Design and synthesis of dual peroxisome proliferator-activated receptors γ and δ agonists as novel euglycemic agents with a reduced weight gain profile

Article abstract of DOI:10.1021/jm060617c

The design and synthesis of the dual peroxisome proliferator-activated receptor (PPAR) γ/δ agonist (R)-3-{4-[3-(4-chloro-2-phenoxy-phenoxy) -butoxy]-2-ethyl-phenyl}-propionic acid (20) for the treatment of type 2 diabetes and associated dyslipidemia is described. The compound possesses a potent dual hPPAR γ/δ agonist profile (IC₅₀ = 19 nM/4 nM; EC₅₀ = 102 nM/6 nM for hPPARγ and hPPARδ, respectively). In preclinical models, the compound improves insulin sensitivity and reverses diabetic hyperglycemia with less weight gain at a given level of glucose control relative to rosiglitazone.

Full text of DOI:10.1021/jm060617c

J. Med. Chem. 2006, 49, 5649-5652
5649
Scheme 1a
Design and Synthesis of Dual Peroxisome
Proliferator-Activated Receptors γ and δ
Agonists as Novel Euglycemic Agents with a
Reduced Weight Gain Profile
Yanping Xu,* Garret J. Etgen,* Carol L. Broderick,
Emily Canada, Isabel Gonzalez, Jason Lamar,
Chahrzad Montrose-Rafizadeh, Brian A. Oldham,
John J. Osborne, Chaoyu Xie, Qing Shi,
Leonard L. Winneroski, Jeremy York, Nathan Yumibe,
Richard Zink, and Nathan Mantlo
Lilly Research Laboratories, A DiVision of Eli Lilly & Company,
Lilly Corporate Center, Indianapolis, Indiana 46285
ReceiVed May 24, 2006
Abstract: The design and synthesis of the dual peroxisome proliferator-
activated receptor (PPAR) γ/δ agonist (R)-3-{4-[3-(4-chloro-2-phenoxy-
phenoxy)-butoxy]-2-ethyl-phenyl}-propionic acid (20) for the treatment
of type 2 diabetes and associated dyslipidemia is described. The
compound possesses a potent dual hPPAR γ/δ agonist profile (IC50
)
19 nM/4 nM; EC50 ) 102 nM/6 nM for hPPARγ and hPPARδ,
respectively). In preclinical models, the compound improves insulin
sensitivity and reverses diabetic hyperglycemia with less weight gain
at a given level of glucose control relative to rosiglitazone.
Type 2 diabetes is a debilitating metabolic disorder, affecting
over 150 million people worldwide,1 that culminates in a range
of progressive secondary complications.2 Therapy for type 2
diabetes primarily has been aimed at improving glycemic control
via a combination of diet, exercise, and the use of oral agents3
including sulfonylureas, metformin, acarbose, and thiazolidine-
diones (TZDs). TZDs, which are high affinity ligands for the
peroxisome proliferator-activated receptor γ (PPARγ), impact
a key underlying feature of type 2 diabetes, insulin resistance.4,5
The peroxisome proliferator-activated receptors (PPARs) are
a highly conserved set of ligand-activated transcription factors
in the nuclear hormone receptor superfamily.6 Three distinct
PPAR subtypes (PPARγ, PPARR, and PPARδ or PPARâ) have
been identified in most mammalian species,7 each forming a
functional heterodimer complex with the 9-cis retinoid acid
receptor (RXR). In addition to its role in modulating the
antidiabetic activity of the TZDs, PPARγ is well-known for its
role in adipogenesis at a cellular level.8 A selective PPARγ
agonist, rosiglitazone (5-{4-[2-(methyl-pyridin-2-yl-amino)-
ethoxy]-benzyl}-thiazoli-dine-2,4-dione), reduces fasting plasma
glucose concentration and fasting insulin level in type 2 diabetic
patients.9 However, some notable side effects, weight gain and
edema, were also observed in patients at efficacious doses.9,10
In contrast to the other PPAR isoforms, the physiological
function of PPARδ is less well understood. It appears, however,
to play a prominent role in lipid metabolism.11 A selective
PPARδ agonist, {2-methyl-4-[4-methyl-2-(4-trifluoromethyl-
phenyl)-thiazol-5-ylmethylsulfanyl]-phenoxy}-acetic acid, has
demonstrated the ability to dose-dependently increase serum
high-density lipoprotein cholesterol while lowering the level of
small dense low-density lipoprotein cholesterol, fasting tri-
glycerides, and fasting insulin.11 The cholesterol mediating
a Reagents and conditions: (a) Ac2O, CH2Cl2, -78 °C; (b) MsCl, Et3N;
(c) K2CO3, DMF, 50 °C; (d) K2CO3, MeOH, rt; (e) Cs2CO3, DMF, 55 °C;
(f) 5N NaOH, EtOH, reflux.
