SAR-oriented discovery of peroxisome proliferator-activated receptor pan agonist with a 4-adamantylphenyl group as a hydrophobic tail

Article abstract of DOI:10.1016/j.bmcl.2007.12.001

3-(4-Alkoxyphenyl)propanoic acid derivatives were prepared as candidate peroxisome proliferator-activated receptor (PPAR) α/δ/γ pan agonists, based on our previous SAR studies directed toward the development of subtype-selective PPAR agonists. Those studi

Full text of DOI:10.1016/j.bmcl.2007.12.001

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 1110–1115
SAR-oriented discovery of peroxisome
proliferator-activated receptor pan agonist with a
4-adamantylphenyl group as a hydrophobic tail
Jun-ichi Kasuga,a Daisuke Yamasaki,b Kiyoshi Ogura,c Motomu Shimizu,c Mayumi Sato,c
Makoto Makishima,d Takefumi Doi,b Yuichi Hashimotoa and Hiroyuki Miyachia,*
aInstitute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
bGraduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita City, Osaka 565-0871, Japan
cTumor Therapy Project, The Tokyo Metropolitan Institute of Medical Science,
Tokyo Metropolitan Organization for Medical Research, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan
dNihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
Received 23 October 2007; revised 15 November 2007; accepted 1 December 2007
Available online 26 December 2007
Abstract—3-(4-Alkoxyphenyl)propanoic acid derivatives were prepared as candidate peroxisome proliferator-activated receptor
(PPAR) a/d/c pan agonists, based on our previous SAR studies directed toward the development of subtype-selective PPAR ago-
nists. Those studies indicated that the steric bulkiness of substituents introduced at the distal benzene ring had an important influ-
ence on PPAR activity. The finding that a 4-adamantyl derivative exhibited not only PPARa/d activity but also significant PPARc
activity prompted us to search for structurally novel phenylpropanoic acid derivatives with more potent adipocyte differentiation
activity than the well-known PPARc agonist, rosiglitazone, as well as well-balanced PPARa and PPARd agonistic activities. A rep-
resentative phenylpropanoic acid derivative (12) bearing a 4-adamantylphenyl substituent proved to be a well-balanced PPAR-pan
agonist with activities to regulate the expression of genes involved in lipid and glucose homeostasis, and should be useful as a can-
didate drug for the treatment of altered PPAR function.
Ó 2007 Elsevier Ltd. All rights reserved.
The peroxisome proliferator-activated receptors
(PPARs) are ligand-dependent transcription factors
belonging to the nuclear receptor superfamily; they are
activated by endogenous fatty acids and their metabo-
lites, and by synthetic ligands.1 Three subtypes have
been isolated to date: PPARa, PPARd, and PPARc.
These subtypes share a high level of structural homol-
ogy, but each has distinct physiological functions and
shows a unique tissue distribution pattern. PPARa is ex-
pressed mostly in tissues involved in lipid oxidation,
such as liver, kidney, skeletal and cardiac muscle, and
adrenal glands. PPARc is expressed in adipose tissue,
macrophages, and vascular smooth muscles. In contrast
to the specific distributions of PPARa and PPARc,
PPARd is ubiquitously expressed.2
Upon ligand binding, PPARs heterodimerize with an-
other nuclear receptor partner, retinoid X receptor
(RXR), and the heterodimers regulate gene(s) expres-
sion by binding to specific consensus DNA sequences,
termed peroxisome proliferator responsive element
(PPRE). These elements are a direct repeat of the hexa-
meric AGGTCA recognition motif, separated by one
nucleotide (DR1), present in the promoter region of
the target genes.3
Each of the PPAR subtypes plays a pivotal role in lipid,
lipoprotein, and glucose homeostasis. PPARa regulates
genes involved in fatty acid uptake, b-oxidation, and x-
oxidation. It down-regulates apolipoprotein C-III, and
it also regulates genes involved in reverse cholesterol
transport, such as apolipoprotein A-I and apolipopro-
tein A-II.4 PPARc is reported to be a master regulator
of adipocyte differentiation, but more recent molecu-
lar-biological studies have indicated that its activation
is also linked to the expression of many genes that affect
energy metabolism, such as the TNF-a, leptin, and
Keywords: PPAR; PPAR-pan agonist; Metabolic syndrome; Phenyl-
propanoic acid.
