Discovery of tertiary sulfonamides as potent liver X receptor antagonists

Article abstract of DOI:10.1021/jm901797p

Tertiary sulfonamides were identified in a HTS as dual liver X receptor (LXR, NR1H2, and NR1H3) ligands, and the binding affinity of the series was increased through iterative analogue synthesis. A ligand-bound cocrystal structure was determined which elucidated key interactions for high binding affinity. Further characterization of the tertiary sulfonamide series led to the identification of high affinity LXR antagonists. GSK2033 (17) is the first potent cell-active LXR antagonist described to date. 17 may be a useful chemical probe to explore the cell biology of this orphan nuclear receptor.

Full text of DOI:10.1021/jm901797p

3412 J. Med. Chem. 2010, 53, 3412–3416
DOI: 10.1021/jm901797p
Discovery of Tertiary Sulfonamides as Potent Liver X Receptor Antagonists
William J. Zuercher,* Richard G. Buckholz,† Nino Campobasso, Jon L. Collins, Cristin M. Galardi, Robert T. Gampe,
Stephen M. Hyatt, Susan L. Merrihew, John T. Moore, Jeffrey A. Oplinger, Paul R. Reid,‡ Paul K. Spearing,
Thomas B. Stanley, Eugene L. Stewart, and Timothy M. Willson
GlaxoSmithKline, Five Moore Drive, Research Triangle Park, North Carolina 27709. †Current address: Talecris Biotherapeutics, 4101 Research
Commons, 79 T. W. Alexander Drive, Research Triangle Park, North Carolina 27709. ‡Current address: Vanderbilt University Institute of
Chemical Biology, 12410-D MRB-IV (LG), 2213 Garland Avenue, Nashville, Tennessee 37232-0412.
Received December 3, 2009
Tertiary sulfonamides were identified in a HTS as dual liver X receptor (LXR, NR1H2, and NR1H3)
ligands, and the binding affinity of the series was increased through iterative analogue synthesis. A
ligand-bound cocrystal structure was determined which elucidated key interactions for high binding
affinity. Further characterization of the tertiary sulfonamide series led to the identification of high
affinity LXR antagonists. GSK2033 (17) is the first potent cell-active LXR antagonist described to date.
17 may be a useful chemical probe to explore the cell biology of this orphan nuclear receptor.
Introduction
screendelivered the biaryl tertiary sulfonamide4, representing
a new LXR chemotype. Optimization of this series led to the
identification of potent LXR ligands with an unprecedented
range of functional activity, from full agonists to full antago-
nists.
The nuclear receptor (NRa) superfamily of ligand-activated
transcription factors comprises 48 members in the human
genome; asNRs bindtotheir cognateligands, conformational
changes are induced which modulate cofactor recruitment
and, consequently, the expression of target genes.1 LXRR
(NR1H2) and LXRβ (NR1H2) are NRs which play impor-
tant roles in lipid homeostasis and serve as intracellular
sensors of cholesterol load.2 Endogenous ligands include
oxysterols such as 24(S),25-epoxycholesterol (1, Chart 1).3,4
The potent dual LXRR/β agonists T1317 (2) and GW3965 (3)
have been used as chemical probes to uncover biology of the
LXRs and their roles in mammalian physiology.5,6 These
chemical probes have been used to identify LXR target genes,
such as sterol regulatory element binding protein 1c (SREBP-
1c) and carbohydrate response element binding protein
(ChREBP) through which the receptor regulates hepatic
lipogenesis.7,8 This liability has limited the utility of LXR
agonists as drugs for the treatment or prevention of cardio-
vascular disease.9
Results and Discussion
To optimize activity of the initial hit 4, analogues were
prepared via the three-step synthetic route shown. 4-Bromo-
benzylamine was reacted with a variety of sulfonyl chlorides,
and the resulting sulfonamides 5 were alkylated with benzylic
and heterobenzylic halides to produce tertiary sulfonamides6.
Suzuki coupling formed the desired biaryl species 7. Utilizing
this three-step sequence, arrays of several hundred com-
pounds were prepared.
In an effort to identify a new class of LXR ligands devoid of
the hepatic liability, we conducted a high-throughput screen
(HTS) of the GlaxoSmithKline compound collection using a
fluorescence resonance energy transfer (FRET) assay to
measure the interaction between the LXRβ ligand-binding
domain (LBD) and a peptide containing the second NR box
of steroid receptor coactivator-1 (SRC-1). Hit compounds
were further characterized in a radioligand binding assay. The
Screening of the tertiary sulfonamides in an LXRβ compe-
tition binding assay revealed several SAR trends. Systematic
truncation of 4 showed that the piperazine was not required
but defined the importance of the biaryl moietyin maintaining
binding affinity (data not shown). Modification of the tertiary
sulfonamide revealed several important findings as high-
lighted by the data in Table 1. The sulfonamide group was
required for high LXR affinity; replacement of the sulfonyl
with a carbonyl or a methylene spacer (as in 9 and 10) reduced
LXR affinity. Certain biaryl substituents at R1 led to a boost
in affinity with 11 and 12, which incorporated a 3-MeSO2
group showing the best activity. All subsequent arrays main-
tained the 3-MeSO2 group, and results from the binding assay
demonstrated that receptor affinity could be maintained near
10 nM with a range of sulfonamide substituents R2, as in
12-15 and 18.
*To whom correspondence should be addressed. Phone: 919-483-
5275. E-mail: william.j.zuercher@gsk.com. Address: Exploratory
Chemistry and Biology, GlaxoSmithKline, Five Moore Drive, Research
Triangle Park, North Carolina 27709.
a Abbreviations: ABCA1, ATP-binding cassette transporter A1;
AF-2, activation function 2; ChREBP, carbohydrate response element
binding protein; FRET, fluorescence resonance energy transfer; HTS,
high throughput screen; LBD, ligand-binding domain; LXR, liver
X receptor; NR, nuclear receptor; SRC-1, steroid receptor coactivator 1;
SREBP-1c, sterol regulatory element binding protein 1c; TIF2, transcrip-
tional intermediary factor 2.
r
pubs.acs.org/jmc
Published on Web 03/26/2010
2010 American Chemical Society

