Discovery of para-alkylthiophenoxyacetic acids as a novel series of potent and selective PPARδ agonists

Article abstract of DOI:10.1016/j.bmcl.2007.05.007

A novel series of potent and selective PPARδ agonists, para-alkylthiophenoxyacetic acids, was identified. The synthesis and structure-activity relationships are described.

Full text of DOI:10.1016/j.bmcl.2007.05.007

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3855–3859
Discovery of para-alkylthiophenoxyacetic acids as a novel series
of potent and selective PPARd agonists
Rui Zhang,* Aihua Wang, Alan DeAngelis, Patricia Pelton, Jun Xu, Peifang Zhu,
Lubing Zhou, Keith Demarest, William V. Murray and Gee-Hong Kuo
Drug Discovery, Johnson and Johnson Pharmaceutical Research and Development, LLC, 8 Clarke Drive, Cranbury, NJ 08512, USA
Received 16 February 2007; revised 1 May 2007; accepted 4 May 2007
Available online 10 May 2007
Abstract—A novel series of potent and selective PPARd agonists, para-alkylthiophenoxyacetic acids, was identified. The synthesis
and structure–activity relationships are described.
Ó 2007 Elsevier Ltd. All rights reserved.
The peroxisome proliferator-activated receptors (PPARs)
are ligand-activated transcription factors acting as met-
abolic sensors regulating the expression of genes in-
volved in glucose and lipid homeostasis. Agonists of
the PPARa subtype,1,2 such as LOPIDÒ (gemfibrozil)
and TRICORÒ (fenofibrate), and agonists of the
PPARc subtype,3,4 such as AVANDIAÒ (rosiglitazone
maleate) and ACTOSÒ (pioglitazone HCl), are used
for the treatment of dyslipidemia and diabetes, respec-
tively. PPARd subtype is also involved in lipid metabo-
lism and, unlike the other two PPAR receptors, is
ubiquitously expressed, but the highest expression levels
are found in tissues with high lipid metabolism including
adipose, skeletal muscle, developing brain, intestine, and
heart.5 PPARd subtype has both distinct and overlap-
ping functions, particularly with PPARa, as there are
many common target genes.6 PPARd subtype may also
act in a regulatory or complimentary manner to PPARa
or PPARc activities based on in vitro and knockout
mice studies.7,8
ides, and an improvement in the atherogenic profile (de-
creases in small dense LDL particles) with little effect on
glucose (although insulin levels were decreased in mon-
keys).9 The increase in HDL-C was attributed to gene
induction by PPARd activation of the ABC-A1 trans-
porter, a key gene involved in reverse cholesterol trans-
port and HDL-C metabolism. There was also an
increase in cholesterol efflux in lipid-loaded macro-
phages, further implicating a role for PPARd in modu-
lating HDL-C levels and reverse cholesterol transport.
In early clinical studies with normal male volunteers,
GW501516 increased circulating HDL-C and decreased
triglycerides, although the decrease in triglycerides was
not statistically significant.10 On the other hand, in over-
weight, dyslipidemic males with the metabolic syn-
drome, treatment with GW501516 had no marked
effect on HDL-C but rather significantly decreased plas-
ma total cholesterol, apolipoprotein B levels and im-
proved remnant particle clearance.11 These data
indicate that PPARd agonists may have clinical utility
in the treatment of dyslipidemia, obesity, and diabetes,
and may complement the actions of existing therapies
such as the widely used statins.
The synthesis and development of a potent and selective
PPARd agonist, GW501516, has provided a greater
understanding of the role of PPARd and the potential
clinical utility of selective agonists.9 In obese, dyslipi-
demic, and hyperinsulinemic rhesus monkeys treatment
with GW501516 resulted in an increase in high density
lipoprotein cholesterol (HDL-C), a decrease in triglycer-
The structures of GW501516 and another published
PPARd agonist, L-165041, are shown in Figure 1.12
Compared with the PPARa and c subtypes, reports on
selective PPARd agonists remain limited,13 and new po-
tent and selective agonists are needed to shed light on
the further understanding of pharmacological responses
to the PPARd activation. In this paper, we report the
identification of the Y-shaped molecules (listed in Table 1)
as highly potent and highly selective PPARd agonists.
Keywords: PPARd agonists; Y-shaped molecules; Dyslipidemic.
*
Corresponding author. Tel.: +1 609 409 3487; fax: +1 609 655
6930; e-mail: rzhang4@prdus.jnj.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.05.007