*
Corresponding author. E-mail: miyachi@iam.u-tokyo.ac.jp
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.12.001

J. Kasuga et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1110–1115
1111
adiponectin genes.5 PPARd is the least well-defined sub-
type among the PPARs, but recent biological studies
have disclosed that its activation significantly increases
HDL cholesterol levels, and it influences glycemic con-
trol in a primate model of metabolic syndrome.6–8 Re-
cent studies also suggest that the overexpression of
PPARd in adipose tissue protects against diet-induced
obesity in mice, and treatment with a PPARd-selective
agonist reduces weight gain without affecting food in-
take in fat-fed mice.
nists,15 a PPARa/d dual agonist,16 and PPARd-selective
agonists.17 Based on the SAR results obtained, our
substituted-a-phenylpropanoic acid scaffold shows affin-
ity preferentially for PPARa and PPARd. PPAR ago-
nists can be structurally divided into three parts, for
example, (1) an acidic head part, (2) a linker part, and
(3) a hydrophobic tail part, and our SAR studies clearly
indicated that chemical modification of the acidic head
part and the linker part of phenylpropanoic acid deriv-
atives greatly influences the activity toward both
PPARa and PPARd, but has little effect on the activity
toward PPARc. Therefore, we turned our attention to
the SAR of the hydrophobic tail part. Based on limited
data, it appeared that the PPAR transactivation activity
was influenced by the structural bulkiness of the substi-
tuent at the 4-position of the distal benzene ring. There-
fore, we anticipated that the introduction of a bulkier
substituent than a cyclohexyl group would enhance the
activity toward PPARs, including PPARc. We therefore
designed and synthesized compounds bearing an ada-
mantyl group for further study.
Considering the above-mentioned beneficial pharmaco-
logical effects of the PPAR subtypes, the concept of
simultaneously activating all of the PPAR subtypes with
a single compound, for example, a PPAR-pan agonist, is
extremely attractive, especially for the treatment of met-
abolic syndrome, which consists of an accumulation of
metabolic and cardiovascular risk factors that predis-
pose to heart attack, stroke, heart failure, sudden car-
diac death, and certain cancers. Simultaneous
activation of all the PPARs might also reduce the occu-
rence of adverse side effects, such as weight gain, fluid
accumulation, and pulmonary and macular edemas
(leading to increased frequency of congestive heart fail-
ure), which are often associated with PPARc agonists,
such as rosiglitazone and pioglitazone. Recently, some
PPAR-pan agonists, including bezafibrate, a well-
known fibrate class antilipidemic agent, have been dis-
closed in the literature (Fig. 1),9–13 and among them
sodelglitazar (2) is under phase II clinical study.10
The synthetic routes were as follows (Chart 1). 4-Ada-
mantyltoluene (6) was oxidized with O2 in the presence
of
a catalytic amount of both Co(OAc)2 and
18
Mn(OAc)2 to afford 4-adamantylbenzoic acid (7).
Compound (7) was treated with thionyl chloride, fol-
lowed by aqueous ammonia, to afford 4-adamantylben-
zamide (8). This compound was amidealkylated with
substituted benzaldehyde in the presence of triethylsi-
lane and trifluoroacetic acid, followed by alkaline
hydrolysis to afford the racemic target compounds
(10f, 10h–10l). Other racemic compounds were prepared
by similar procedures to those used for compound (10f).
Optically active derivatives (12, 13) were prepared by the
amidealkylation of compound (8) with an optically ac-
tive benzaldehyde derivative, followed by LiOOH
hydrolysis of the chiral oxazolidinone.
