Discovery of a novel class of PPARδ partial agonists

Article abstract of DOI:10.1016/j.bmcl.2008.08.011

Anthranilic acid GW9371 was identified as a novel class of PPARδ partial agonist through high-throughput screening. The design and synthesis of SAR analogues is described. GSK1115 and GSK7227 show potent partial agonism of the PPARδ target genes CPT1a and PDK4 in skeletal muscle cells.

Full text of DOI:10.1016/j.bmcl.2008.08.011

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5018–5022
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of a novel class of PPARd partial agonists
a
b
b
c
Barry G. Shearer a, , Hari S. Patel , Andrew N. Billin , James M. Way , Deborah A. Winegar ,
Millard H. Lambert d, Robert X. Xu d, Lisa M. Leesnitzer e, Raymond V. Merrihew e, Stephane Huet f,
Timothy M. Willson g
*
a Department of Metabolic Chemistry, Metabolic Diseases Centre of Excellence for Drug Discovery, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA
b Discovery Technology Group, Molecular Discovery Research, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA
c Department of Metabolic Diseases, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA
d Department of Computational & Structural Chemistry, Molecular Discovery Research, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA
e Department of Screening & Compound Profiling, Molecular Discovery Research, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA
f Department of Biology, Cardiovascular and Urogenital Centre of Excellence for Drug Discovery, GlaxoSmithKline, 25-27 Avenue du Quebec, 91951 Les Ulis, France
g Discovery Medicinal Chemistry, Molecular Discovery Research, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Anthranilic acid GW9371 was identified as a novel class of PPARd partial agonist through high-through-
put screening. The design and synthesis of SAR analogues is described. GSK1115 and GSK7227 show
potent partial agonism of the PPARd target genes CPT1a and PDK4 in skeletal muscle cells.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 17 June 2008
Revised 4 August 2008
Accepted 5 August 2008
Available online 9 August 2008
Keywords:
PPARd
Partial agonist
CPT1a
PDK4
The peroxisome proliferator activated receptors (PPARs) are
important members of the nuclear receptor superfamily. These
receptors are ligand activated transcription factors known to play
a key role in the catabolism and storage of dietary fats. Three
positive results suggest that PPARd is a promising target for the no-
vel treatment of metabolic diseases.
The development of selective small molecule regulators of the
PPAR family has been instrumental in deciphering the biological
pathways regulated by these receptors. A number of PPAR agonists
have been described in the literature. The availability of PPARd spe-
cific compounds, however, is limited. Recently, a selective PPARd
partial agonist was reported to correct plasma lipid parameters
and improve insulin sensitivity in a high fat fed ApoB100/CETP-
Tgn mouse model, highlighting the therapeutic potential of PPARd
partial agonists as a novel treatment of dyslipidemia.7 Additional
chemical tool compounds with a range of functional activity pro-
files are still needed to further elucidate the biological roles of
PPARd and provide new insights into potential therapeutic utilities.
We recently reported a novel selective PPARd antagonist ligand
for use as a research tool.8 As part of our continuing efforts to iden-
tify additional PPARd tool compounds, we executed a high-
throughput screen of our compound collection. Anthranilic acid
GW9371 was identified as a chemically unique PPARd ligand.
Structurally, GW9371 resembles the anthranilic acid BVT.762
receptor subtypes, PPARa, PPARc, and PPARd, exhibiting distinct
tissue expressions have been identified, and represent attractive
therapeutic targets with promising clinical potential.1 The fibrate
class of drugs including clofibrate, fenofibrate, and bezafibrate
are known PPAR
the clinic as hypolipodemic agents.2 PPAR
lin sensitivity, and lower plasma glucose and fatty acid levels.3 Ros-
iglitazone (Avandia) and pioglitazone (Actos) are PPAR agonists
a
activators that have been used for decades in
c
agonists enhance insu-
c
currently used for the clinical treatment of type 2 diabetes. PPARd
remains the least understood PPAR subtype and currently no mar-
keted PPARd drugs exist. However, evidence implicating PPARd as a
key regulator of lipid homeostasis and glucose disposal is grow-
ing.4 The PPARd agonist GW501516 has been shown to improve
insulin resistance and reduce plasma glucose in rodent models of
type 2 diabetes and correct the metabolic syndrome in obese pri-
mates.5 Most notably, it has also been recently shown that
GW501516 reduces serum triglycerides and prevents the decrease
of HDL-c and apoA-1 levels in sedentary human volunteers.6 These
(Fig. 1) reported by Biovitrum as a PPARa/c
partial agonist.9,10
GW9371, however, has a distinct PPARd selectivity profile.
