Design, synthesis and evaluation of trifluoromethane sulfonamide derivatives as new potent and selective peroxisome proliferator-activated receptor α agonists

Article abstract of DOI:10.1016/j.bmcl.2007.11.053

Starting from the structure of 5, a two-step strategy was applied to identify a new generation of trifluoromethane sulfonamides as potent PPARα agonists. Synthesis, in vitro and in vivo evaluation of the most potent compound are reported.

Full text of DOI:10.1016/j.bmcl.2007.11.053

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 710–715
Design, synthesis and evaluation of trifluoromethane
sulfonamide derivatives as new potent and selective peroxisome
proliferator-activated receptor a agonists
Nicolas Faucher,a,* Paul Martres,a Alain Laroze,a Olivier Pineau,a
Florent Potvainb and Didier Grillotb
aDepartment of Medicinal Chemistry, Laboratoire GlaxoSmithKline, Centre de Recherches, 25–27 avenue du Que´bec,
91951 Les Ulis, France
bDepartment of Biology, Laboratoire GlaxoSmithKline, Centre de Recherches, 25–27 avenue du Que´bec, 91951 Les Ulis, France
Received 25 September 2007; revised 14 November 2007; accepted 15 November 2007
Available online 21 November 2007
Abstract—Starting from the structure of 5, a two-step strategy was applied to identify a new generation of trifluoromethane sulfon-
amides as potent PPARa agonists. Synthesis, in vitro and in vivo evaluation of the most potent compound are reported.
Ó 2007 Elsevier Ltd. All rights reserved.
Peroxisome proliferator-activated receptors (PPARs)
are members of the superfamily of nuclear transcription
factors regulating lipid metabolism. Upon ligand bind-
ing, PPARs heterodimerize with the retinoid X receptor
(RXR) and the resulting heterodimers regulate gene
expression by binding to specific peroxisome prolifera-
tor response elements (PPRE) located in the regulatory
regions of the target genes.1
of fibrates are thought to be mediated in part by PPARa
activation,6 but the fibrates are neither particularly po-
tent nor very selective for PPARa. Consequently, in hu-
mans, fibrates must be used at very high doses (about
300–1200 mg/day) to achieve a sufficient lipid-lowering
effect.7 Therefore, the search for more potent and selec-
tive activators of PPARa could lead to the discovery of
activators potentially superior to fibrates for the treat-
ment of altered lipid homeostasis. Here, we describe
the design and synthesis of novel trifluoromethane sul-
fonamide derivatives as potent human PPARa selective
activators.
Three PPAR subtypes have been isolated to date
(PPARa, PPARd, and PPARc) and each subtype dis-
plays distinct tissue-selective expression patterns, ligand
selectivity, and biological actions.2,3 PPARa is mostly
expressed in organs with a high rate of fatty acid catab-
olism such as the liver where it regulates the expression
of genes encoding for proteins involved in lipid and lipo-
protein metabolism.4 The fibrates (Fig. 1, Fenofibrate 1,
Bezafibrate 2, Ciprofibrate 3, and Clofibrate 4) have
been widely used for the clinical treatment of dyslipide-
mia since these drugs can effectively decrease triglyceride
(TG), low-density lipoprotein cholesterol (LDLc), and
very-low-density lipoprotein cholesterol (VLDLc) levels,
and increase high-density lipoprotein cholesterol
(HDLc) level.5 These beneficial pharmacological effects
We have recently reported the design and evaluation of
a novel substituted thiazole 5 (GW590735) as a potent
and selective PPARa agonist.8 In the present studies,
modification or replacement of the oxyisobutyric acid
found in classical fibrates was carried out starting from
5 (Fig. 2). This modification was followed by a subse-
quent replacement of the phenylthiazole moiety thus
leading to a new class of PPARa agonists.
The oxyisobutyric acid head group was replaced by frag-
ments containing a range of bioisosteres from the more
generally used tetrazole 7 to the less common 3-hydro-
xy-3-cyclobutene-1,2-dione 8 (Table 1, compounds 6–
10).9,10 All compounds were prepared following stan-
dard O-alkylation, N-acylation or N-sulfonylation pro-
cedures except for compound 7 which was prepared by
Keywords: Peroxisome proliferator-activated receptors; Fibrate; Tri-
fluoromethane sulfonamide.
*
Corresponding author. Tel.: +33 1 69 29 61 29; e-mail: nicolas.
faucher@gsk.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.11.053