Here, we present our structural development studies
aimed at the discovery of novel PPAR-pan agonists
based on the a-substituted phenylpropanoic acid struc-
ture as a versatile template for the creation of PPAR
agonists.
We have been engaged in structural development studies
of NR ligands (agonists and antagonists), based on our
working hypothesis concerning the nature of the NR li-
gand superfamily,14 and we have already successfully de-
The PPAR transactivation activities of these compounds
are summarized in Table 1. As regards PPARa and
PPARd, introduction of a bulky substituent at the 4-po-
sition of the hydrophobic tail part of the benzene ring
signed and synthesized
a
series of substituted
phenylpropanoic acid human PPARa-selective ago-
Br
O
O
O
O
O
OH
OH
O
F
OH
S
F
S
N
H
O
F
O
3
N
Cl
F
Br
1; Bezafibrate
2; sodelglitazar
O
O
N
O
S
F
O
OH
OH
N
F
N
F
O
O
O
O
4
5
Figure 1. Chemical structures of representative PPAR-pan agonists.

1112
J. Kasuga et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1110–1115
O
O
Me
OH
NH2
a)
b)
c)
6
7
8
O
O
O
O
N
OEt
N
H
OH
H
R2
R2
d)
R1
1
O
O
R
10f, 10h-l
9
O
O
O
O
O
N
H
N
O
NH2
e)
f)
O
8
11
O
N
H
OH
O
12
Chart 1. Synthetic route to present series of phenylpropanoic acid derivatives. Reagents and conditions: (a) Co(OAc)2, Mn(OAc)2, NaBr, O2, AcOH,
1,4-dioxane, 90 °C, overnight, 94%; (b) 1—SOCl2, reflux, 4 h, 2—aqNH3, acetone, rt, overnight, quant (two steps); (c) ethyl 2-alkyl-3(4-alkoxy-3-
formyl)phenylpropanoate, triethylsilane, tifluoroacetic acid, toluene, reflux, 24 h, 70%; (d) LiOHaq, EtOH, 50 °C, 6 h, 85%; (e) 5-[2-((S)-(R)-4-
benzyl-2-oxooxazolidine-3-carbonyl)butyl]-2-propoxybenzaldehyde, triethylsilane, trifluoroacetic acid, toluene, reflux, 24 h, 70%; (f) LiOH H2O,
30% H2O2, THF:H2O = 4:1 (V/V), 0 °C, 85%.
was apparently effective in increasing the transactivation
activity, especially for PPARa. The rank order of the
activity increased in the order H (10a) < Me (10b) < t-
Bu (10c) < Ph (10d) < cyclohexyl (10e). Compound 10e
exhibited nanomolar-order activity toward PPARa.
The activity toward PPARc also appeared to correlate
with the sterical bulkiness of the 4-substituent on the
benzene ring in the hydrophobic tail part. Although they
were less active toward PPARa and PPARd, 10d and
10e exhibited submicromolar PPARc activity. Overall,
compounds 10d and 10e exhibited potent PPARa-selec-
tive agonistic activity, combined with submicromolar
PPARd and PPARc agonistic activity. Based on these
SAR, we anticipated that the introduction of a bulkier
substituent would further enhance the transactivation
activity toward PPARs, including PPARc. Therefore,
we prepared the 4-adamantyl derivative 10f and 4-(tri-
methyl)adamantyl derivative 10g. As we expected, the
PPARc transactivation activity of 10f was increased as
compared with that of 10e, while the activity toward
PPARd decreased to some extent, and that toward
PPARa was greatly decreased. These results prompted
us to speculate that the volume of the hydrophobic
pocket hosting the 4-position of the distal benzene ring
differs among the three PPAR subtypes, with PPARc
having the largest pocket, and PPARa the smallest. In
order to enhance the PPARc activity, we prepared the
bulkier trimethyl adamantyl derivative l0g, but this
showed decreased PPARc activity. The PPARa and
PPARd activities of 10g were also decreased as com-
pared to those of 10f. These results indicated that the
pocket of PPARc is not large enough to accommodate
this substituent, and so an adamantyl group is
preferable.
