Design and Synthesis of α-Aryloxy-α-methylhydrocinnamic Acids: A Novel Class of Dual Peroxisome Proliferator-Activated Receptor α/ γ Agonists

Article abstract of DOI:10.1021/jm0342616

The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) α/γ agonist (S)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenyl} -2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated d

Full text of DOI:10.1021/jm0342616

2422
J . Med. Chem. 2004, 47, 2422-2425
Design a n d Syn th esis of
r-Ar yloxy-r-m eth ylh yd r ocin n a m ic Acid s:
A Novel Cla ss of Du a l P er oxisom e
P r olifer a tor -Activa ted Recep tor r/γ
Agon ists
F igu r e 1. Dual PPAR R/γ agonists.
Alternatively, PPARR regulates lipid homeostasis via
its role in fatty acid catabolism9 including fatty acid
binding, uptake, and oxidation as well as lipoprotein
assembly and transport. PPARR agonists, e.g., gemfi-
brozil, have demonstrated the ability to reduce serum
triglycerides and increase HDL cholesterol,10 along with
an ability to reduce serum fibrinogen and plasminogen
activator inhibitor 1.11 The pivotal role that these
receptors play in the regulation of metabolism makes
them inviting targets for the treatments of diabetes
mellitus, atherosclerosis, and obesity,12-15 as demon-
strated by the TZDs and fibrates. Recently, however,
there has been considerable interest in combining the
beneficial activities of PPARR activation and PPARγ
activation, since the dual agonist approach should be
well suited for the treatment of insulin resistance and
the cardiovascular disease prevalent in type 2 diabetes
and syndrome X.16 Compared to combination therapy,
the dual agonist approach offers additional benefits, i.e.,
patient compliance, avoidance of potential drug-drug
interactions. We have previously reported on a class of
dual agonists derived from the fusion of the putative
pharmacophores of the known PPARR and PPARγ
agonists, represented by 1a 16c (Figure 1), and report the
design, synthesis, and preclinical evaluation of a highly
potent dual PPAR R/γ agonist (2, LY510929) that
resulted from the rational elaboration of 1a /1b.
Yanping Xu,*,† Christopher J . Rito,*,†
Garret J . Etgen,*,† Robert J . Ardecky,‡
J ames S. Bean,† William R. Bensch,†
J acob R. Bosley,† Carol L. Broderick,†
Dawn A. Brooks,† Samuel J . Dominianni,†
Patric J . Hahn,† Sha Liu,‡ Dale E. Mais,‡
Chahrzad Montrose-Rafizadeh,† Kathy M. Ogilvie,‡
Brian A. Oldham,† Mary Peters,† Deepa K. Rungta,‡
Anthony J . Shuker,† Gregory A. Stephenson,†
Allie E. Tripp,† Sarah B. Wilson,†
Leonard L. Winneroski,† Richard Zink,†
Raymond F. Kauffman,† and J ames R. McCarthy*,†
Lilly Research Laboratories,
A Division of Eli Lilly & Company, Lilly Corporate Center,
Indianapolis, Indiana 46285, and Ligand Pharmaceuticals,
10275 Science Center Drive, San Diego, California 92121
Received December 18, 2003
Abstr a ct: The design and synthesis of the dual peroxisome
proliferator activated receptor (PPAR) R/γ agonist (S)-2-
methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]-
phenyl}-2-phenoxypropionic acid (2) for the treatment of type
2 diabetes and associated dyslipidemia are described. 2 pos-
sesses a potent dual hPPAR R/γ agonist profile (IC50 ) 28 and
10 nM; EC50 ) 9 and 4 nM, respectively, for hPPARR and
hPPARγ). In preclinical models, 2 substantially improves
insulin sensitivity and potently reverses diabetic hyperglyce-
mia while significantly improving overall lipid homeostasis.
Type 2 diabetes is a debilitating metabolic disorder
affecting over 100 million people worldwide1 that cul-
minates in a range of progressive secondary complica-
tions.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 more recently
thiazolidinediones (TZDs). Unlike other oral agents, the
TZDs, which are high-affinity ligands for the peroxisome
proliferator activated receptor γ, affect 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 recep-
tor (RXR). As noted above, PPARγ has been implicated
as the primary receptor modulating the antidiabetic
activity of the TZDs and at a cellular level is well-known
for its role in adipogenesis.8
The syntheses of 8a -e and 10-17 are described in
Scheme 1. Compound 3 was treated with LDA at -78
°C and quenched with 4-benzyloxybenzaldehyde to
provide alcohol 4 as a mixture of diastereomers. Ben-
zylic deoxygenation with BF3‚Et2O/Et3SiH, followed by
catalytic hydrogenation to remove the benzyl group,
afforded the phenol 5. The enantiomers of phenol 5 were
separated by chiral chromatography using a Chiralpak
AD 4.6 mm × 250 mm column. The structure of the S
enantiomer was unequivocally established by X-ray
crystallographic analysis of the (R)-R-methylbenzy-
lamine salt (crystallized from methanol, data not shown).
To complete the syntheses, 5 was treated with tosylates
6a -e16c,17 under basic conditions, followed by the sa-
ponification with 5 N NaOH to provide acids 8a -e, 12,
and 13. Optically pure isomers, 2, 15, and 17, were
prepared from the corresponding S enantiomer of phenol
5 (R2 ) Me), while 14 and 16 were prepared from the R
enantiomer of 5 (R2 ) Me). The X-ray crystal structure
of 2 was also obtained (see Figure 1 in the Supporting
Information section).
Access to the analogue 10 started with the R-benzy-
lation of 7 by the treatment with LDA/BnBr to afford
18. Cleavage of the benzyl ether using Pd/C yielded
phenol 19. Treatment of 19 with tosylate 6b followed
by a saponification of the resulting intermediate pro-
vided 10.
* To whom correspondence should be addressed. For Y.X.: phone,
317-433-1113; fax, 317-277-2035; e-mail, xu_yanping@lilly.com. For
C.J .R: phone, 317-276-4231; fax, 317-651-6510; e-mail, cjrito@lilly.com.
For G.J .E.: phone, 317-276-9800; fax, 3170277-2035; e-mail, g.etgen@
lilly.com. For J .R.M.: phone, 317-433-1345; fax, 317-277-2035;
e-mail: jmccarthy@lilly.com.
Through our in vitro screening efforts (see assays in
† Lilly Research Laboratories.
‡ Ligand Pharmaceuticals.
Supporting Information), 918 (Figure 2) was identified
10.1021/jm0342616 CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/10/2004