3856
R. Zhang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3855–3859
O
HO2C
O
HO2C
O
S
S
O
O
OH
CF3
N
L-165041 (Merck)
GW501516 (phase II trial, GSK)
Figure 1. Structures of selective PPARd agonists.
Table 1. Activity of compounds 1–19 in cell based transactivation assay against human PPARd receptora
HO2C
O
CF3
X
Y
R
Compound
X
Y
R
Human PPARdEC50 (nM)
Efficacy (%)
1
S
O
OH
79.0
18.8
3.4
114
95
2
S
O
OMe
OEt
OEt(R)
3
S
O
98
3Rb
S
O
1.9
105
93
3Sb
S
O
OEt(S)
O(n-Pr)
25.0
4.3
4
S
O
104
105
97
5
S
O
O(n-Bu)
OAllyl
7.0
3.9
6
S
O
7
S
O
OMOM
OMOM(R)
OMOM(S)
OBn
6.3
2.1
94
98
7Rb
S
O
7Sb
S
O
70.0
60.0
126
62.1
23.9
4.6
77
8
S
O
107
84
9
10
S
O
OCH2CO2H
O(4-methoxylphenyl)
S
O
95
93
11
12
S
O
O(4-n-propylcarbonylphenyl)
CH2OEt
S
O
87
79
13
14
S
O
CH2O(4-trifluoromethylphenyl)
Me
17.0
7.4
S
O
81
15
S
O
Et
Et(R)
OEt
0.06
0.03
6.9
109
102
102
103
102
3.4
15Rb
16
S
O
S
CH2
CH2
O
17
18
S
OMSM
OEt
OEt(R)
15.2
24.3
>3000
1.0c
O
S@O
19
GW501516
O
a EC50s of all the compounds are >1 lM in PPARa and PPARc assays.
b R and S represent the absolute configurations, respectively. ee% > 99%.
c The data was reported in Ref. 12b.
The general synthesis of compounds 1–11 is outlined in
Scheme 1. The epoxide 20 was obtained from para-triflu-
oromethylphenol and epichlorohydrin under basic con-
dition.14 The epoxide opening15 with thiophenol 2116
prepared by reduction of the corresponding sulfonyl
chloride with tin in refluxing HCl ethanol solution affor-
ded the common intermediate alcohol 22. Alkylation of
the alcohol 22 and subsequent hydrolysis of the ester 23
yielded compounds 1–11. The enantiomeric compounds
3R, 3S and 7R, 7S were derived from the corresponding
enantiomeric epoxides 20, which were obtained from the
corresponding enantiomeric epoxypropanol and trifluo-
romethylphenol under Mitsunobu condition. Com-
pounds 16–18 were synthesized in a similar fashion to
Scheme 1.
Scheme 2 illustrates the synthesis of compounds
12–13. Dimerization17 of 21 to give 24 was affected by
Ba(MnO4)2 in high yield. The diol 25, generated from
2-(hydroxymethyl)-1,3-propanediol
by
Mitsunobu
reaction, reacted with disulfide 24 in the presence of
n-Bu3P in pyridine providing monoalcohol 26.18 Subse-
quent transformations of the intermediates gave the
compounds 12 and 13.
Preparations of compounds 14, 15, and 15R are exem-
plified by the synthesis of 15R in Scheme 3. The enan-
tiomeric alcohol 27 was prepared according to
literature procedures.19 Protection of the hydroxyl
group with TBSCl followed by reduction of the ester
with DIBALH gave alcohol 28. Activation of the

R. Zhang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3855–3859
3857
EtO2C
O
CF3
CF3
21
a
SH
Cl
+
O
O
HO
b
O
20
CF3
EtO2C
O
CF3
EtO2C
O
c
S
O
S
O
OR
OH
23
22
CF3
HO2C
O
d
S
O
OR
1-11
Scheme 1. Reagents and condition: (a) Cs2CO3, dioxane, 100 °C 80%; (b) TBAF (cat), THF, 85%; (c) NaH, RI, THF or DMF for esters of 2–5, 8–9,
10–80%; iPr2NEt, RBr or MOMCl, THF for esters of 6–7, 58–79%; ADDP, Ph3P, phenol, CH2Cl2 for esters of 10–11, 68–73%; (d) LiOH, H2O,
THF, 90–95%.
EtO2C
O
EtO2C
O
O
CO2Et
a
SH
S S
21
24
CF3
CF3
c
b
HO
OH
HO
O
+
HO
OH
OH
25
HO2C
O
CF3
EtO2C
O
CF3
d
S
O
S
O
OR
OH
26
12-13
Scheme 2. Reagents: (a) Ba(MnO4)2, CH2Cl2, 89%; (b) DIAD, Ph3P, DMF, THF, 17%; (c) n-Bu3P, 24, Py, 55%; (d) i—NaHMDS, EtOTf, THF for
the ethyl ester of 12, 47%; DIAD, Ph3P, para-trifluoromethylphenol for the ethyl ester of 13, 79%; ii—LiOH, H2O, THF, 84–88%.
hydroxyl group as mesylate followed by nucleophilic
replacement with thiophenol under basic condition
yielded sulfide 29. After removal of TBS group, Mits-
unobu reaction gave compound 31, which led to acid
15R upon hydrolysis.
best side chain, however, is the simple ethyl group with
subnanomolar potency (compounds 15 and 15R). Sec-
ond, branching with phenyl rings on the side chain
(compounds 8, 10, 11, and 13) diminishes the potency,
so does the polar group (compound 9). Third, the mol-
ecules with X = S, Y = CH2 (compounds 16–17) are
inferior to the counterparts with X = S and Y = O (com-
pounds 3 and 7). Fourth, replacement of the sulfur atom
with sulfoxide reduces the potency dramatically. For
example, the sulfoxide 19, readily available by oxidation
of corresponding sulfide 3 with hydrogen peroxide,
shows greater than 3 lM EC50. Finally, the molecules
with R configuration are at least 13-fold more potent
All the compounds investigated show weak activity in
both PPARa and PPARc assays (EC50 > 1 lM). The
PPARd functional transactivation data for compounds
1–18 are listed in Table 1, and the structure–activity
relationship (SAR) is summarized here. First, ethoxy
group (compound 3) seems to be preferred among the
alkoxyl substituents examined (compounds 1–7). The