Compound 10f proved to be PPARa/c dual agonist
with somewhat superior activity to the initial lead,
KRP-29719 (the EC50 values of the transactivation
activity of KRP-297 for PPARa, PPARd, and
PPARc were 300 nM, 10,000 nM, and 300 nM,
respectively, in our assay system). According to our
previous SAR data,17 PPARd activity correlated
positively with the length of the alkoxyl group at
the center benzene ring, and the length of the alkyl
substituent at the a-position of the head part car-
boxylic acid moiety.
Therefore, we prepared further compounds, focusing on
variation at these two positions, and we found that com-
pound 10k with an n-propoxy group at the center ben-
zene ring exhibited improved PPARd activity without
apparent loss of PPARa and PPARc activities as com-
pared with those of 10f. Compound 10k was found to
be a well-balanced PPAR-pan agonist (although com-
pound 10j exhibited more potent PPARc activity than
10k, we did not go forward with this compound, because
the balance of PPAR-pan agonism was worse than that
of 10k).

J. Kasuga et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1110–1115
Table 1. PPAR transactivation activity of phenylpropanoic acid derivatives
1113
O
O
OH
N
H
R3
O
R1
R2
R1
R2
R3
Stereo
a
EC50 (nM)
Compound
PPARa
PPARd
PPARc
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
12
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Et
Et
Et
Me
n-Pr
Et
Et
Et
Et
Et
rac
rac
rac
rac
rac
rac
rac
rac
rac
rac
rac
rac
S
1700
100
37
8100
3800
720
iab
9400
2300
320
220
120
340
280
120
50
t-Bu
Phenyl
6
210
300
Cyclohexyl
Adamantyl
Trimethyladamantyl
Adamantyl
Adamantyl
Adamantyl
Adamantyl
Adamantyl
Adamantyl
Adamantyl
4
95
1100
>10,000
iab
210
41
140
28
1400
250
n-Pr
n-Hex
n-Pr
n-Pr
140
1400
61
220
810
70
620
43
120
870
13
R
500
83
a Compounds were screened for agonist activity on PPAR-GAL4 chimeric receptors in transiently transfected HEK-293 cells as described. EC50 value
is the molar concentration of the test compound that affords 50% of the maximal reporter activity.
b ‘ia’ means inactive (no apparent activity) at the concentration of 10 lM.
Our SAR data15–17 indicated that the (S)-conformer is
more potent than the antipodal (R)-conformer in the
case of our phenylpropanoic acid PPAR agonists. So,
we prepared both enantiomers and reconfirmed that
the (S)-conformer 12 is more potent than the (R)-con-
former 13. However, although the activity resided pri-
marily in the (S)-enantiomer, the enantioselectivity was
less marked than in the case of the PPARa/d dual ago-
nist, TIPP-401.
To characterize the PPARc agonistic profile of 12, we
examined the ability of MCC-555, rosiglitazone (which
are well-known PPARc agonists), and compound 12
to stimulate adipocyte differentiation of murine prea-
dipocyte 3T3-L1 cells (Fig. 3). PPARc agonists promote
the conversion of a variety of preadipocyte and stem cell
lines into mature adipocytes.20 All three compounds in
the concentration range from 1 nM to 100 nM dose-
dependently stimulated adipocyte differentiation and in-
duced triglyceride accumulation, as indicated by Oil Red
O staining and by measurements of triglyceride content
(data not shown). The ability of 12 to differentiate pre-
adipocytes is similar to that of rosiglitazone, and far
more potent than that of MCC-555.
Finally, based on the accumulated SAR data, we pre-
pared the human PPARa/d/c pan agonist 12, which
proved able to activate all three PPAR subtypes with
EC50 values of about 100 nM or less in our assay system.
