Studies towards the conception of new selective PPARβ/δ ligands

Article abstract of DOI:10.1016/j.bmcl.2006.06.028

In order to define new PPARβ/δ ligands, SAR study on the selective PPARβ/δ activator L-165,041 led to the identification of one key functional group for selective PPARβ/δ activation. Furthermore, taking advantage of SAR studies done elsewhere on the most selective PPARβ/δ ligand GW501516, the conception of new ligands showing good affinity for PPARβ/δ is reported. Finally, synthesis and biological evaluation of pyridine analogues have shown the benefical effect of the pyridine ring on the PPARβ/δ subtype selectivity.

Full text of DOI:10.1016/j.bmcl.2006.06.028

Bioorganic & Medicinal Chemistry Letters 16 (2006) 4528–4532
Studies towards the conception of new selective PPARb/d ligands
a
a
b
b
´
´
Carine Ekambome Bassene, Franck Suzenet, Nathalie Hennuyer, Bart Staels,
c
d
e
a,
*
´
Daniel-Henri Caignard, Catherine Dacquet, Pierre Renard and Gerald Guillaumet
aInstitut de Chimie Organique et Analytique (I.C.O.A.), UMR-CNRS 6005, FR CNRS 2708,
Universite´ d’Orle´ans, Rue de Chartres, BP 6759, 45067 Orle´ans Cedex 02, France
bDe´partement d’Athe´roscle´rose, U545 Institut Pasteur de Lille, 1 Rue du Pr Calmette, 59019 Lille cedex, France
cEtudes exte´rieures et Alliances strate´giques, Institut de Recherches Servier, 125 Chemin de Ronde, 78390 Croissy sur Seine, France
dDivision Maladies Me´taboliques, Institut de Recherches Servier, 11 Rue des Moulineaux, 92150 Suresnes, France
eProspective et Valorisation Scientifiques, Institut de Recherches Servier, 11 Rue des Moulineaux, 92150 Suresnes, France
Received 27 April 2006; revised 8 June 2006; accepted 8 June 2006
Available online 23 June 2006
Abstract—In order to define new PPARb/d ligands, SAR study on the selective PPARb/d activator L-165,041 led to the identifica-
tion of one key functional group for selective PPARb/d activation. Furthermore, taking advantage of SAR studies done elsewhere
on the most selective PPARb/d ligand GW501516, the conception of new ligands showing good affinity for PPARb/d is reported.
Finally, synthesis and biological evaluation of pyridine analogues have shown the benefical effect of the pyridine ring on the PPARb/
d subtype selectivity.
ꢀ 2006 Published by Elsevier Ltd.
Peroxisome proliferator-activated receptors (PPARs)
are members of the nuclear receptors, which include ste-
roid, thyroid or retinoid receptors.1 These receptors are
ligand-dependent transcription factors. Upon ligand
binding, the activated PPARs heterodimerize with
another nuclear receptor, the 9-cis-retinoic acid receptor
(RXR), and alter the transcription of the target genes
after binding to specific peroxisome proliferator re-
sponse elements (PPREs).2 Three subtypes of PPARs,
termed PPARa, PPARd (also known as PPARb) and
PPARc, have been identified so far in various species,
including humans.3 Whereas many studies have been
carried out on the PPAR subtypes a and c, the fact that
PPARb/d is ubiquitously expressed, and that there are a
few potent selective ligands available, has hampered
research in determining its biological function.1,4 Only
very recently, design and synthesis of PPARa/d dual
agonists as well as a highly selective PPARb/d has been
reported.5
reported in a GlaxoSmithKline patent and only recently
published6–8 (Fig. 1). Further synthetic route improve-
ments and modulations were reported.9 When we start-
ed on this project, the Merck-developed ligand L-
165,041 was described (Fig. 1), at this time, as the most
selective PPARb/d ligand with a 15- and 8-fold selectiv-
ity for human PPARb/d over human PPARa and
PPARc, respectively (EC50).3 L-165,041 is about 122-
fold selective for PPARb/d binding over PPARc (Ki)
and was found to raise HDLc in db/db mice in contrast
to the effect of PPARa ligands.10
Our first objective was to run some structure–activity
relationship study on compound L-165,041 and, in par-
allel, to evaluate the potency of pyridine analogues. At
this stage, to set out new potent and selective ligands
for PPARb/d subtype, we combined our SAR results
to those reported by GlaxoSmithKline on GW5015016.6
In order to determine whether the three functional
groups (hydroxyl, acetyl and propyl) of ligand L-
165,041 had a key role in the activity towards the
PPARb/d receptor, compounds 6–9 were prepared as
shown in Scheme 1. p-Benzyloxyphenol was reacted
with 1,3-dibromopropane with K2CO3 in refluxing
water using phase transfer catalysis.11 After hydrogenol-
ysis of the benzyl group and further alkylation with
In the course of our studies on PPAR ligands, we were
interested in selective PPARb/d ligands. Indeed, the first
highly selective PPARb/d ligand (GW501516) was
Keywords: Nuclear receptor; PPARb/d; Pyridine.