effects observed in this study were explained, at least in part,
through the PPARδ’s ability to upregulate the expression of
the ABC-A1a reverse cholesterol transporter, which promotes
apolipoprotein A1-specific cholesterol transport of cholesterol
to the liver. In addition, PPARδ also plays a critical role in the
transcriptional repression of atherogenic inflammation in mac-
rophages.12
The pivotal role that PPAR receptors play in the regulation
of metabolism makes them inviting targets for the treatment of
diabetes mellitus, atherosclerosis, and obesity.12-15 It is our
hypothesis that a PPARγ/δ dual agonist could differentiate from
other currently marketed antidiabetic agents through its ability
to effectively lower glucose and hemoglobin A1c levels while
simultaneously improving the dyslipidemia common in diabetic
patients (elevated triglycerides and low HDL cholesterol). It is
expected to have significant impact on the progression of
atherosclerosis not only stemming from lipid alterations but also
as a result of its ability to stimulate reverse cholesterol transport.
As a result of PPARδ’s propensity to improve insulin sensitiv-
ity11 and stimulate fatty acid oxidation,16 our hypothesis was
that a dual PPARγ/δ agonist could mitigate some of the weight
gain associated with a selective PPARγ agonist. Previously two
* To whom correspondence should be addressed. Regarding chemistry,
Y.X. Tel: 317-433-1113, Fax: 317-277-2035. E-mail: xu_yanping@lilly.com.
Regarding biology, G.J.E. Tel: 317-276-9800, Fax: 317-276-3344. E-
mail: g.etgen@lilly.com.
a Abbreviations: ABC-A1, ATP-binding cassette, subfamily A (ABC1),
member 1; TZD, thiazolidinedione; PK, pharmacokinetic; HDL, high-density
lipoprotein; ZDF rat, Zucker diabetic fatty rat.
10.1021/jm060617c CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/23/2006

5650 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 19
Letters
a
b
Table 1. Binding IC50 and Receptor Transactivation EC50 Datac on Human PPAR Receptor Subtypesd
hPPARRg hPPARγh
EC50 (nM)
PPARδg
EC50 (nM)d
compound
stereof
IC50 (nM)
EC50 (nM)e
IC50 (nM)
IC50 (nM)
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1398 ( 0
1323 ( 0
8251 ( 1592
4257 ( 235
i
710 ( 278
686 ( 211
1529 ( 123
877 ( 174
j
38 ( 0
6 ( 0
112 ( 11
6 ( 0
6 ( 0
5 ( 0
7 ( 1
3 ( 1
183 ( 0
6 ( 1
9 ( 0
8 ( 0
4 ( 0
4 ( 0
5 ( 0
5 ( 0
5 ( 0
4 ( 0
4 ( 1
i
47 ( 12
45 ( 8
7 ( 1
rac
rac
R
12 ( 1
5 ( 1
9 ( 1
4 ( 0
674 ( 0
46 ( 3
5 ( 1
S
1130 ( 0
18 ( 0
417 ( 0
59 ( 0
6 ( 0
15 ( 1
6 ( 0
6 ( 1
61 ( 0
63 ( 6
19 ( 2
67 ( 8
339 ( 0
25 ( 5
52 ( 12
70 ( 22
5 ( 0
rac
rac
R
R
R
R
R
R
R
8919 ( 0
2929 ( 23
i
j
968 ( 128
228 ( 17
8 ( 0
10897 ( 0
3758 ( 0
5303 ( 466
897 ( 117
1037 ( 61
4386 ( 0
2681 ( 145
6932 ( 677
i
2813 ( 163
1524 ( 346
2204 ( 183
642 ( 154
488 ( 0
2067 ( 424
2224 ( 0
2800 ( 33
j
52 ( 8
8 ( 3
5 ( 1
2 ( 1
4 ( 0
1 ( 0
355 ( 87
402 ( 0
102 ( 16
308 ( 21
73 ( 6
34 ( 0
6 ( 0
R
rac
rosiglitazone
j
a Concentration of test compound required to displace 50% of tritiated ligand. b Concentration of test compound that produced 50% of the maximal
reporter activity. c n ) 3-6. d Compounds 6-20 showed no binding or receptor transactivation on murine PPARR receptor. e Gal4-hPPARR and hPPARδ
was used to eliminate interference by endogenous PPARγ receptors in CV-1 cells. f Stereochemistry of the chiral center. g Tritium-labeled PPARR/PPARδ
agonist, 2-(4-{2-[3-(2,4-difluoro-phenyl)-1-heptyl-ureido]-ethyl}-phenoxy)-2-methyl-butyric acid, was used as radioligand for generating displacement curves
and IC50 values. h Tritium-labeled PPARγ agonist, 2-methyl-2-(4-{3-[propyl-(5-pyridin-2-yl-thiophene-2-sulfonyl)-amino]-propyl}-phenoxy)-propionic acid,
was used as radioligand for generating displacement curves and IC50 values. i No binding. j Efficacy relative to control was less than 20% at 10 µΜ.