N. Faucher et al. / Bioorg. Med. Chem. Lett. 18 (2008) 710–715
711
O
O
O
O
Cl
HO
O
O
N
H
O
Cl
Fenofibrate 1
Bezafibrate 2
O
O
O
HO
O
Cl
Cl
O
Cl
Ciprofibrate 3
Clofibrate 4
Figure 1. Chemical structures of the marketed Fibrates.
O
R
O
N
HO
H
N
N
H
N
S
S
O
O
CF3
CF3
5
Figure 2. Design of new PPARa agonists.
Table 1. In vitro evaluation of PPARa agonists on both murine (m) and human (h) receptorsb
Compound
Ra
EC50 (lM) h
PPARa
EC50 (lM) m
PPARa
EC50 (lM) h
PPARd
EC50 (lM) m
PPARd
EC50 (lM) h
PPARc
EC50 (lM) m
PPARc
(%activation)c
(%activation)c
(%activation)c
(%activation)c
(%activation)c
(%activation)c
OH
5
6
7
8
0.004 (95)
0.45 (79)
>10
0.02 (103)
>10
2.8 (82)
>10
1.7 (101)
>10
9.7 (29)
>10
9.7 (19)
>10
O
O
H
F3C
N
O
N
N
N
O
>10
>10
>10
>10
>10
N
H
O
>10
>10
>10
>10
>10
>10
O
OH
O
S
O
O
F3C
O
9
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
N
H
H
N
O
H
H
S
10
0.06 (100)
0.8 (78)
O
H
a The R substituent refers to Figure 2.
b Data generated using cell based transient transfection assays.13
c % of maximal activation of all compounds was compared to reference compounds normalized to 100%. For the PPARa activity, the reference
compound was 5. For the PPARd and PPARc activities, the reference compounds were GW516 and rosiglitazone, respectively.
alkylation of the phenol with chloroacetonitrile followed
by the tetrazole formation using the DBTO method
developed by Wittenberger and Donner,11 and for com-
pound 8 which was prepared via the Liebeskind
stannane.10
their agonist activity on PPAR-GAL4 chimeric recep-
tors in transiently transfected CV-1 cells.13
However, encouraging results were observed with the
methane sulfonamide analogue 10, which showed an
EC50 of 60 nM on human PPARa. Consequently, a set
of different sulfonamide derivatives was synthesized and
tested in vitro (Table 2). All compounds from Table 2
were prepared using standard N-sulfonylation proce-
Compounds 7 and 9, employing two of the most com-
mon carboxylic acid bioisosteres, tetrazole and acyl sul-
fonamide,12 showed no in vitro activity when tested for

