Discovery and SAR of para-alkylthiophenoxyacetic acids as potent and selective PPARδ agonists

Article abstract of DOI:10.1016/j.bmcl.2008.12.113

Synthesis and SAR of para-alkylthiophenoxyacetic acids is described. Achiral compounds 30, 31 and 32 were identified as potent and selective PPARδ agonists.

Full text of DOI:10.1016/j.bmcl.2008.12.113

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1101–1104
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery and SAR of para-alkylthiophenoxyacetic acids as potent
and selective PPARd agonists
*
Rui Zhang , Alan DeAngelis, Aihua Wang, Ellen Sieber-McMaster, Xun Li, Ronald Russell, Patricia Pelton,
Jun Xu, Peifang Zhu, Lubing Zhou, Keith Demarest, William V. Murray, Gee-Hong Kuo
Drug Discovery, Johnson and Johnson Pharmaceutical Research and Development, LLC, 8 Clarke Drive, Cranbury, NJ 08512, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis and SAR of para-alkylthiophenoxyacetic acids is described. Achiral compounds 30, 31 and 32
were identified as potent and selective PPARd agonists.
Received 24 December 2008
Accepted 31 December 2008
Available online 8 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Selective PPARd agonists
Dyslipidemic
Achiral analogs
The peroxisome proliferator-activated receptors (PPARs) are li-
gand-activated transcription factors acting as metabolic sensors
regulating the expression of genes involved in glucose and lipid
HDL-C metabolism. There was also an increase in cholesterol efflux
in lipid-loaded macrophages, further implicating a role for PPARd
in modulating 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 overweight, dyslipidemic males with the meta-
bolic syndrome, treatment with GW501516 had no marked effect
on HDL-C but rather significantly decreased plasma total choles-
terol, apolipoprotein B levels and improved remnant particle clear-
ance.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.
homeostasis. Agonists of the PPAR
a
subtype,1,2 such as LOPIDÒ
(gemfibrozil) and TRICORÒ (fenofibrate), and agonists of the PPAR
c
subtype,3,4 such as AVANDIAÒ (rosiglitazone maleate) and ACTOSÒ
(pioglitazone HCl), are used for the treatment of dyslipidemia and
diabetes, respectively. PPARd, involved in lipid metabolism is
unlike the other two PPAR receptors, 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 has both distinct and overlapping
functions, particularly with PPAR
target genes.6 PPARd may also act in a regulatory or complimentary
manner to PPAR or PPAR activities based on in vitro and knock-
out mice studies.7,8
a, as there are many common
a
c
While the structure of GW501516 is shown in Figure 1,12 there
are only a few PPARd selective agonists reported recently in litera-
ture.13 We previously identified the Y-shaped molecules 1 as po-
tent and selective PPARd agonists, and the chirality at the Y
intersection is pivotal to PPARd agonist activity.14 To reduce the
‘cost of goods’, we now report that certain achiral analogs of 1
may also maintain the high PPARd agonist potency and selectivity.
PPAR agonists generally consist of three parts: a lipophilic tail
moiety, a linker and a head moiety bearing a carboxylate functional-
ity. We started with the SAR study of the substitutions on the lipo-
philic tail moiety, and the results were summarized in Table 1.
Following the Topliss tree principle,15 olefin compounds 2–10 were
made, and their straight forward synthesis was shown in Scheme 1.
The key intermediate 14, a differentially activated olefin, was ob-
tained by treatment of 2-methylene-1,3-propanediol with methyl-
sulfonyl chloride and triethylamine in 58% yield. Phenoxide
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, dyslipidemic, and hyperinsulinemic rhesus monkeys
treatment with GW501516 resulted in an increase in high density
lipoprotein cholesterol (HDL-C), a decrease in triglycerides, an
improvement in the atherogenic profile (decreases in small dense
LDL particles) with little effect on glucose (although insulin levels
were decreased in monkeys).9 The increase in HDL-C was attrib-
uted to gene induction by PPARd activation of the ABC-A1 trans-
porter, a key gene involved in reverse cholesterol transport and
* Corresponding author. Tel.: +1 609 409 3487; fax: +1 609 655 6930.
E-mail address: rzhang4@prdus.jnj.com (R. Zhang).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.12.113