research groups also reported their dual PPARγ/δ agonist
studies.17 We herein report our design, synthesis, and preclinical
evaluation of a novel class of dual PPARγ/δ agonists.
receptor potency. Methyl branching (R2 ) Me) in 7 significantly
improved PPARγ in vitro profile (EC50γ ) 6 nM, EC50δ ) 45
nM). However, this modification had little effect on PPARR
activity (EC50R ) 686 nM). The PPARR selectivity is further
improved by using a dihydrocinnamic acid headpiece. Com-
pound 8 was identified as a potent dual PPARγ/δ agonist with
excellent selectivity. The enantiomers of this racemate were
separated by preparative HPLC using a chiral column. The
absolute configurations of the enantiomer were assigned by
comparing the chiral HPLC retention times with the material
synthesized from (S)-butane-1,3-diol. R-Stereoisomer 9 was ca.
100 times more potent than the S isomer 10 on all PPAR
subtypes. Increasing the size of the R2 group, for example, 11
A general synthetic scheme is outlined in Scheme 1. Mono-
mesylates 1 were prepared from commercially available diols
by first selective acylation of the primary alcohols followed by
mesylation of the secondary alcohols. Nucleophilic substitution
of mono-mesylates 1 with phenols 2 afforded ethers 3. Removal
of the acetyl groups of 3 followed by methylsulfonylation gave
4. Treatment of 4 with various phenols 518 and subsequent
hydrolyses afford carboxylic acids 6-20.
Diabetic male db/db mice, purchased from Harlan Sprague
Dawley, were placed on study at ∼7 weeks of age. Plasma
glucose was assessed for all animals (tail vein) at the beginning
of the study under fed conditions. Animal were assigned to
groups (n ) 5) based on plasma glucose levels. All animals
were dosed by oral gavage with either vehicle (CMC/Tween
80) or vehicle and compound (30 mg‚kg-1) once daily for 7
days. One hour after the seventh dose, plasma glucose was re-
assessed for all animals.
Diabetic male and nondiabetic female ZDF rats, purchased
from Charles River Labs, were divided into groups (control,
rosiglitazone, and compound at indicated doses). Vehicle (1%
w/v CMC, 0.25% Tween 80) was used in all in vivo studies.
Male ZDF rats (∼8 weeks of age, n ) 5 per group) were dosed
once daily by oral gavage in the morning for 7 days. Male ZDF
rat plasma glucose levels were determined 1 h after dosing. Body
weight and food consumption were assessed in all groups over
the course of the study. Female ZDF rats (∼8 weeks of age, n
) 6 per group) were dosed by oral gavage for 14 days and
then subjected to an oral glucose tolerance test (2.5 g of glucose/
kg of body weight) following an overnight fast. Plasma was
collected at times 0, 15, 30, 60, and 120 min post oral glucose
administration. Plasma glucose and insulin levels were assessed
at all the indicated time points. Body weight and food consump-
tion were assessed in all groups over the course of the study.
n
(R2 ) Et) and 12 (R2 ) Pr), resulted in sharp losses (5-10-
fold loss) of PPARγ/δ activities. In liver microsome assays, 9
showed 70%, 60% and 69% metabolism in mouse, rat, and
human liver microsomes, respectively. Studies from human and
rat liver slices identified multiple metabolic pathways for 9,
namely, reduction of the benzoyl carbonyl group, oxidation of
the tailpiece Et group, and oxidation of the dihydrocinnamate
headpiece to cinnamate.19 In a search for metabolically stable
replacements of the benzoyl carbonyl group, a dramatic loss of
PPARγ activity in 13 was noticed when the carbonyl group
was replaced by a CH2 group. However, PPAR γ/δ activities
were maintained when the carbonyl group was replaced by an
oxygen atom in 14. Various R1 groups were evaluated to address
the metabolic liability of the ethyl group. Results indicated that
a lipophilic group at this position, for example, 15 (R1 ) Cl),
16 (R1 ) OCF3), and 17 (R1 ) CF3), is desirable for PPARγ/δ
dual activity. Compound 15 maintained good selectivity, while
lipophilic groups such as OCF3 (16) and CF3 (17) increased
PPARR activity. Various R3 groups were pursued to improve
the stability of the dihydrocinnamate headpiece. Electron
withdrawing groups, for example, CF3 (18) and F (19), attenuate
both PPAR γ and δ activities. Compound 20, with an electron-
donating group R3 ) Et, offered a potent PPAR γ/δ dual agonist
profile with good selectivity over PPARR. In theory, this ethyl
group could sterically block the â-oxidative degradation of the
cinnamate headpiece. In liver microsome assays, 20 showed
improvement in metabolic stability with 27%, 20%, and 25%
metabolism in mouse, rat, and human liver microsomes,
Through our early SAR effort, compound 6 was identified
as a dual agonist (EC50γ ) 112 nM, EC50δ ) 47 nM, Table 1)
with moderate selectivity over the PPARR isoform (EC50R )
710 nM) (see assays description in Supporting Information).