*
Corresponding author. E-mail: gerald.guillaumet@univ-orleans.fr
0960-894X/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2006.06.028

´
C. E. Bassene et al / Bioorg. Med. Chem. Lett. 16 (2006) 4528–4532
4529
O
CO2H
S
S
F3C
O
CO2H
N
O
R
HO
O
O
GW 501516, R = H
GW 0742, R = F
L-165, 041
Figure 1. Compounds L-165,041, GW501516 and GW0742, respectively, selective and highly selective PPARb/d ligands.
HO
(a)
Br
O
(b)
Br
O
(c)
OBn
OH
OBn
3 (86%)
1
2 (88%)
R2
CO2R3
R2
R1
O
R1
OH
Br
O
R
CO2Me
O
O
O
(d), (e)
R
4 (82%)
R = H, nPr ; R1 = H, OH
R2 = H, Ac ; R3 = H, Me
5 (82%) 6 (43%) 7 (48%)
8 (60%)
9 (53%)
Scheme 1. Reagents and conditions: (a) dibromopropane, K2CO3, Bu4NBr, H2O, reflux; (b) Pd/C, H2 (55 psi), MeOH, rt; (c) methyl bromoacetate,
K2CO3, acetone, reflux; (d) commercially available phenols, K2CO3, DMF, rt; (e) further saponification for compounds 8 and 9: NaOH (1 M),
THF, rt.
methyl bromoacetate, the common bromide intermedi-
ate 4 was isolated in 82% yield. Williamson reaction in
refluxing acetone with the commercially available 2-n-
propylphenol, resorcinol, 4-hydroxyacetophenone and
2,4-dihydroxyacetophenone allows us to, respectively,
isolate the desired compounds 6–9. Due to synthetic
facilities, we choose to evaluate the biological activities
on the ester moieties for compounds 6 and 7. For these
reasons and to be able to compare biological activities,
we also synthesized the L-165,041 methyl ester 5 by
reacting 2,4-dihydroxy-3-propylacetophenone with the
bromide 4.
Transfection was stopped by addition of DMEM sup-
plemented with 10% FCS and cells were then incubated
at 37 ꢁC. After 16 h, cells were trypsinised and seeded in
96-well plates at the density of 2 · 104 cells/well and
incubated for 6 h in 10% FCS containing DMEM. Cells
were then incubated for 16 h in DMEM containing 0.2%
FCS and increasing concentrations of the compound
tested (10 lM–10 nM) or vehicle (DMSO). At the end
of the experiment, cells were washed once with ice-cold
PBS and the luciferase activity was measured and nor-
malized to internal control b-galactosidase activity as
described previously.12 Compounds which elicited on
average at least 80% activation of PPAR(s) versus rosig-
litazone (PPARc), WY14.643 (PPARa) or MWI 66
(PPARb/d) (GAL4) (positive controls) were considered
full agonists. EC50 were estimated using Prism software
(GraphPad). All transfection experiments were per-
formed at least three times.