The PPARd binding affinity and subtype selectivity was mea-
sured in an in vitro ligand displacement assay.11 GW9371 is a po-
tent and selective PPARd ligand (pIC50 = 6.9) without appreciable
* Corresponding author. Tel.: +1 919 483 9860; fax: +1 919 483 0430.
E-mail address: barry.g.shearer@gsk.com (B.G. Shearer).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.08.011

B. G. Shearer et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5018–5022
5019
Cl
Cl
O
O
N
S
O
O
N
N
H
H
S
O
CO2H
CO2H
GW9371
BVT.762
Figure 1. Structure of anthranilic acid-derived PPAR ligands.
affinity for either PPARa or PPARc (pIC50’s < 5). The functional
PPARd activity of GW9371 was assessed in a standard Gal4 chimera
cell-based reporter assay,12 and it was found to be a weak partial
agonist (pEC50 = 5.9,% max = 61 compared to full agonist
GW501516).
Using GW9371 as a lead, we initiated an effort to develop a no-
vel series of PPARd partial agonists. Most PPAR agonists have an
acidic group and previous ligand bound crystal structures13 have
shown that the acidic group usually forms hydrogen bonds with
Tyr473 (in the AF2 helix), His323, and/or His449 (all residue num-
Figure 2. Crystal structure of GW9371 bound to the ligand binding domain of
PPARd, PDB code 3DY6. Carbon atoms in the ligand, PPARd, and the PPARd AF2 are
shown in green, light blue, and pink, respectively. Nitrogen, oxygen, and sulfur are
shown in dark blue, red, and yellow, respectively. The PPARd backbone is depicted
with a tube, colored pink for the AF2 helix.
bers given in PPAR
differently, and BVT.762 binds to PPAR
c
numbering). Partial agonists sometimes bind
with its carboxylate direc-
c
b, c, d
a
ted away from the AF2 helix, forming a hydrogen bond instead
with the backbone NH of Ser342.10 In an effort to understand the
key receptor binding interactions of our anthranilic acid template
with PPARd, GW9371 was co-crystallized with the ligand binding
domain (LBD) of the hPPARd receptor. The crystal structure, solved
at 2.9 Å resolution (R = 21%, Rfree = 24%, PDB code 3DY6), shows
that the GW9371 anthranilate group binds similarly to BVT.762
between helix-3 and the b-sheet, with the carboxylate directed
away from the AF2 helix (Fig. 2). The carboxylate makes a possible
hydrogen bond with Thr288 (2.8 Å O–O distance), and makes addi-
tional interactions with the side chains of Arg284 and Trp264, and
the backbone NH of Ala342 with O-H distances of4.2, 4.6 and 4.2 Å,
O
N
HO
Cl
S
S
O
O
O
O
OH
O
1
O
N
R4
R1
S
R3
R2
O
O
N
H
CO2H
respectively. Thr288 is conserved in PPAR
Arg284 and Trp264 are unique to PPARd. All three of these side
chain interactions are different from those in the PPAR /BVT.762
a but not in PPARc, while
2-9
Scheme 1. Reagents and conditions: (a) 1,2,3,4-tetrahydroisoquinoline, Et3N,
acetone; (b) thionyl chloride, reflux; (c) substituted methyl anthranilate, DIEA,
CHCl3, 45 °C; (d) NaOH, THF/H2O, 50 °C.
c
structure, and tend to promote PPARd selectivity. The carboxylate
is further stabilized by an intramolecular hydrogen bond with
the ligand amide NH group, which serves to rigidify the core struc-
ture within the binding pocket. The sulfonamide adopts a confor-
mation that directs the tetrahydroisoquinoline group toward
Tyr473, His323 and His449 (heavy atom distances of 3.2, 4.1, and
3.4 Å, respectively). With the acid binding site occupied by the
lipophilic tetrahydroisoquinoline group, Tyr473 shifts slightly to
make hydrogen bonds with His323 and His449. The X-ray struc-
ture reveals a small vacant lipophilic pocket below the anthranilic
acid headgroup with a second narrow lipophilic pocket available
near the tetrahydroisoquinoline region.
The structure of GW3971 bound within the PPARd LBD suggests
that the potency of this series could be improved by optimizing the
interactions within one or both of the vacant lipophilic pockets. In
addition, we surmised that appropriate structural modifications to
the tetrahydroisoquinoline fragment could be designed to interact
with the AF-2 helix and influence the activity profile. Using the
PPARd bound structure of GW9371 as a guide, we synthesized a
series of compounds to explore the SAR of this new class of PPARd
ligand. Our initial efforts focused on the anthranilic acid region.