712
N. Faucher et al. / Bioorg. Med. Chem. Lett. 18 (2008) 710–715
Table 2. Sulfonamides as PPARa agonistsb
Compound
Ra
EC50 (lM) h
PPARa
EC50 (lM) m
PPARa
EC50 (lM) h
PPARd
EC50 (lM) m
PPARd
EC50 (lM) h
PPARc
EC50 (lM) m
PPARc
(%activation)c
(%activation)c
(%activation)c
(%activation)c
(%activation)c
(%activation)c
H
O
N
S
11
1 (79)
>10
>10
>10
>10
>10
O
H
O
N
12
13d
14
15
16
0.05 (87)
>10
>10
>10
>10
>10
S
O
H
O
N
0.32 (125)
0.0003 (115)
0.003 (72)
0.08 (114)
>10
>10
>10
5.5 (69)
0.5 (78)
0.3 (66)
>10
6.7 (52)
0.6 (64)
0.3 (42)
>10
S
O
H
O
N
0.002 (98)
0.06 (74)
>10
0.4 (61)
>10
0.3 (91)
>10
S
F3C
O
H
O
N
F3C
S
O
H
O
N
>10
>10
S
F3C
O
a The R substituent refers to Figure 2.
b Data generated using cell based transient transfection assays.13
c % of maximal activation of all compounds was compared to reference compounds normalized to 100%. For the PPARa activity, the reference
compound was 5. For the PPARd and PPARc activities, the reference compounds were GW516 and rosiglitazone, respectively.
d Sulfonylation was carried out on the 4-(tert-butoxycarbonylamino)aniline followed by TFA deprotection and HATU mediated coupling with 4-
methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylic acid to afford 13.
dures using the corresponding sulfonyl chloride except for
compound 14 which was prepared from triflic anhydride.
Leu-456 could be replaced by the alkyl group of the sul-
fonamide. The selectivity versus PPARd could arise
from the relative hindrance of the protein side chains
in PPARd in this region compared to PPARa.
Although the aromatic sulfonamide 11 showed only
weak potency, small alkyl sulfonamides were more effec-
tive (compounds 12–13). It is noteworthy that the po-
tency of the sulfonamides appeared to correlate with
the acidity of the NH group as exemplified by com-
pounds 10, 14, and 15 with EC50s of 60–0.3 nM. It could
be hypothesized from docking experiments (not shown)
that the sulfonyl group is overlapping the carboxylate of
the fibrate head group making four hydrogen bonds
with Ser-280, Tyr-314, Tyr-464, and His-440 as observed
with GW590735.8 The gem-dimethyl substituents of the
fibrate head group which are directed into a lipophilic
pocket bounded by Phe-273, Gln-277, Val-444, and
Having established that the trifluoromethane sulfon-
amide was more than ten times more potent in vitro
than the original fibrate (0.3 nM for 14 vs. 5 nM for
5), this acidic group was retained and SAR studies
were performed on the remainder of the structure.
Previous investigations on the SAR of 5 had demon-
strated that the optimal structure for PPARa agonism
comprised a benzylamine tethered to a biaryl unit via
an amide bond.8 Therefore, a further range of com-
pounds of this general structure were prepared and
tested (Fig. 3).
O
H
RCO2H
O
H
N
F3C S
H
N
F3C S
N
R
O
NH2
O
HO
O
O
het.
or
17
HO
het.
O
or
HO
Ar
O
Figure 3. Focused array of trifluoromethane sulfonamides.

N. Faucher et al. / Bioorg. Med. Chem. Lett. 18 (2008) 710–715
713
Sulfonylation of 4-cyanoaniline followed by catalytic
hydrogenation of resulting nitrile 18 gave the benzyl-
amine 17. Further EDCI mediated coupling of 17 with
the carboxylic acids furnished the targeted set of
amides (Scheme 1).
A selection of the most potent and selective trifluorom-
ethane sulfonamide agonists (EC50 for PPAR-
a < 500 nM and at least 10-fold selective vs. PPARc
and PPARd) was compared with the corresponding fi-
brates and in accordance with the previous observation
O
H
O
H
N
H2N
N
a
c
F3C S
F3C S
H
N
R
O
O
CN
X
O
18 : X = CN
b
17: X = CH2NH2
Scheme 1. Reagents and conditions: (a) (F3CSO2)2O, Et3N, CH2Cl2, 0 °C; (b) Pd/C, H2, EtOH/AcOH, rt; (c) EDCI, DMAP, RCOOH, CH2Cl2,
reflux then rt.
Table 3. In vitro activities of selected sulfonamidesa
Structure
R
Compound
EC50 (lM) h
EC50 (lM) m
PPARa (%activation)b
PPARa (%activation)b
H
N
CF3
19
25
0.06 (121)
5 (107)
0.08 (96)
>25
N
S
S
R
O
O
S
H
N
O
O
OH
O
H
N
CF3
20
26
0.005 (138)
0.07 (134)
0.03 (123)
1 (130)
Cl
O
O
R
R
O
N
O
OH
O
H
N
CF3
N
21
27
0.02 (133)
1 (133)
0.2 (152)
>25
S
S
O
O
O
N
O
OH
O
H
N
CF3
22
28
0.36 (102)
3 (135)
0.7 (116)
>25
O
N
O
O
O
R
R
N
H
O
N
O
OH
O
O
H
N
CF3
23
29
0.08 (120)
2.8 (97)
0.34 (97)
>25
S
O
O
N
O
O
OH
Cl
H
N
CF3
24
30
0.08 (94)
6 (133)
0.13 (132)
>25
S
O
O
O
R
O
H
N
O
S
OH
O
a Data generated using cell based transient transfection assays.13
b % of maximal activation of all compounds was compared to compound 5 normalized to 100%.