Compounds were screened for functional potency in a
transient transfection assay performed on Cos7 cells
where a previously established chimeric receptor system
was used to allow comparison on the relative transcrip-
tional activity on the same target gene. Cos-7 cells were
transiently transfected with luciferase reporter plasmid
(pG5-TK-pGL3) in the presence of pGal4hPPARc,
pGAL4hPPARa or pGAL4hPPARb/d (these vectors
expressed chimeric proteins containing the Gal4 DNA-
binding domain fused to the human PPARc, PPARa
or PPARb/d ligand binding domain coding sequence)
expression vectors. Plasmids pGal4-hPPARs, and
pG5-TK-pGL3 were constructed as described previous-
ly.12 Cells were seeded in 60-mm dishes at a density of
5.5 · 105 cells/dish in DMEM supplemented with 10%
FCS and incubated at 37 ꢁC for 24 h prior to transfec-
tion. Cells were transfected in OptiMEM without FCS
for 3 h at 37 ꢁC, using polyethylenimine (PEI), with
reporter and expression plasmids. The plasmid pBlue-
script (Stratagene, La Jolla, CA) was used as carrier
DNA to set the final amount of DNA to 5.5 lg/dish.
The pCMV-b-galactosidase expression plasmid was
cotransfected as a control for transfection efficiency.
Table 1 shows the EC50 for compounds 5–9 in the
transient transactivation assay against the three hu-
man PPAR subtypes: a, c and d. First, we can notice
that ligand L-165,041 and its methyl ester 5 have
comparable activities towards the PPARb/d subtype.
Compounds 7 and 8 bearing only the hydroxyl and
acetyl function, respectively, were completely inactive
towards all three PPAR subtypes. On the other hand,
compound 6 bearing only the propyl function proved
to be active (EC50 = 1049 nM, activity = 129%) and
highly selective towards PPARb/d. Those results were
confirmed with compound 9, indeed, this L-165,041
analogue devoid of the propyl group was completely
inactive. From those results, it is clear that the pro-
pyl chain (which was already present in the original
screening hit)4b has a crucial impact for PPARb/d
activity in this series.

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C. E. Bassene et al / Bioorg. Med. Chem. Lett. 16 (2006) 4528–4532
4530
Table 1. Activity of compounds 5–9 in cell-based transactivation assay against human PPAR
R1
R2
R3
Transactivation EC50 nM (% activity)b
a
Compound
R
hPPARb/d
hPPARa
hPPARc
L-165,041
n-Pr
n-Pr
n-Pr
H
OH
OH
H
Ac
Ac
H
H
125 (51)
457 (80)
1046 (129)
Na
977 (97)
1068 (32)
na
1824 (79)
288 (90)
NA
5
6
7
8
9
Me
Me
Me
H
OH
H
H
NA
NA
NA
NA
H
Ac
Ac
Na
10,000 (6)
H
OH
H
NA
NA
a Values are means of three experiments (NA, not active).
b Refer to maximal activity obtained with each compound expressed in percentage of maximal activity of MWI 66 at 10À6 M for PPARb/d; of
rosiglitazone at 10À6 M for PPARc; of WY 14.643 at 10À5 M for PPARa.
Table 2. Activity of compound 16 in cell-based transactivation against
human PPAR
In order to increase interactions (hydrogen bonds, elec-
tronic effect,. . .) with the ligand binding domain, we
planed to evaluate what would be the effect of a pyridine
ring instead of a benzene ring. Thus, the synthesis of L-
165,041 pyridine analogue 16 was envisaged and is
reported in Scheme 2. Metallation of 3,5-dibromo-pyri-
dine with LDA and subsequent quenching with iodo-
propane gave compound 10.13 Substitution of the
bromines using sodium methanolate in the presence of
CuBr furnished the 3,5-dimethoxy-4-propylpyridine 11.