The synthesis of these compounds is detailed in Scheme 1. The
coupling reaction of commercially available 3-(chlorosulfonyl)ben-
zoic acid with 1,2,3,4-tetrahydroiso-quinoline in acetone provided
sulfonamide 1. Refluxing intermediate 1 in thionyl chloride fol-
lowed by reaction of the crude acid chloride with substituted
anthranilic esters and saponification gave the final targets 2–9 in
good yields.
The ability of these compounds to bind to each of the PPAR sub-
types was measured in vitro in a ligand displacement assay.11
Functional PPARd activity was assessed in a standard cell-based
Gal4 chimera reporter assay.12 These results are summarized in Ta-
ble 1. Data for PPARd agonist GW501516 (GW1516) are included
for comparison. Substitution of the anthranilic acid ring had signif-
icant effects upon potency. Placement of a substituent ortho to
either the carboxylic acid (2, R1 = Me) or nitrogen (9, R4 = Me) re-
sulted in inactive compounds. Based upon the PPARd bound struc-
ture of GW9371, placement of the methyl group ortho to the acid
as in compound 2 creates unfavorable steric interactions with
the receptor, most notably with the indole ring of Trp264 and to
a lesser extent with a side chain carbon of Arg284. Movement of
the receptor to relieve the unfavorable steric interaction between
the methyl substituent and Trp264 would weaken any hydrogen
bonding interaction between the acid group of compound 2 and
the indole NH group thereby reducing binding affinity. In the case
of compound 9, placement of a methyl group ortho to the amide
group does not appear to create detrimental steric interactions
with any receptor residues. However, significant steric interaction
between the methyl substituent and the adjacent amide oxygen
could force the amide considerably out of the plane of the anthra-
nilic acid ring. Ultimately, this would disrupt the intramolecular
hydrogen bond between the amide NH and adjacent carboxylic

5020
B. G. Shearer et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5018–5022
Table 1
3-(chlorosulfonyl)benzoyl chloride and methyl 5-chloro anthrani-
liate in toluene. Reaction of intermediate 10 with various substi-
tuted tetrahydroisoquinolines followed by saponification readily
provided the desired final targets.
Human PPAR binding and functional potency of substituted anthranilic acidsa
a
Compound
R1
R2
R3
R4
hPPAR binding pIC50
hPPARd reporter
a
c
d
pEC50
% Max
The binding potency and PPARd functional activity of these
substituted tetrahydroisoquinoline analogues is summarized in Ta-
ble 2. Substitution of the aromatic tetrahydroisoquinoline ring pro-
duced analogues with binding affinities and functional activity
profiles similar to the unsubstituted analogue 4. The placement
of a hydroxy or carboxylic acid group at R1 in an attempt to interact
with the AF-2 helix maintained binding affinity, but failed to im-
prove functional potency as evidenced by compounds 12 and 13.
The alkoxyacetic acid analogue 14 extends the carboxylic acid
group further from the tetrahydroisoquinoline ring. This modifica-
tion resulted in little effect on binding potency. However, no func-
tional activity was observed with this analogue. The lack of cell-
based activity may be due to poor cell penetration stemming from
the physical properties of a diacid compound. Alternatively, this
modification may have shifted the analogues efficacy below the
sensitivity of the functional assay (ꢀ20%).
GW1516
GW9371
—
H
Me
H
H
H
H
H
H
H
—
H
H
Me
Cl
Br
F
CF3
H
—
H
H
H
H
H
H
H
Br
H
—
H
H
H
H
H
H
H
H
5.7
<5
<5
5.0
5.3
5.4
5.2
5.8
5.3
<5
5.2
5.1
<5
5.3
5.4
5.6
5.2
5.5
5.4
<5
8.3
6.9
<5
7.9
8.1
8.1
7.6
8.3
8.3
<5
8.5
5.9
<5
6.7
6.9
6.7
6.3
6.8
6.8
<5
98
61
—
51
53
48
50
55
51
—
2
3
4
5
6
7
8
9
H
Me
a
Values had a standard deviation of 610% (n P 3).
acid and twist the phenyl rings away from the shape that fits with-
in the binding pocket.