Letters
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 10 2423
Sch em e 1a
of the R-alkyl group adjacent to the carboxylic acid from
methyl to ethyl (12) or n-butyl (13) also resulted in
decreased binding that was more pronounced with the
longer alkyl chain.
Varying substitution (phenyl, 2-thiophenyl, and cy-
clohexyl) at the 2-position of the oxazole ring provided
8b-d , which are essentially equipotent dual PPAR R/γ
agonists. However, when larger groups were introduced
to give p-biphenyl- and m-biphenyl-substituted ana-
logues 8a and 8e, a significant diminution in binding
at both receptors was observed.
To address the impact of chirality on receptor binding,
the enantiomers 14/15 and 2/16 were compared with
the corresponding racemates 8b and 8c (Table 1). The
binding results show that the S enantiomers (2 and 15)
have substantially better affinity at both the hPPAR R
and γ receptors than the R counterparts (14 and 16). It
is important to note that neither 2 nor any of the
analogues demonstrated potent binding at the PPARδ
receptor (>2 µM, Table 1). Thiophene analogue 2 had
the best overall physical properties among the S enan-
tiomers 2, 15, and 17. The cyclohexyl analogue 17 could
not be obtained in a crystalline form and was not
suitable for formulation or production on a large scale.
The thiophene analogue 2 exhibited adequate water
solubility (100 µg/mL) and was selected for further in
vivo evaluation.
To examine the PPAR-mediated pharmacodynamic
effects of 2 in vivo, three preclinical models were
utilized. Female Zucker (fa/fa) and male Zucker diabetic
fatty (ZDF) rats were used to assess insulin sensitivity
and antihyperglycemic potency, respectively. The hu-
man apolipoprotein A-1 transgenic (apoA-1 TG) mouse
was used to measure alterations in HDL cholesterol and
serum triglycerides.
a
Reagents and conditions: (a) LDA, -78 °C, then p-benzyloxy-
benzaldehyde (70%); (b) BF3‚Et2O, Et3SiH, CH2Cl2 (70%); (c) H2,
5-10% Pd/C, EtOAc (100%); (d) LDA, BnBr, TBAI; (e) Cs2CO3,
DMF, 55 °C (70%); (f) 5 N NaOH, EtOH, reflux (>99%).
Consistent with the potent PPARγ binding and recep-
tor activation profile, 2 substantially lowered fasting
insulin levels and improved insulin and glucose re-
sponses to a glucose challenge in obese insulin resistant
female (fa/fa) Zucker rats (Figure 3). The compound
potently improved hyperglycemia with a threshold
glucose reduction at 0.003 mg/kg and glucose normal-
ization at 0.03 mg/kg. The ED50 for glucose normaliza-
tion was determined to be 0.0041 mg/kg (Figure 4).
F igu r e 2. Early lead and SAR evolution.
The PPARR-mediated antidyslipidemic effects of 2
were assessed in the apoA-1 TG mouse model. In these
mice, 2 dose-dependently elevated serum HDL choles-
terol and lowered triglycerides (Figure 5). HDL choles-
terol was elevated by 50% at a dose of 4.5 mg/kg, and
similarly, the ED50 for triglyceride lowering was esti-
mated to be ∼9 mg/kg in this model.
as a moderate dual PPARR/γ agonist (IC50(R) ) 4.4 µM;
IC50(γ) ) 3.9 µM). This result was of particular interest
to us because 9 possesses a bulky lipophilic group R to
the carboxylic acid and binds to both hPPARR and
hPPARγ receptors. From a standpoint of designing a
novel dual PPARR/γ agonist, it suggested that the
benzyl substitution R to the carboxylic acid of the
prototypical dual agonist 1b might improve in vitro
binding. The R-benzyl analogue 1019 (Figure 2) did show
increased binding to hPPARR and hPPARγ receptors
relative to 1b. The position of the oxygen atom R to the
carboxylic acid and the quaternary stereogenic center
were found to be critical for binding. Moving the ether
oxygen in 10 to the alternative benzylic position pro-
vided the substantially more potent dual agonist 8b
(hPPARR IC50 ) 42 nM and hPPARγ IC50 ) 18 nM).
Compound 11, lacking the R-methyl group of 8b ,
demonstrated substantially decreased binding at both
hPPARR and hPPARγ receptors. Increasing the length
Despite the equivalent in vitro potency on hPPARR
and hPPARγ, there is a notable difference in the in vivo
dose-response relationship for the presumed PPARγ
driven response in the ZDF rat and the PPARR driven
response in the apoA-1 TG mouse. The relative insen-
sitivity of the apoA-1 TG mouse correlates with the poor
murine PPARR receptor activation profile observed for
2 (mPPARR EC50 ≈ 2 µM vs hPPARR EC50 ) 9 nM).
Several key species-specific amino acid differences
previously noted within the ligand binding domain of
PPARR20 most likely accounted for this human/murine
potency divergence. This hypothesis has been further
substantiated through an SAR study in which mPPARR