The dose–response relationship of 12 is depicted in
Figure 2.
To further characterize 12 as a PPAR-pan agonist, we
examined its activating effect on representative genes
having a peroxisome proliferator responsive element
(PPRE) in the promoter region at the cellular level in
human hepatocellular carcinoma Huh-7 (Fig. 4). Carni-
tine palmitoyl acyl-CoA transferase 1A (CPT1A),
HMG-CoA synthase 2 (HMGCS2), adipocyte differenti-
ation-related protein (ADRP), and angiopoietin-like
protein 4 (ANGPTL4) were selected, as the human
genes were reported to possess PPRE in the promoter
region.21–23 CPT1A is the key enzyme in carnitine-
dependent transport across the mitochondrial inner
membrane and its deficiency results in a decreased rate
of fatty acid b-oxidation. HMGCS2 is a potential regu-
latory enzyme in the pathway that converts acetyl-CoA
to ketone bodies. This enzyme condenses acetyl-CoA
with acetoacetyl-CoA to form HMG-CoA, which is
the substrate for HMG-CoA reductase. Defects in
HMGCS2 are the cause of HMG-CoA synthase defi-
ciency, which leads to severe hypoketotic hypoglycemia,
1.2
PPARα
PPARδ
PPARγ
0.8
0.4
0
-9
-8
-7
-6
-5
Log (M)
Figure 2. Dose–response relationship of 12 for PPAR transactivation.
The vertical line represents the relative luciferase unit versus the
maximal luciferase unit of each representative PPAR agonist. The
horizontal axis represents the log scale concentration of compound 12.

1114
J. Kasuga et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1110–1115
mild hepatomegaly, or fatty liver. ANGPTL4 is a mem-
1.6
1.2
0.8
0.4
0
ber of the angiopoietin/angiopoietin-like gene family
and encodes a glycosylated, secreted protein with a
fibrinogen C-terminal domain. This gene is the target
of peroxisome proliferation activators, such as the fi-
brate class of antihyperlipidemic agents. ADRP is asso-
ciated with the globule surface membrane material, and
is a major constituent of the globule surface; an increase
of ADRP mRNA is one of the earliest indicators of adi-
pocyte differentiation.
We first investigated the effects of the PPAR-subtype-
selective agonists GW-7647 (abbreviated as 7647; a
PPARa-selective agonist), GW-501516 (abbreviated as
1516; a PPARd-selective agonist), and troglitazone
(abbreviated as Tro; a PPARc-selective agonist). As
indicated in Figure 4, when Huh-7 cells were treated
with 1 lM 7647, 0.1 lM 1516, or 10 lM Tro (these con-
centrations were sufficient to induce subtype-selective
transactivation activity), expression of the four mRNAs
was augmented subtype-selectively, although the nature
of the selectivity was not entirely clear: CPT1A affected
mainly PPARa and to a lesser extent PPARd, HMGCS2
affected mainly PPARc and to a lesser extent PPARa
and PPARd, ADRP affected mainly PPARc and to a
lesser extent PPARa, and ANGPTL4 affected mainly
PPARc and PPARa, but also PPARd. These results
indicated that all three PPAR subtypes are functionally
active in Huh-7, and are consistent with previous reports
that these three PPAR subtypes show partially overlap-
1
1
1
1
100 nM
1
100 nM
100 nM
vehicle
MCC-555
rosiglitazone
12
Figure 3. Induction of adipocyte differentiation by PPAR agonists:
MCC-555, rosiglitazone, and compound 12. MCC-555 and rosiglitaz-
one are well-known PPARc agonists. Estimation of triacylglycerol and
protein content was performed as follows: 3T3-L1 cell monolayers
were rinsed twice with phosphate-buffered saline (PBS-) and were dried
briefly before extraction of lipids with isopropanol. Triacylglycerol was
estimated by acetylacetone colorimetry as described by Fletcher.24 The
lipid cleared cell sheet was then solubilized with 1 mol/L NaOH and
assayed for protein content according to the method of Lowry et al.25
Each compound was added to medium from day 1 until day 10. ST 13
cells were harvested 10 days after cell seeding and evaluated for
triacylglycerol and protein content. Values are means of triplicate
wells.