Substitution of the anthranilic acid with small substituents
meta or para to the carboxylic acid led to a significant increase in
PPARd binding affinity as predicted by the ligand bound crystal
structure of GW9371. All of these compounds were at least 10-fold
more potent than GW9371, with compounds 7 and 8 exhibiting
binding affinities equipotent to the full agonist GW501516
(pIC50 = 8.3). All of the compounds in this series are functional par-
tial agonists in the reporter assay with measured efficacies less
than 55% versus GW501516 at saturation. The functional potencies
of these compounds are approximately 10-fold weaker than their
corresponding binding affinities. This trend is similar to the result
observed with GW9371. The potency differences observed be-
tween the binding and cell-based functional assay may be due to
various factors. For example, the cell penetration properties of a
compound can influence cell-based assay results. In addition, PPAR
activity is known to be influenced by a number of factors other
than ligand binding including the presence of coactivator and core-
pressor proteins, which are absent in the binding assay.14
We next investigated the tetrahydroisoquinoline region of the
series. Based upon the crystal structure of GW3971 bound to the
PPARd ligand binding domain, this region of the molecule binds
in the vicinity of the AF-2 helix and the incorporation of additional
substituents could potentially enhance binding and induce confor-
mational changes that influence functional activity. A limited num-
ber of compounds were synthesized according to Scheme 2.
Intermediate 10 was prepared in modest yield (58%) by heating
The failure to improve functional activity through structural
modifications of the tetrahydroisoquinoline group may be influ-
enced by the conformational flexibility of the tetrahydroisoquino-
line ring system. Adding rigidity to this region of the molecule
could provide conformations that lead to increased ligand-receptor
interactions and enhance functional potency. In an effort to explore
this hypothesis, we replaced the tetrahydroisoquinoline ring with
substituted indoles to reduce conformational flexibility.
Our indole sulfonamide analogues were prepared according to
the synthetic route described in Scheme 3. An appropriately substi-
tuted anthranilic ester was converted to sulfonyl chloride interme-
diate 19 as described for intermediate 10 in Scheme 2. Reaction of
sulfonyl chloride 19 with substituted indoles using cesium carbon-
ate in refluxing THF provided the desired sulfonamide intermedi-
ates. Alternatively, using BEMP in CH3CN at room temperature
provided milder and more efficient reaction conditions for the syn-
thesis of the sulfonamide intermediates.15 Finally, saponification
with aqueous LiOH in THF at 50 °C provided the final targets 20–
36. Yields for the saponification reaction varied and were often
low due to cleavage of the sulfonamide. We found that the methyl
Table 2
Human PPAR binding and functional potency of substituted tetrahydroisoquinoline
analoguesa
R1
R2
R3
O
Cl
O
N
S
S
O
O
R4
O
O
N
N
b, c
a
H
H
Cl
Cl
Cl
S
CO2Me
Cl
CO2H
R3 R4
O
O
O
Compound R1
R2
hPPAR binding
hPPARd
reporter
10
a
pIC50
a
c
d
pEC50
% Max
R1
R2
R3
GW1516
4
—
H
OMe
OH
CO2H
—
H
H
H
H
H
OMe
H
H
H
—
H
H
H
H
H
H
F
—
5.7
5.3
5.1
<5
5.4
5.3
5.0
5.2
5.1
5.2
5.4
5.3
5.3
5.1
5.1
5.2
5.5
5.4
5.3
8.3
8.1
7.9
7.7
8.4
8.0
8.0
7.8
7.6
7.8
8.5
6.9
5.9
5.7
5.9
<5
6.1
6.0
6.1
6.5
98
53
63
45
37
—
48
50
42
54
H
H
H
H
H
H
H
H
O
N
11
12
13
14
15
16
17
18
S
R4
O
O
N
H
OCH2CO2H
Cl
CO2H
H
H
H
H
11-18
Cl
Scheme 2. Reagents and conditions: (a) methyl 5-chloro anthranilate, toluene,
100 °C; (b) substituted 1,2,3,4-tetrahydroisoquinoline, DIEA, CHCl3, rt; (c) NaOH,
THF/H2O.
Cl Me 5.0
a
Values had a standard deviation of 610% (n P 3).

B. G. Shearer et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5018–5022
5021
14
CPT1a
PDK4
O
Cl
S
12
O
O
N
b, c
a
H
10
8
Cl
Cl
X
S
CO2Me
O
O
O
19
6
R1
R2
4
O
N
S
O
O
2
N
R4
H
R3
0
X
CO2H
20-36
Scheme 3. Reagents and conditions: (a) substituted 5-chloro anthranilate, toluene,
100 °C; (b) substituted indole, Cs2CO3, THF, 80 °C or BEMP, CH3CN, rt; (c) NaOH,
THF/H2O, 50 °C or LiI, pyridine, 120 °C, microwave, 10 min.
GW0742
GSK1115
GSK7227
GW0742
GSK1115
GSK7227
Figure 3. Expression of PPARd target genes CPT1a and PDK4.
ester compounds could be readily converted to the desired carbox-
ylic acid analogues in excellent yields using LiI in pyridine16 with
heating in a microwave at 120 °C for 10 min.