3858
R. Zhang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3855–3859
EtO2C
O
b
MeO2C
a
HO
OTBS
OH
O
S
OTBS
CF3
28
27
29
EtO2C
EtO2C
O
d
c
S
OH
S
O
31
30
HO2C
O
CF3
e
S
O
15R
Scheme 3. Reagents: (a) i—TBSCl, Imidazole, 92%; ii—DIBALH, 88%; (b) i—MsCl, Et3N; ii—Cs2CO3, 21, 61%; (c) TBAF, 81%; (d) DIAD, Ph3P,
para-trifluoromethylphenol, 69%; (e) LiOH, 88%.
F3C
F3C
O
F3C
a
b
O
+
OCH2Ph
Cl
OCH2Ph
OH
O
32
F3C
c
d
OCH2Ph
OH
34
O
O
33
EtO2C
O
HO2C
O
e
O
O
S
S
CF3
CF3
36
35
Scheme 4. Reagents: (a) Et3N, 94%; (b) Tebbe reagent, THF, 80%; (c) Pd/C, H2, EtOH, THF, 91%; (d) MsCl, Et3N; Cs2CO3, 21, 11%; (e) LiOH,
H2O, THF, 62%.
than the corresponding S enantiomers (compounds 3R
versus 3S and 7R versus 7S).
molecules with a short side arm are better than those
with larger aryl groups. The compound 15R, for exam-
ple, is very potent and possesses a favorable pharmaco-
kinetic (PK) profile. The oral bioavailability in rat is
In addition, we investigated the effect of the backbone
length on the PPARd potency. To that end, com-
pound 36 was synthesized (Scheme 4). Olefination20
of the ester 32 with Tebbe reagent yielded enol ether
33. Concurrent reduction of the enol ether and re-
moval of the benzyl group was achieved by Pd-C
and H2 to give alcohol 34. Activation of the hydroxy
group and subsequent displacement with thiophenol
21 produced sulfide 35, which was then hydrolyzed
to acid 36. A dramatic drop in potency (EC50 of this
analog is 211 nM) was observed by the removal of
one methylene group, suggesting the backbone length
is critical to achieving good potency.
84% with high maximum plasma concentration (Cmax
=
8872 ng/mL), rapid oral absorption (Tmax = 0.5 h), high
plasma exposure (AUC = 13567 ng-h/mL), and long
plasma duration (t1/2 = 8.2 h). In addition, we also dem-
onstrated that the lengths of both backbone and side
chain, as well as the chirality at the Y intersection, are
all pivotal to PPARd agonist activity.
References and notes
1. Isseman, I.; Green, S. Nature 1990, 347, 645.
2. Barish, G. D.; Evans, R. M. Trends Endocri. Metabol.
2004, 15, 158.
In summary, we identified a novel series of highly potent
and highly selective PPARd agonists with the Y-shaped
structure. However, it seems to us that the Y-shaped
3. Knouff, C.; Auwerx, J. Endocrine Rev. 2004, 25, 899.
4. Willson, T. M.; Cobb, J. E.; Cowan, D. J.; Wiethe, R. W.;
Correa, I. D.; Prakash, S. R.; Beck, K. D.; Moore, L. B.;

