45, 789-804.
(38) Desai, R. C.; Han, W.; Metzger, E. J .; Bergman, J . P.; Gratale,
D. F.; MacNaul, K. L.; Berger, J . P.; Doebber, T. W.; Leung, K.;
Moller, D. E.; Heck J . V.; Sahoo, S. P. 5-Arylthiazolidine-2,4-
diones: Discovery of PPAR dual R/γ agonists as antidiabetic
agents. Bioorg. Med. Chem. Lett. 2003, 13, 2795-2789.
(39) Adams, A. D.; Hu, Z.; von Langen, D.; Dadiz, A.; Elbrecht, A.;
MacNaul, K. L.; Berger, J . P.; Doebber, T. W.; Meurer, R.;
Forrest, M. J .; Moller, D. E.; J ones, A. B. O-Arylmandelic acids
as highly selective human PPARR/γ agonists. Bioorg. Med.
Chem. Lett. 2003, 13, 3185-3190.
(40) Miller, A. R.; Etgen, G. J . Novel peroxisome proliferators-
activated receptor ligands for type 2 diabetes and the metabolic
syndrome. Exp. Opin. Invest. Drugs 2003, 12 (9), 1439.
(41) Parks, D. K.; Tomkinson, N. C. O.; Villeneuve, M. S.; Blanchard,
S. G.; Willson, T. M. Differential activity of rosiglitazone
enantiomers at PPARγ. Bioorg. Med. Chem. Lett. 1998, 8, 3657-
3658.
(42) Sohda, T.; Mizuno, K.; Kawamatsu, Y. Studies on antidiabetic
agents. VI. Asymmetric transformation of (()-5-[4-(1-methylcy-
clohexylmethoxy)benzyl]-2,4-thiazolidinedione(ciglitazone) with
optically active benzylamines. Chem. Pharm. Bull. 1984, 32,
4460-4465.
(43) Witiak, D. T.; Stratford, E. S.; Nazareth, R.; Wagner, G.; Feller,
D. R. 6-Chlorochroman-2-carboxylic acids: Synthesis and bio-
logical evaluation as antagonists for cholesterol biosynthesis and
lipolysis in vitro. J . Med. Chem. 1971, 14, 758-766.
(44) Loiodice, F.; Longo, A.; Bianco, P.; Tortorella, V. 6-Chloro-2,3-
dihydro-4H-1-benzopyran carboxylic acids: Synthesis, optical
resolution and absolute configuration. Tetrahedron Asymmetry
1995, 6, 1001-1011.
(45) Barker, G.; Ellis, G. P. Benzopyranones. Part I. 6-Amino, and
6-hydroxy-2-substituted chromone. J . Chem. Soc. C, 1970, 2230.
(46) Shitara, H.; Aoki, Y.; Nohira, H. Synthesis of optically active
2-methylchroman derivatives and application to chiral dopants
for nematic liquid crystals. Bull. Chem. Soc. J pn. 2000, 73, 259.
(47) Fitton, A. O.; Hatton, B. T. Pharmacologically active 4-oxo-4H-
chromen-2-carboxylic acids. Part 11. The synthesis of 4-oxo-4H-
chromene-2-carboxylic acids containing a fused imidazole or
oxazole ring. J . Chem. Soc. C 1970, 2518.
(18) Ginsberg, H. N.; Stalenhoef, A. F. The metabolic syndrome:
targeting dyslipidaemia to reduce coronary risk. J . Cardiovasc.
Risk 2003, 10, 121-128.
(19) Zimmet, P.; Alberti, K. G. M. M.; Shaw, J . Global and societal
implication of the diabetes epidemic. Nature 2001, 414, 782-
787.
(20) Executive summary of the third report of the National Choles-
terol Education Program Expert Panel of detection, evaluation,
and treatment of high blood cholesterol in adults. J . Am. Med.
Assoc. 2001, 285, 2486-2496.
(21) American Diabetes Association. Detection and management of
lipid disorders in diabetes. Diabetes Care 1993, 16, 828-834.
(22) American Diabetes Association. Position Statement: Manage-
ment of dyslipidemia in adults with diabetes. Diabetes Care
1998, 21 (Suppl. 1), 160-178.
(23) Davis, P. H.; Dambrosia, J . M.; Shoenberg, B. S. Risk factors
for ischemic stroke: a prospective study in Rochester, Minnesota.
Ann. Neurol. 1987, 22, 319-327.