2424 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 10
Letters
a
b
Ta ble 1. Binding IC50 and Cotransfection EC50 Datac on Human and PPAR Receptor Subtypes
hPPARRf hPPARγg
EC50 (nM)d
hPPARδf
EC50 (nM)d
compd
stereoe
IC50 (nM)
IC50 (nM)
EC50 (nM)
IC50 (nM)
2
8a
8b
8c
8d
8e
10
11
12
13
14
15
16
17
S
28 ( 2
9 ( 4
10 ( 1
4 ( 1
5253 ( 230
na
na
na
na
na
na
na
na
rac
rac
rac
rac
rac
rac
rac
rac
rac
R
503 ( 41
42 ( 6
69 ( 6
12 ( 2
19 ( 2
18 ( 3
7 ( 1
169 ( 22
18 ( 3
7 ( 1
nb
8 ( 1
7113 ( 1908
5137 ( 650
nb
45 ( 7
24 ( 5
6 ( 1
73 ( 14
167 ( 25
678 ( 92
1106 ( 98
473 ( 41
1846 ( 109
1546 ( 36
21 ( 4
51 ( 9
9 ( 2
71 ( 3
6 ( 1
nb
549 ( 0
833 ( 254
75 ( 22
2558 ( 108
390 ( 23
5 ( 1
491 ( 32
128 ( 4
290 ( 22
2241 ( 13
388 ( 174
14 ( 2
1776 ( 0
390 ( 35
285 ( 52
2507 ( 50
382 ( 52
3 ( 0
4448 ( 216
7040 ( 1266
5074 ( 1140
7232 ( 968
2685 ( 149
5519 ( 728
6749 ( 0
na
na
3014 ( 31
S
R
S
na
na
na
618 ( 42
18 ( 3
67 ( 7
1 ( 0
297 ( 47
15 ( 2
121 ( 32
1 ( 0
9688 ( 334
a
b
Concentration of test compound required to displace 50% of tritiated ligand. Concentration of test compound that produced 50% of
the maximal reporter activity. c n ) 3-6; nb ) no binding; na ) efficacy relative to control was less than 20% at 10 µΜ. Gal4-hPPARR
d
was used to eliminate interference by endogenous PPARγ receptors in CV-1 cells. e Stereochemistry of the chiral center. f Tritium-labeled
PPARR/PPARδ agonist 2-(4-{2-[3-(2,4-difluorophenyl)-1-heptylureido]ethyl}phenoxy)-2-methylbutyric acid was used as radioligand for
generating displacement curves and IC50 values. g Tritium labeled PPARγ agonist 5-{4-[2-(methylpyridin-2-ylamino)ethoxy]benzyl}thiazolidine-
2,4-dione was used as radioligand for generating displacement curves and IC50 values.
discrepantly less potent on PPARR-mediated endpoints
(HDL cholesterol elevation). This observation is believed
to reflect the relative lack of cross-species consistency
for PPARR activation by 2. Overall, these results
support the hypothesis that 2 will stimulate both
PPARR and PPARγ at similar plasma exposures in the
clinical setting, thus providing optimal control of both
hyperglycemia and dyslipidemia. 2 was selected for
advancement to clinical trials for the treatment of type
2 diabetes and associated dyslipidemia and is currently
undergoing evaluation in man.
F igu r e 3. Glucose and insulin responses to an oral glucose
challenge in female fa/fa rats.
Ack n ow led gm en t. The authors thank Don J ett,
Michael Denney, Robert Brickley, and Lawrence Good-
win for technical support.
Su p p or tin g In for m a tion Ava ila ble: Synthetic proce-
dures and characterization data for intermediates and final
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
F igu r e 4. Glucose response in male ZDF rats.
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