Brief Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 8 3413
To date, ligand-bound LXR cocrystal structures have been
published for 1-3.10-12 These crystal structures exhibit plas-
ticity with ligand-binding pockets that vary in size and shape
depending on the nature of the ligand. Whereas 1-3 show
different interactions with residues in the pocket that are distal
to AF-2, they activate the receptor by promoting similar
electrostatic interactions between a conserved histidine on
helix 10/11 and tryptophan on the C-terminal activation
function-2 (AF-2) helix.13
Chlorine from the 2-chloro-6-fluorobenzyl moiety resides
˚
3.4 A from His 435 NE2 and the entire functional group
occupies much of the same hydrophobic pocket as one of the
benzhydryl phenyl rings in 2 or the trifluoroethyl substituent
in 3. The N-methylimidazole extends far deeper into a hydro-
phobicpocket than the gem-dimethyl group of 1, the 2-chloro-
3-trifluoromethylbenzyl group of 2, or the trifluoromethyl
˚
groups of 3 so that its methyl is positioned 3.2 A from Phe
˚
268 CE1 and 3.5 A from Leu 442 CD2. Only on the distal end
of the biaryl moiety is a hydrogen bond noted. Methyl sulfone
To elucidate the intermolecular interactions for a high
affinity tertiary sulfonamide presented here, we obtained the
cocrystal structure of 18 with the human LXRβ ligand LBD
and a 12 residue peptide containing the third NR box of
transcriptional intermediary factor 2 (TIF2). As illustrated in
Figure 1, we observed the canonical three-layered R-helical
fold where the C-terminal AF-2 helix is packed against the
ligand-binding pocket in a conformation that enables coacti-
vator binding. Intermolecular contacts between 18 and the
receptor are dominated by hydrophobic side chains that line
the binding pocket. The sulfonamide oxygen O1 lies poised to
˚
oxygen atom O3 accepts a 3.0 A hydrogen bond from the
backbone NH of Leu330 in the β-hairpin loop between helix
5 and 6; the guanidinium NH1 side chain atom of Arg 319 at
˚
the end of helix 5 is also 3.0 A from methyl sulfone oxygen
atom O3.
The tertiary sulfonamide arrays were further characterized
in a heterologous reporter assay utilizing CV-1 cells transi-
ently expressing an LXR-Gal4 chimera along with a reporter
harboring the Gal4 enhancer region linked to a luciferase
reporter gene. Consistent with the binding data, many tertiary
sulfonamideswere potentagonists inthe transactivationassay
(Table 2). No subtype selectivity greater than 10-fold was
observed. Nearlyallofthe compounds (11-14) profiled as full
agonists, withefficacyinthe transactivationassaycomparable
tothe first generation LXRagonists2 and 3. However, 15 with
its bulky 2,4,6-trimethylphenyl group profiled as a partial
agonist relative to 2. Subsequent variation of the R3 substi-
tuent demonstrated that efficacy could be further reduced to
such an extent that no agonist response was observed with 17
in the transactivation assay.
˚
interact with NE2 of His 435 in helix 10/11, but the 3.9 A
distance is too long to invoke a hydrogen bond. Sulfonamide
oxygen O2is directed toward a region formed by hydrophobic
sidechain atoms from Thr 272, Ala 275, Leu453, and Trp457.
Chart 1. Known LXR Ligands 1-3 and LXR HTS Hit 4
Given that 17 showed high binding affinity for LXR and
that the chemical modifications relative to other compounds
in the series were not predicted to affect cell permeability, it
was profiled as a potential LXR antagonist. Remarkably, 17
demonstrated potent antagonism of 2 (LXRR pIC50 = 7.0
and LXRβ pIC50 = 7.4) with no evidence of cell toxicity. To
further characterize the functional activity of 17, we tested its
ability to block the induction of known LXR target genes. In
intact cells stimulated with LXR agonist 3 (50 nM), 17 showed
a dose-dependent reduction in the expression of the ATP-
binding cassette transporter A1 (ABCA1) in THP-1 cells and
Table 1. Evaluation of LXRβ Binding Affinity of Tertiary Sulfonamides
compd
R1
X
R2
R3
LXRβ binding pIC50
2
8.1
7.7
3
4
6.4
5.5
8
H
H
H
SO2
CH2
CO
Ph
Ph
Ph
Ph
Ph
2-Cl-4-F-Ph
2-Cl-4-F-Ph
2-Cl-4-F-Ph
2-Cl-4-F-Ph
2-Cl-6-F-Ph
2-Cl-6-F-Ph
2-Cl-6-F-Ph
2-Cl-6-F-Ph
2-Cl-4-F-Ph
5-CF3-2-furanyl
2-Cl-6-F-Ph
9
<5.0
<5.0
8.4
10
11
12
13
14
15
16
17
18
MeSO2
MeSO2
MeSO2
MeSO2
MeSO2
MeSO2
MeSO2
MeSO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
8.3
8.2
cyclopropyl
2-Me-Ph
7.9
7.8
2,4,6-Me3-Ph
2,4,6-Me3-Ph
2,4,6-Me3-Ph
1-Me-4-imidazolyl
7.1
7.5
8.0