714
N. Faucher et al. / Bioorg. Med. Chem. Lett. 18 (2008) 710–715
R1O2C
pound 20 were evaluated in mice and found to be
EtO2C
O
O
a
H
suitable for chronic administration (Table 4). Total
plasma clearance was low (0.78 mL/min/kg) with a
half-life of 4.9 h. Following a single oral dose of com-
pound 20 at 5 mg/kg, the maximum concentration of
compound in the plasma was 4515 ng/mL and the bio-
availability was 16%.
NH2
OR
N
O
R1 = Et
R1 = H
31
b
Scheme 2. Reagents and conditions: (a) EDCI, DMAP, RCOOH,
CH2Cl2, reflux then rt; (b) 1 N NaOH, EtOH, reflux.
As shown in Table 5, oral administration of compound
20 at a dose of 20 mg/kg twice a day for 5 days induced a
significant elevation of HDL-cholesterol (+102%) in
addition to a lowering of serum TG and VLDL-choles-
terol by 69% and 85%, respectively.
with 14, the trifluoromethane sulfonamide compounds
were at least 8-fold more potent than their fibrate ana-
logues (Table 3).
Interestingly, the sulfonamide derivatives were found to
be more active on the murine isoform than their fibrate
analogues.
It is noteworthy that the pharmacological effects ob-
served with compound 20 were almost exclusively
PPARa related since only a weak and partial activity
on PPARc and no PPARd activity were observed
in vitro as shown in Table 6.
Benzylamine 31 was prepared from 4-cyanophenol via
alkylation with 2-bromo-2-methylpropionate and
hydrogenation.8 Fibrate derivatives were prepared from
31 by EDCI and DMAP mediated coupling followed by
hydrolysis under standard conditions (Scheme 2).
A two-step strategy was applied to the generation of
new potent and selective PPARa agonists. The clas-
sical fibrate head group has been replaced by a tri-
fluoromethane sulfonamide giving a new series of
potent PPARa agonists. The finding that 20 is able
to lower VLDLc and TG and increase HDL choles-
terol in the Apo-A-I-transgenic mouse model sug-
gests that it could deliver significant therapeutic
benefit in the treatment of dyslipidemia and
hypertriglyceridemia.
The most potent trifluoromethane sulfonamide 20 was
selected for in vivo evaluation to determine its efficacy
in increasing HDL-cholesterol levels. The human Apo-
A-I-transgenic mouse model was used because of its
relevance to human disease since in this model fibrates
upregulate Apo-A-I, the major lipoprotein of HDL
particles.14 The pharmacokinetic parameters of com-
Table 4. Pharmacokinetic data for compound 20 in micea
F %
Cl (mL/min/kg)
Cmax (ng/mL)
Vdss (L/kg)
0.22
T1/2 (h)
AUCpo (ng h/mL)
18824
16
0.78
4145
4.9
a IV dose: 0.2 mg/kg (DMSO/cyclodextrin 20% (5/95 v/v)); PO dose: 5 mg/kg (0.5% HPMC K100/0.1%Tween 80).
Table 5. In vivo activities of sulfonamide 20a
Structure
Dose (mg/kg)
TG (g/l) (p)b
VLDLc (g/l) (p)b
LDLc (g/l) (p)b
HDLc (g/l) (p)b
Cl
H
O
N
S
20
À69%
À85%
À55%
+102%
***
H
F3C
O
N
***
***
***
O
a Five days chronic bid C57B6 mice transgenic human Apo-A-I.
b
indicates values of p < 0.0005, as determined by a One-Way-ANOVA.
***
Table 6. In vitro activities of compound 20a
Compound
EC50 (lM) h
PPARa
EC50 (lM) m
PPARa
EC50 (lM) h
PPARd
EC50 (lM) m
PPARd
EC50 (lM) h
PPARc
EC50 (lM) m
PPARc
(%activation)b
(%activation)b
(%activation)b
(%activation)b
(%activation)b
(%activation)b
20
0.005 (138)
0.02 (123)
>10
>10
1.1 (86)
0.6 (59)
a Data generated using cell based transient transfection assays.13
b % of maximal activation of all compounds was compared to reference compounds normalized to 100%. For the PPARa activity, the reference
compound was 5. For the PPARd and PPARc activities, the reference compounds were GW516 and rosiglitazone, respectively.