C4 substituted analogues. The placement of substituents at either
C6 or C7 of the indole ring as exemplified by analogues 26–31
did not significantly affect binding potency. However, the place-
ment of substituents at C7 (R4) produced compounds with appre-
ciably lower functional potencies relative to binding affinity. This
may be the result of reduced interactions of the indole ring with
the AF-2 helix arising from conformational changes of the ligand
induced by unfavorable steric interactions between the R4 substit-
uents and the sulfonamide group. For the indole series, the C7
substituted analogues possess the greatest potency differential be-
tween binding and cell-based receptor activation. The disubsti-
tuted analogues 32 (GSK7227) and 36 (GSK1115) represent the
most potent and selective compounds in this series with pEC50 val-
ues of 7.9 (% max = 33) and 7.8 (% max = 35), respectively.
GSK7227 and GSK1115 were studied for their effects on the
expression of two important PPARd-regulated genes in human
skeletal muscle cells as previously described.8 The target gene
CPT1a is a key regulator of fatty acid b-oxidation in skeletal muscle
cells.17 PDK4 plays a key role in skeletal muscle metabolism by
contributing to the regulation of glucose metabolism.18 GW0742
is a full PPARd agonist that robustly induces the target genes CPT1a
and PDK4 (Fig 3). Both anthranilic acid analogues GSK7227 and
GSK1115 induce these same target genes, but with reduced effi-
cacy compared to the full agonist. All of the compounds were
exceptionally potent, yielding maximal activity at the 10 nM dose.
Thus, these two new PPARd ligands act as potent partial agonists
on endogenous PPARd target gene expression consistent with their
profiles in the cell-based reporter assay.
The ability of the indole sulfonamide analogues to bind and
functionally activate hPPARd in cells is summarized in Table 3.
All compounds exhibited potent and selective affinity for PPARd
with the significant majority exhibiting pIC50 values P7.3. Unlike
the tetrahydroisoquinoline analogues, these compounds generally
possess functional potencies in the cell-based assay consistent
with their binding affinities. Substitution of the indole ring had
small effects on the PPARd binding affinity but did influence func-
tional potency and efficacy. For example, monosubstitution of the
indole ring at the C4 position (R1) gave analogues with slightly
higher efficacies in the cell-based assay as evidenced by com-
pounds 20–22 and 33. Substitution at the C5 position (R2) is also
well tolerated with functional efficacies slightly lower than the
Table 3
Human PPAR binding and functional potency of substituted indole sulfonamide
analoguesa
R1
O
N
S
R2
O
O
N
R4
H
R3
X
CO2H
Compound
X
R1
R2
R3
R4
hPPAR binding
hPPARd
reporter
a
pIC50
In this disclosure, we have described the identification of a no-
vel class of PPARd ligand. Compounds with potent and selective
partial PPARd transcriptional activity in a cell-based reporter assay
have been detailed. Two compounds, GSK1115 and GSK7227, have
been shown to affect partial induction of key PPARd-regulated tar-
get genes in skeletal muscle cells and represent useful tool com-
pounds for the further elucidation of PPARd biology.
a
c
d
pEC50 % Max
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
Me Me
Me Br
Me OMe
H
H
H
Me
Cl
OMe
H
H
H
H
H
H
H
H
H
H
H
H
Me
Cl
OMe
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
H
6.0 5.7 8.2 7.7
5.9 5.9 8.0 7.9
5.9 5.8 8.0 7.4
6.0 5.6 8.0 7.5
5.7 5.8 7.7 7.3
5.1 5.0 6.8 6.3
5.6 5.6 8.0 7.3
5.5 5.7 7.2 6.7
5.4 5.1 7.5 7.0
5.8 6.0 8.4 7.1
5.5 6.1 7.8 6.8
42
45
44
34
27
31
37
33
35
47
45
37
33
49
29
32
35
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
Acknowledgment
H
Me
Cl
The authors thank Lisa M. Shewchuk for additional refinement
of the crystal structure.
OMe <5
5.3 7.3 6.2
Me Me
OMe
H
OMe
H
H
H
H
H
H
5.5 5.5 7.7 7.9
6.1 5.7 8.2 6.8
5.5 5.4 7.9 6.8
5.8 5.6 7.9 7.0
5.5 5.5 7.8 7.8
Cl
Cl
Cl
Cl
OMe
H
H
Me
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OMe
a
Values had a standard deviation of 610% (n P 3).

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B. G. Shearer et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5018–5022
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