The cyanation in position 2 of the pyridine ring was real-
a
Compound
Transactivation EC50 nM (% activity)b
hPPARd
hPPARa
hPPARc
L-165,041
125 (51)
457 (80)
82 (94)
977 (97)
1068 (32)
8391 (64)
1824 (79)
288 (90)
757 (105)
5
16
a Values are means of three experiments.
b Refer to maximal activity obtained with each compound expressed in
percentage of maximal activity of MWI 66 at 10À6 M for PPARb/d;
of rosiglitazone at 10À6 M for PPARc; of WY 14.643 at 10À5 M for
PPARa.
ized by the Vorbruggen method.14 N-Oxide pyridine 12
¨
was isolated after treatment with mCPBA and then was
condensed with trimethylsilyl cyanide to afford the
cyanopyridine 13. Addition of MeMgBr on the nitrile
in the presence of trimethylsilyl chloride followed by
the deprotection of the hydroxyl functions with AlCl3
afforded the tetrasubstituted pyridine 15. The pyridine
analogue 16 was obtained by the Williamson synthesis
of an ether bond between the bromide 4 and the pyridol
15.
Transactivation tests for the pyridine analogue 16 are
reported in Table 2. Interestingly, if we compare the
activities for compound 16 with those of the reference
L-165,041 methyl ester 5, we can notice that the pyridine
ring increases the PPARb/d activity (16 EC50 = 82 nM
vs 5 EC50 = 457 nM, EC50 PPARb/d ratio = 6) and
improves the selectivity against PPARa (EC50 PPARa
ratio = 8) and PPARc (EC50 PPARc ratio = 2.5). More-
over, the compound 16 activity is stronger on PPARb/d
subtype. This effect is illustrated by the maximal trans-
activation percentage obtained (94%) which expresses
full agonist activity. This is a major difference with
reference compound L165.041 which is a partial agonist
on PPARb/d transactivation test (51%).
nPr
Br
Br
(a)
(b)
Br
Br
N
N
10
nPr
nPr
(d)
(f)
(c)
MeO
OMe
MeO
OMe
The SAR studies done on compound GW5015166 have
shown the importance of the trifluoromethyl group as
well as the enhancement of PPARb/d activity by methyl
substitution at the ortho position on the phenoxy moie-
ty. We decided to evaluate what would be the effect of
those two substituents on our molecules. For this, we
planed the synthesis of two new compounds bearing
both a CF3 substituent in meta position to the crucial
n-propyl chain but differing by the methyl substituent
on the phenoxy moiety (compounds 21 and 22, and
Scheme 3).
N
O
N
12
11
nPr
nPr
MeO
NC
OMe
OMe
MeO
(e)
N
N
13
O
14
nPr
nPr
N
HO
O
OH
(g)
HO
O
O
O
N
O
CO2Me
As reported in Scheme 3, the commercially available
4-trifluoromethylphenol was first protected as OTHP
to allow direct ortho-metallation and subsequent formy-
lation with DMF.15 Wittig condensation followed by
catalytic hydrogenation in acidic medium gave the phe-
nol intermediate 20 in good yields. Direct alkylation
with n-propyl iodide after the ortho-lithiation reaction
gave only starting material. Williamson reaction in
16
15
Scheme 2. Reagents and conditions: (a) 1—LDA (1.6 equiv), THF,
À78 ꢁC; 2—n-PrI (1.5 equiv), 16 h (74%); (b) MeONa, CuBr, MeOH,
150 ꢁC, sealed tube, 24 h (57%); (c) mCPBA, CHCl3 (98%); (d)
TMSCN, Et3N, CH3CN, reflux (63%); (e) MeMgBr, TMSCl, Et2O, rt
(76%); (f) AlCl3, CH2Cl2, reflux, 16 h (66%); (g) 4, K2CO3, KI, DMF,
rt (63%).