R. Zhang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3855–3859
3859
Kliewer, S. A.; Lehmann, J. M. J. Med. Chem. 1996, 39,
665.
5. Braissant, O.; Foufelle, F.; Scotto, C.; Dauc¸a, M.; Wahli,
W. Endocrinology 1996, 137, 354.
6. Wang, Y.-X.; Lee, C.-H.; Tiep, S.; Yu, R. T.; Ham, J.;
Kang, H.; Evans, R. M. Cell 2003, 113, 159.
X.; Cow, C.; Wityak, J.; Karanewsky, D.; Bursulaya, B.;
Kreusch, A.; Tuntland, T.; Gerken, A.; Iskandar, M.;
Saez, E.; Seidel, H. M.; Tian, S.-S. Bioorg. Med. Chem.
Lett. 2006, 16, 5488; (c) Epple, R.; Azimioara, M.; Russo,
R.; Bursulaya, B.; Tian, S.-S.; Gerken, A.; Iskandar, M.
Bioorg. Med. Chem. Lett. 2006, 16, 2969; (d) Weigand, S.;
Bischoff, H.; Dittrich-Wengenroth, E.; Heckroth, H.;
Lang, D.; Vaupel, A.; Woltering, M. Bioorg. Med. Chem.
Lett. 2005, 15, 4619.
7. Muoio, Deborah M.; MacLean, Paul S.; Lang, David B.;
Shi, Li; Houmard, Joseph A.; Way, James M.; Winegar,
Deborah A.; Corton, J. Christopher; Dohm, G. Lynis;
Kraus, William E. J. Biol. Chem. 2002, 277, 26089.
8. Shi, Y.; Hon, M.; Evans, R. M. Proc. Natl. Acad. Sci.
U.S.A. 2002, 99, 2613.
9. Oliver, W. R.; Shenk, J. L.; Snaith, M. R.; Russell, C. S.;
Plunket, K. D.; Bodkin, N. L.; Lewis, M. C.; Winegar, D.
A.; Sznaidman, M. L.; Lambert, M. H.; Xu, H. E.;
Strernbach, D. D.; Kliewer, S. A.; Hansen, B. C.; Willson,
T. M. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 5306.
10. Sprecher, D., Massien, C., Patterson, S., Zalewski, A., and
Johnson, A., Circulation 2004, 110 (17 Suppl 3), Abstract
244.
11. Sprecher, D., Johnson, A., Pierce, G., Watts, G., Barrett,
H., Circulation 2005, 112 (17 Suppl 2), Abstract 1211.
12. (a) Leibowitz, M. D.; Fievet, C.; Hennuyer, N.; Peinado-
Onsurbe, J.; Duez, H.; Berger, J.; Cullinan, C. A.;
Sparrow, C. P.; Baffic, J.; Berger, G. D.; Santini, C.;
Marquis, R. W.; Tolman, R. L.; Smith, R. G.; Moller, D.
E.; Auwerx, J. FEBS Lett. 2000, 473, 333; (b) 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.; Lambert, M. H.; Willson, T. M.;
Oliver, W. R.; Sternbach, D. D. Bioorg. Med. Chem. Lett.
2003, 13, 1517.
14. Connolly, S.; Bennion, C.; Botterell, S.; Croshaw, P. J.;
Hallam, C.; Hardy, K.; Hartopp, P.; Jackson, C. G.; King,
S. J.; Lawrence, L.; Mete, A.; Murray, D.; Robinson, D.
H.; Smith, G. M.; Stein, L.; Walters, I.; Wells, E.;
Withnall, W. J. J. Med. Chem. 2002, 45, 1348.
15. Albanese, D.; Landini, D.; Penso, M. Synthesis 1994,
34.
16. (a) Protiva, M.; Rajsner, M.; Adlerova, E.; Seidlova, V.;
Vejdelek, Z. J. Coll. Czech. Chem. Comm. 1964, 29, 2161;
(b) Tippe, A.; Eckstein, Z. Przemysl Chem. 1974, 53, 675;
(c) 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.; Lambert,
M. H.; Willson, T. M.; Oliver, W. R., Jr.; Sternbach, D. D.
Bioorg. Med. Chem. Lett. 2003, 13, 1517; (d) Hansch, C.;
Schmidhalter, B.; Reiter, F.; Saltonstall, W. J. Org. Chem.
1956, 21, 265.
17. Firouzabadi, H.; Mottghinejad, E.; Seddighi, M. Synthesis
1989, 378.
18. Nakagawa, I.; Aki, K.; Hata, T. J. Chem. Soc., Perkin
Trans. 1 1983, 1315.
19. Senanayake, C. H.; Larsen, R. D.; Bill, T. J.; Liu, J.;
Corley, E. G.; Reider, P. J. Synlett 1994, 199.
13. (a) Sternbach, D. D. Ann. Rep. Med. Chem. 2003, 38, 71;
(b) Epple, R.; Zaimioara, M.; Russo, R.; Xie, Y.; Wang,
20. Pine, S. H.; Zahler, R.; Evans, D. A.; Grubbs, R. H.
J. Am. Chem. Soc. 1980, 102, 3270.