(24) Garg, A.; Grundy, S. M. Diabetic dyslipidemia and its therapy.
Diabetes Rev. 1997, 5, 425-433.
(25) Garg, A.; Grundy, S. M. Treatment of dyslipidemia in patients
with noninsulin-dependent diabetes mellitus. Diabetes 1995, 3,
433-445.
(26) Howard, B. V.; Howard, W. J . Dyslipidemia in noninsulin-
dependent diabetes mellitus. Endocrinol. Rev. 1994, 15, 263-
274.
(27) Rubins, H. B.; Robins, S. J .; Collins, D.; Fye, C. L.; Anderson, J .
W.; Elam, M. B.; Faas, F. H.; Linares, E.; Shaefer, E. J .;
Shectman, G.; Wilt, T. J .; Wittes, J . Gemfibrozil for the second-
ary prevention of coronary heart disease in men with low level
of high-density lipoprotein cholesterol. N. Engl. J . Med. 1999,
341, 410-418.
(28) Robins, S. J .; Collins, D.; Wittes, J . T.; Papademetrious, V.;
Deedwania, P.; Schaefer, E.; McNamara, J . R.; Kashyap, M. L.;
Hershman, J . M.; Wexler, L. F.; Rubins, H. B. Relation of
gemfibrozil treatment and lipid levels with major coronary
events. J . Am. Med. Assoc. 2001, 285, 1585-1591.
(29) Diabetes Atherosclerosis Intervention Study Investigators. Effect
of fenofibrate on progression of coronary-artery disease in type
2 diabetes: The Diabetes Atherosclerosis Intervention Study, a
randomized study. Lancet 2001, 357, 905-910.
(30) Nomura, M.; Kinoshita, S.; Satoh, H.; Maeda, T.; Murakami, K.;
Tsunoda, M.; Miyachi, H.; Awano, K. (3-Substituted Benzyl)-
thiazolidine diones as structurally new antihyperglycemic Agents.
Bioorg. Med. Chem. Lett. 1999, 9, 533-538.
(31) Auwerx, J . Altered fatty acid partitioning by PPAR activators
improves glucose homeostasis: A case for PPARR and γ coago-
nists. Insulin Resist., Metab. Dis. Diabetic Complications 1999,
167-172.
(32) Oplinger, J .; Spearing, P.; Collins, J .; Dezube, M.; Plunket, K.;
Lewis, M.; Oliver, W., J r.; Tong, T.; Alva, G. Discovery of Potent
PPARR and PPARγ Dual Agonists; Presented at the American
Chemical Society Annual Meeting, San Diego, March 2001;
poster MEDI 238.
(33) Cronet, P.; Petersen, J . F. W.; Folmer, R.; Blomberg, N.; Sjoblom,
K.; Karlsson, U.; Lindstedt, E.-L.; Bamberg, K. Structure of the
PPARR and -γ ligand binding domain in complex with AZ 242:
Ligand selectivity and agonist activation in the PPAR family.
Structure 2001, 9, 699-706.
(48) U.S. Patent 6,090,836, J uly 18, 2000.
(49) U.S. Patent 6,008,237, December 28, 1999.
(50) U.S. Patent 6,090,839, J uly 18, 2000.
(51) Berger, J . P.; Petro, A. E.; MacNaul, K. L.; Kelly, L. J .; Zhang,
B. B.; Richards, K.; Elbrecht, A.; J ohnson, B. A.; Zhou, G.;
Doebber, T. W.; Biswas, C.; Parikh, M.; Sharma, N.; Tanem, M.
R.; Thompson, M.; Ventre, J .; Adams, A. D.; Mosley, R.; Surwit,
R. S.; Moller, D. E. Distinct properties and advantages of a novel
peroxisome proliferator-activated protein γ selective modulator.
Mol. Endocrinol. 2003, 17, 662-676.
(52) Berger, J .; Leibowitz, M. D.; Doebber, T. W.; Elbrecht, A.; Zhang,
B.; Zhou, G.; Biswas, C.; Cullinan, C. A.; Hayes, N. S.; Li, Y.;
Tanen, M.; Ventre, J .; Wu, M.; Berger, G. D.; Mosley, R.;
Marquis, R. W.; Santini, C.; Sahoo, S. P.; Tolman, R. L.; Smith,
R. G.; Moller, D. E. Novel peroxisome proliferator-activated
receptor PPARγ and PPARδ ligands produce distinct biological
effects. J . Biol. Chem. 1999, 274, 6718-6725.
J M030621D