´
C. E. Bassene et al / Bioorg. Med. Chem. Lett. 16 (2006) 4528–4532
4531
OH
Br
O
O
CO2Me
OBn
( )2
(a),(b),(c)
(d),(e),(f)
Me
HO
O
18
17
F3C
CHO
F3C
nPr
OH
F3C
(g), (h)
F3C
(j)
(i),
OTHP
OH
20
CO2Me
19
nPr
O
R
(k), (l)
O
O
R = H, 21; R = Me, 22
nPr
F3C
O
CO2H
(m)
O
O
Me
23
Scheme 3. Reagents and conditions: (a) BnBr, Bu4NBr (cat.), NaOH 10%, CH2Cl2, rt (99%); (b) mCPBA, PTSA, CH2Cl2, reflux 16 h (87%); (c)
MeONa/MeOH, rt, 1 h (99%); (d) 1,3-dibromopropane, K2CO3, Bu4NBr, H2O, reflux (95%); (e) Pd/C 10%, H2 (4 bar), MeOH, rt (76%); (f) methyl
bromoacetate, K2CO3, acetone, reflux (86%); (g) DHP, PTSA, CH2Cl2, rt (83%); (h) BuLi, TMEDA, THF, À10 ꢁC then DMF, À10 ꢁC, 3 h (60%); (i)
Ph3PEtBr, BuLi, THF, rt (79%); (j) H2 (4 bar), Pd/C (10%), MeOH, HCl (1 N), rt, 16 h (91%); (k) R@H, 4, K2CO3, DMF, rt (50%); (l) R@Me, 18,
K2CO3, DMF, rt (76%); (m) R@Me, KOH, MeOH/H2O/THF then AcOH (69%).
DMF with bromo derivatives 4 and 18 (obtained in a
protection/Bayer–Villiger oxidation/saponification/al-
kylation/deprotection/alkylation sequence from 4-hy-
droxy-3-methylacetophenone, Scheme 3) at room
temperature for 48 h in the presence of K2CO3 allows
us to, respectively, isolate ligands 21 and 22 in 50%
and 76% yields.
KOH in MeOH in 69% yield (Scheme 3). We were very
pleased to note that compound 23 had a nanomolar
affinity for PPARb/d very close to the reference
PPARb/d ligand GW501516. Unfortunately, this acid
form was not selective as it has also shown a good affin-
ity for PPARa and PPARc (compound 23 and Table 3).
Nevertheless, encouraged by this result, we logically
planed to take advantage of the higher affinity of CF3
containing ligand 23 and the higher selectivity of pyri-
dine analogue 16 for PPARb/d subtype. The synthesis
is described in Scheme 4.
Transactivation tests are reported in Table 3. As expect-
ed, the presence of the CF3 group had a crucial benefical
effect on the affinity for PPARb/d. Furthermore, affinity
for PPARa and PPARc was also increased (compound
21, Table 3 vs compound 6, Table 1). On the other hand,
compound 22, with an extra methyl group, has shown
much higher affinity for PPARb/d (6-fold enhancement),
the affinity for the two other subtypes being similar
(compound 22 vs compound 21 and Table 3).
Br
N
F3C
N
F3C
F3C
N
(a),(b)
(c),(d)
Br
Br
OMe
OH
With this new potent ligand in hand, we evaluated the
corresponding acid 23 obtained by saponification with
CHO
N
24
25
F3C
N
(e),(f)
(h),(i)
(g)
OMe
Table 3. Activity of CF3 containing compounds in cell-based trans-
activation assay against human PPAR
nPr
nPr
26
27
a
Compound
Transactivation EC50 nM (% activity)b
CO2H
F3C
N
O
hPPARb/d
hPPARa
hPPARc
GW5015016
L-165,041
1 (95)
10,000 (452)
977 (97)
10,000 (37)
1824 (79)
1185 (71)
1261 (65)
153 (100)
1582 (62)
O
O
Me
125 (51)
98 (93)
16 (114)
7 (100)
15 (110)
nPr
28
21
22
23
28
1401 (49)
1010 (85)
103 (40)
Scheme 4. Reagents and conditions: (a) HI 67%, 100 ꢁC, 16 h then
170 ꢁC 4 h then NaOH 40% (95%); (b) CuI, KF, TMSCF3, NMP/
DMF (1:1), rt, 16 h (87%); (c) MeONa, DMF, 65 ꢁC, 2 h (90%); (d)
t-BuLi (2 equiv), THF, À78 ꢁC then DMF, À78 ꢁC, 3 h (58%); (e)
Ph3PEtBr, BuLi, THF, rt, 65%; (f) Pd/C (20%), H2 (1 bar), MeOH, rt,
24 h, 86%; (g) BCl3, Bu4NI, CH2Cl2, À78 ꢁC to rt, 24 h (43%); (h) 18,
K2CO3, KI (10%), DMF, rt (86%); (i) LiOH, H2O/THF then AcOH
(87%).