Introduction of an R2 group significantly improved in vitro

Letters
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 19 5651
Figure 1. Dose-response for effects of compound 20 on plasma glucose
in ZDF rats (n ) 5 per group) after 7 days of oral gavage dosing.
Figure 3. Weight gain profiles for female ZDF rats (n ) 6 per group)
dosed by oral gavage for 14 days with 20 or rosiglitazone.
plasma triglycerides by 27% and plasma free fatty acids by 9%
compared with the control group. In female ZDF rats, 20
significantly improved both the glucose and the insulin response
to a glucose challenge. Animals dosed with 2 mg‚kg-1 of 20
showed significantly less weight gain (P < 0.05) and fat mass
relative to animals treated with 1 mg‚kg-1 of rosiglitazone where
glycemic efficacy was equivalent. These studies suggest that a
PPARγ/δ dual agonist approach can attenuate the weight gain
side effect commonly associated with marketed TZDs. Our
recent SAR suggests that a PPARγ/δ agonist with a properly
controlled γ/δ ratio can be effective on glucose control with
less weight gain relative to rosiglitazone in our preclinical
models. The result will be reported in due course.
Figure 2. Glucose and insulin responses to a glucose challenge (2.5
g‚kg-1 BW) in female ZDF rats (n ) 6 per group) dosed by oral gavage
for 14 days with 20 or rosiglitazone (/ indicates significantly different
than control; // indicates significantly different than rosiglitazone).
respectively. In db/db mice, at single dose of 30 mg‚kg-1, 20
showed significantly better glucose lowering of 64% compared
with 28% for 9.
Compound 20 was tested over a range of oral dose levels in
51 day old male ZDF rats. As shown in Figure 1, 20 dose-
dependently lowered plasma glucose levels in ZDF rats. The
ED50 for half-maximal glucose normalization was estimated by
curve fitting to be 1.19 mg‚kg-1‚d-1. Included as a positive
control, rosiglitazone, exhibited 50% glucose normalization at
1.0 mg‚kg-1‚d-1. At the ED50 dose, 20 lowers plasma tri-
glycerides 27% compared with control animals (data not shown).
Similarly, plasma free fatty acids were reduced by 9% compared
with the control group (data not shown).
Acknowledgment. The authors thank Don Jett for technical
support.
Supporting Information Available: Experimental details on
in vitro binding and co-transfection studies, animal models, and
the synthetic procedures and characterization data for intermediates
and final compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
A two week female ZDF study was conducted with 20 to
determine whether the previously noted effects on glucose
homeostasis were attributable to an improvement in insulin
sensitivity and to more thoroughly evaluate the weight gain
profile. At 2 mg‚kg-1‚d-1 dose, 20 significantly lowered the
glucose response to an oral glucose challenge (Figure 2). This
response is equivalent to the effects exhibited by a 1 mg‚kg-1‚d-1
dose of rosiglitazone. Furthermore, both fasting insulin levels
and the insulin response to the glucose challenge were signifi-
cantly reduced in the rats treated with both 20 and rosiglitazone.
Thus both compounds enhanced whole body insulin sensitivity
equally at the corresponding doses.
The weight gain profiles for this study are depicted in Figure
3. At 2 mg‚kg-1, 20 increased body weight 14.4 g above control
levels whereas an equally efficacious dose of rosiglitazone (1
mg‚kg-1) induced a 26.0 g increase in body weight above con-
trol. Whereas both 20 and rosiglitazone significantly increased
weight gain relative to control, the weight gain induced by 20
was significantly different than that induced by rosiglitazone
in this study (P < 0.05). Furthermore rosiglitazone-treated rats
possessed significantly more fat mass (148.4 ( 4.3 g) than either
20-treated (136.8 ( 2.6 g) or control animals (129.9 ( 2.9 g)
as assessed by quantitative magnetic resonance spectroscopy.
In summary, 20 was identified as a dual PPAR γ/δ agonist
with high-affinity binding to hPPARγ and hPPARδ and potent
agonist activity in cell-based transactivation assays. In male ZDF
rats, it exhibited potent glucose lowering activity with an ED50
of 1.19 mg‚kg-1. At the same dose, the compound lowered
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