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R. Zhang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1101–1104
HO2C
O
HO2C
O
CF3
S
S
S
O
CF3
R
N
1
GW501516 (phase II trial, GSK)
Figure 1. Structures of selective PPARd agonists.
Table 1
Table 2
In vitro human PPARd potency of compounds 2–13a
In vitro human PPARd potency of compounds 18–22a
CF3
HO2C
O
Ar
R
X
O
S
X
b
Compound
Ar–X
Human PPARd EC50 (nM)
Compound
X
R
PPARd
EC50 (nM)
Compound
X
R
PPARd
EC50 (nM)
b
b
Cl
2
3
4
O
O
O
H
711
8
9
O
O
O
4-
238
138
28.4
HO2C
O
O
NMe2
2,4-
Cl2
4-
OCF3
18
46.7
4-Cl
65.5
S
S
S
3,4-Cl2 49.8
10
CF3
5
6
O
O
4-CF3
3-
CF3,4-
Cl
17.1
>500
11
12
NH
S
4-CF3 >500
4-CF3 54.3
HO2C
19
20
21
>1000
>1000
>500
249
7
O
4-OMe 216
13
CH2 4-CF3 26.8
and PPAR assays.
a
OMe
EC50 of all the compounds are >1
Values are means of at least two experiments.
l
M in PPAR
a
c
b
HO2C
HO2C
O
O
selectively replaced the more reactive methyl sulfonyl group of ole-
fin 14, giving the allylic chloride 15 in very good yields. Subsequent
replacement of the allylic chloro group with thiol afforded esters 17,
which gave acids after hydrolysis. With the successful Topliss tree
approach, we were able to efficiently identify the potent 4-CF3-ana-
log 5 (EC50 = 17.1 nM, Table 1) within nine molecules. We then ex-
plored three bioisosteres of 5 at X position. The NH isostere 1116
(EC50 > 500 nM) reduced the potency dramatically whereas the
hydrophobic sulfur isostere 12 (EC50 = 54.3 nM) and CH2 isostere
1316 (EC50 = 26.8 nM) displayed slightly lower potencies.
Cl
S
HO2C
O
22
O
We then turned our attention to optimize the head moiety, and
compounds 18–22 were synthesized and evaluated (Table 2). The
synthetic route is similar to Scheme 1. The various thiophenols
were obtained in a similar manner described for the synthesis of
thiophenol 16.14 Among the new analogs prepared, 18
(EC50 = 46.7 nM) showed good potency although it was about
2.7-fold lower than that of 5. To our surprise, replacement of Cl
with CF3 (19, EC50 > 1000 nM) or OMe (20, EC50 > 1000 nM) totally
abolished the PPARd activity. Moving the Cl from meta- to ortho-
a
EC50 of all the compounds are >1
Values are means of at least two experiments.
l
M in PPAR
a and PPARc assays.
b
position (relative to sulfur) also decreased the potency dramati-
cally (21, EC50 > 500 nM). When the sulfur atom of 5 was replaced
by the more hydrophilic oxygen atom as in 22 (EC50 = 249 nM), the
potency was reduced ꢀ15-fold.
O
O
a
b
Ar
HO
OH
Cl
OMs
EtO
O
+
Cl
SH
14
16
15
EtO2C
O
HO2C
O
c
d
R
R
O
S
O
S
2-10
17
Scheme 1. Reagents and conditions: (a) MsCl, Et3N, 58%; (b) NaH, corresponding phenols, 80-90%; (c) Cs2CO3, CH3CN, 75–86%; (d) LiOH, 90–95%.

R. Zhang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1101–1104
1103
CF3
EtO2C
O
S
O
OH
a
CF3
HO2C
O
HO2C
O
CF3
23
O
S
S
O
b
c
CF3
F
F
25
26
EtO2C
d
O
f
S
O
O
24
CF3
HO2C
O
CF3
HO2C
O
O
S
O
S
O
O
e
CN
27
29
HO2C
O
CF3
S
O
F
F
28
Scheme 2. Reagents and conditions: (a) DMSO, Ac2O, 83%; (b) i—Br2CF2, HMPT, THF, 78%; ii—LiOH, 91%; (c) i—Ph3P+CH2Ph ClÀ, NaHMDS, 44%; ii—LiOH, 90%;
(d) i—Ph3P@CHCN, 90%; ii—LiOH, 85%; (e) i—(MeOCH2)2NSF3, 92%; ii—LiOH, 91%; (f) i—HO(CH2)3OH, PPTS, 83%; ii—LiOH, 90%.
on the double bond did not improve the potency (Table 3). How-
Table 3
ever, gem-dimethyl substitution on the double bond (30,
22.4 nM) is better than gem-difluoro substitution (25, 69.6 nM).
When the double bond of 5 was replaced with its cyclopropyl
bioisostere (31, 23.3 nM), the potency is comparable. On the
other hand, if the double bond was replaced with less bulkier di-
fluoro group (28, 147 nM), the potency decreased ꢀ9-fold. The
best potency was achieved with the di-n-propyl substitution
(32, 8.6 nM).
In vitro human PPARd activity of compounds 25–32
Compound
Human PPARd EC50 (nM)
Compound
Human PPARd EC50 (nM)
25
26
27
28
69.6
45.5
35.4
147
29
30
31
32
45.6
22.4
23.3
8.6
In summary, to reduce the ‘cost of goods’, beginning with achi-
ral 2 (711 nM) possessing moderate PPARd agonist potency, we
identified several potent agonists (5, 10, and 13) based on the To-
pliss Tree study on the aromatic system. The further SAR study at
the X position, left head moiety, and the central portion of the
Y-shaped molecules led to the identification of achiral potent and
selective PPARd agonists (30, 31, and 32), which show favorable
pharmacokinetic profiles.
Finally, we explored the SAR on the central portion of the mol-
ecules. Scheme 2 shows the synthesis of compounds 25–29. The
common intermediate 24 was produced by oxidation of alcohol
2314 with DMSO and acetic anhydride. The ketone 24 was
smoothly converted to olefinic compounds 25,17 26, and 27 by Wit-
tig-type reactions. Treatment of the ketone with Deoxo-Fluor re-
agent18 afforded gem-difluorinated compound 28. The
preparations of compounds 30–32 were achieved by a similar
route as outlined in Scheme 1.
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S
S
S
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O
31
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O
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1104
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