1330 (136)
a Values are means of three experiments.
b Refer to maximal activity obtained with each compound expressed in
percentage of maximal activity of MWI 66 at 10À6 M for PPARb/d;
of rosiglitazone at 10À6 M for PPARc; of WY 14.643 at 10À5 M for
PPARa.

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C. E. Bassene et al / Bioorg. Med. Chem. Lett. 16 (2006) 4528–4532
4532
771; (b) Kasuga, J.-i.; Makishima, M.; Hashimoto, Y.;
Miyachi, H. Bioorg. Med. Chem. Lett. 2006, 16, 554; For
PPARb/d selective agonist, see: (c) Epple, R.; Azimioara,
M.; Russo, R.; Bursulaya, B.; Tian, S.-S.; Gerken, A.;
Iskandar, M. Bioorg. Med. Chem. Lett. 2006, 16, 2969.
6. 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.
7. (a) Oliver, W. R.; Shenk, J. L.; Snaith, M. R.; Russel, C.
S.; Plunket, K. D.; Bodkin, N. L.; Lewis, M. C.; Winegar,
D. A.; Sznaidman, M. L.; Lambert, M. H.; Xu, H. E.;
Sternbach, D. D.; Kliewer, S. A.; Hansen, B. C.; Willson,
T. M. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 5306; (b)
Chao, E.; Haffner, C. D.; Lambert, M. H.; Maloney, P.
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8. Recently, a second class of potent and selective PPARb/d
agonists (3-(2-methyl-4-{2-[3-methyl-5-(4-trifluoro-meth-
ylphenyl)-thiophen-2-yl]-propoxy}-phenyl)-propionic acid)
was reported as 366- and 67-fold selective for PPARb/d
over PPARc and PPARa, respectively (EC50). Wang, X.;
Zhu, G.; Barr, R.; Montrose-Rafizadeh, C.; Osborne, J. J.;
Yumibe, N.; Jett. D. R.; Zink R. W.; Mantlo, N. B. ACS
Meeting 2004, 228th: Philadelphia.
Starting from the commercially available 2,5-dibromo-
pyridine, the 5-bromo-2-trifluoromethyl-pyridine 24
was obtained following the synthesis described by Sch-
losser et al.16 Nucleophilic substitution of the bromine
by sodium methanolate followed by formylation at C-
4 afforded aldehyde 25. The Wittig/reduction sequence
used previously to obtain the propyl chain was success-
fully applied. After deprotection of the alcohol function
using the smooth conditions BCl3, Bu4NI in dichloro-
methane,17 pyridinol 27 was engaged in a Williamson
reaction with bromo derivative 18. The resulting com-
pound was saponified and the corresponding acid 28
was isolated in 86% yield. The transactivation tests, pre-
sented in Table 3, were consistent with our expectations.
Indeed, new ligand 28 has a high affinity for PPARd and
is 100-fold more selective for human PPARd over
human PPARa and PPARc.
In conclusion, on the basis of a structure-activity rela-
tionship study, we have shown the key role of the propyl
chain in L-165,041-type ligands for a PPARd activity.
Using SAR evidence on GW501516, the affinity for
PPARb/d was increased by adding a trifluoromethyl
group and a methyl group on our structures. Finally,
we have shown that the presence of the pyridine ring
increases the selectivity for PPARb/d subtype by
decreasing the affinity for PPARa and PPARc subtypes.
9. (a) Wei, Z.-L.; Kozikowski, A. P. J. Org. Chem. 2003, 68,
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P.; Gronemeyer, H.; de Lera, A. R. Bioorg. Med. Chem.
Lett. 2006, 16, 49; (c) Ham, J.; Kang, H. Tetrahedron Lett.
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10. 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.;
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Acknowledgments
This work was supported by the French Ministry of Re-
search and Technology: ACI ‘Molecules and Therapeu-
tic Targets.’ The authors thank Fabien Fonteny and
´ ˆ ´
Jerome Luce for the synthesis of starting materials.
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