CPT1A
HMGCS2
12
4
9
6
3
0
3
2
1
0
D
MS
O
7
6
4
7
1
5
1
6
tro
1
2
DMSO
7647
1516
tro
12
ANGPTL4
ADRP
30
24
18
12
6
4
3
2
1
0
0
DMSO
7647
1516
tro
12
DMSO
7647
1516
tro
12
Figure 4. Induction of changes in the expression of selected genes (CPT1A, HMGCS2, ADRP, and ANGPTL4) in Huh-7 cells by several PPAR
agonists. One micromolar GW-7647 (abbreviated as 7647; a PPARa-selective agonist), 0.1 lM GW-501516 (abbreviated as 1516; a PPARd-selective
agonist), and 10 lM troglitazone (abbreviated as Tro; a PPARc-selective agonist) were used as positive control. These concentrations were sufficient
to induce subtype-selective transactivation activity.

J. Kasuga et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1110–1115
1115
9. Fruchart, J. C.; Staels, B.; Duriez, P. Curr. Atheroscler.
Rep. 2001, 3, 83.
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lipoprotein, and glucose homeostasis.
10. Sznaidman, M. L.; Haffner, C. D.; Maloney, P. R.;
Fivush, A.; Chao, E.; Goreham, D.; Sierra, M. L.;
LeGrumelec, C.; Xu, H. E.; Montana, V. G.; Lam-
bert, M. H.; Willson, T. M.; Oliver, W. R., Jr.;
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11. Mogensen, J. P.; Jeppesen, L.; Bury, P. S.; Pettersson, I.;
Fleckner, J.; Nehlin, J.; Frederiksen, K. S.; Albrektsen, T.;
Din, N.; Mortensen, S. B.; Svensson, L. A.; Wassermann,
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Chai, C. H.; Prakash, E.; Chen, C. P.; Hsu, T. A.; Peng, C.
H.; Lu, I. L.; Lee, L. H.; Chang, Y. W.; Chen, W. C.;
Chou, Y. C.; Chen, C. T.; Goparaju, C. M.; Chen, Y. S.;
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Treatment with 1 lM 12, a concentration sufficient to
activate all three PPAR subtypes, augmented the expres-
sion of all four genes, to a similar extent to that obtained
with the positive control agents. These results indicate
that this representative compound (12) is an effective
PPAR-pan agonist and can activate various kinds of
PPAR-regulated genes at the cellular level.
In summary, we have developed potent human PPAR-
pan agonists, which possess potent transactivation activ-
ity toward PPARs. We are planning an X-ray crystallo-
graphic analysis in combination with molecular
modeling to understand the reason why an adamantyl
group is favorable, as well as in vitro and in vivo phar-
macological evaluations of a representative compound
as a candidate anticancer and antimetabolic syndrome
agent.
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M.; Uchiki, H.; Murakami, K.; Miyachi, H. J. Med.
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16. Kasuga, J.; Yamasaki, D.; Araya, Y.; Nakagawa, A.;
Makishima, M.; Doi, T.; Hashimoto, Y.; Miyachi, H.
Bioorg. Med. Chem. 2006, 14, 8405.
The work described in this paper was partially sup-
ported by a Grant-in-Aid for Scientific Research from
The Ministry of Education, Culture, Sports, Science
and Technology, Japan, and grant from Keimeikai
Foundation.
17. Kasuga, J.; Nakagome, I.; Aoyama, A.; Sako, K.;
Ishizawa, M.; Ogura, M.; Makishima, M.; Hirono, S.;
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18. Krasnikov, S. V.; Obuchova, T. A.; Yasinskii, O. A.;
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