N. Faucher et al. / Bioorg. Med. Chem. Lett. 18 (2008) 710–715
715
M.-H.; Gellibert, F. J.; Grillot, D. A.; Lambert, M. H.;
Laroze, A.; Le Grumelec, C.; Linget, J.-M.; Montana, V.
G.; Nguyen, V.-L.; Nicodeme, E.; Patel, V.; Penfornis,
A.; Pineau, O.; Pohin, D.; Potvain, F.; Poulain, G.;
Ruault, C.; Saunders, M.; Toum, J.; Xu, H. E.; Xu, R.
X.; Pianetti, P. M. J. Med. Chem. 2007, 50, 685.
9. Ornstein, P. L.; Arnold, M. B.; Allen, N. K.; Bleisch, T.;
Borromeo, P. S.; Lugar, C. W.; Leander, J. D.; Lodge, D.;
Schoepp, D. D. J. Med. Chem. 1996, 39, 2232.
10. Soll, R. M.; Kinney, W. A.; Primeau, J.; Garrick, L.;
McCaully, R. J.; Colatsky, T.; Oshiro, G.; Park, C.
H.; Hartupee, D.; White, V.; McCallum, J.; Russo, A.;
Dinish, J.; Wojdan, A. Bioorg. Med. Chem. Lett. 1993,
3, 757.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.bmcl.2007.
11.053.
References and notes
1. Kliewer, S. A.; Umesono, K.; Noonan, D. J.; Heyman, R.
A.; Evans, R. M. Nature 1992, 358, 771.
2. Willson, T. M.; Brown, P. J.; Sternbach, D. D.; Henke, B.
R. J. Med. Chem. 2000, 43, 527.
3. Xu, Y.; Mayhugh, D.; Saeed, A.; Wang, X.; Thompson,
R. D.; Dominianni, S. J.; Kauffman, R. F.; Singh, J.;
Bean, J. S.; Bensch, W. R.; Barr, R. J.; Osborne, J.;
Montrose-Rafizadeh, C.; Zink, R. W.; Yumibe, N. P.;
Huang, N.; Luffer-Atlas, D.; Rungta, D.; Maise, D. E.;
Mantlo, N. B. J. Med. Chem. 2003, 46, 5121.
11. Wittenberger, S. J.; Donner, B. G. J. Org. Chem. 1993, 58,
4139.
˚
12. Johansson, A.; Poliakov, A.; Akerblom, A.; Wiklund, K.;
Lindeberg, G.; Winiwarter, S.; Danielson, U. H.; Samu-
elsson, B.; Hallberg, A. Bioorg. Med. Chem. 2003, 11,
2551.
4. van Raalte, D. H.; Li, M.; Pritchard, P. H.; Wasan, K. M.
Pharm. Res. 2004, 21, 1531.
5. (a) Sprecher, D. L. Am. J. Cardiol. 2000, 86, 46; (b) Rader,
D. J. Am. J. Cardiol. 2003, 91, 18; (c) Chong, P. H.;
Bachenheimer, B. S. Drugs 2000, 60, 55.
6. Fruchart, J.-C.; Duriez, P.; Staels, B. Curr. Opin. Lipidol.
1999, 10, 245.
7. Nomura, M.; Tanase, T.; Ide, T.; Tsunoda, M.; Suzuki,
M.; Uchiki, H.; Murakami, O.; Miyachi, H. J. Med.
Chem. 2003, 46, 3581.
13. Henke, B. R.; Blanchard, S. G.; Brackeen, M. F.; Brown,
K. K.; Cobb, J. E.; Collins, J. L.; Harrington, W. W., Jr.;
Hashim, M. A.; Hull-Ryde, E. A.; Kaldor, I.; Kliewer, S.
A.; Lake, D. H.; Leesnitzer, L. M.; Lehmann, J. M.;
Lenhard, J. M.; Orband-Miller, L. A.; Miller, J. F.; Mook,
R. A.; Noble, S. A.; Oliver, W.; Parks, D. J.; Plunket, K.
D.; Szewczyk, J. R.; Willson, T. M. J. Med. Chem. 1998,
41, 5020.
14. Berthou, L.; Duverger, N.; Emmanuel, F.; Langouet, S.;
Auwerx, J.; Guillouzo, A.; Fruchart, J. C.; Rubin, E.;
Denefle, P.; Staels, B.; Branellex, D. J. Clin. Invest. 1996,
97, 2408.
8. Sierra, M. L.; Beneton, V.; Boullay, A.-B.; Boyer, T.;
Brewster, A. G.; Donche, F.; Forest, M.-C.; Fouchet,