3414 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 8
Zuercher et al.
Figure 1. Crystal structure of agonist 18 bound to LXRβ and TIF2 peptide. (A) Global view of the human LXRβ ligand binding domain
(green ribbon), TIF2 LXXLL peptide (salmon ribbon) and GSK1305158 (magenta sticks). The agonist occupies the ligand binding pocket
behind helix 3, allowing helix 12 to adopt the active conformation and pack against the LBD facilitating TIF2 binding. (B) Zoomed view
looking toward the required sulfonamide group. Sulfonamide oxygen O1 lies too distant to hydrogen bond with His 435 in helix 12. On the
opposite end of the ligand, a hydrogen bond is observed between methyl sulfone oxygen O3 and the Leu 330 backbone amide in the β-hairpin.
The remaining intermolecular contacts are hydrophobic core interactions. (C) Two dimensional compound interaction diagram depicting
adjacent residues and the hydrogen bonding interaction with Leu 330 backbone amide. The crystal structure is available from the RCSB with
access code 3L0E and is further described in the Supporting Information.
SREBP-1c in HepG2 cells (Figure 2a). Levels of ABCA1
expression were driven below that observed in the absence of
stimulation with 3, suggesting that even basal gene expression
could be antagonized. Indeed, in untreated HepG2 and THP-
1 cells, 17 antagonized the expression of these genes with
apparent IC50 values less than 100 nM (Figure 2b). Consistent
with the latter observation, 17 reduced the basal level of
triglycerides in HepG2 cells (Figure 2c).
The partial agonism and antagonism of 15-17 might be
explained by the much greater size of the compounds that
could lead to perturbation of the receptor ligand binding
domain. Smaller compounds, such as 18, bind to the ligand
binding pocket of LXRβ and provide a stabilization of the
protein through hydrophobic interactions with the protein
involving residues along Helix 3, Helix 4, Helix 10/11, and the
Helix 12 loop. However, as the compounds increased in size

Brief Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 8 3415
Table 2. Evaluation of LXR Transactivation by Tertiary Sulfonamidesa
and hydrophobic character, the bulky substituents (such as
those found in 17) were more likely to perturb the conforma-
tion of the protein, particularly the region of the binding
pocket constituting Helix 3, Helix 10/11, and the loop before
Helix 12. Because these helices and the Helix 12 loop reside
near the coactivator binding pocket, the bulky ligands may
disrupt the binding of coactivator proteins, leading to partial
agonism and, eventually, full antagonism.
The interesting functional profile of 17 prompted further
efforts to define its utility as a chemical probe for the LXRs.
The tertiary sulfonamide series in general showed good
selectivity against a broad panel of NR assays, and in parti-
cular, 17 was inactive (XC50 > 10 μM) in cellular and
biochemical NR assays, including PXR, LRH-1, and FXR.
However, 17 showed rapid clearance (Clint > 1.0 mL/min/mg
prot) in rat and human liver microsome assays. The rapid
hepatic metabolism of 17 precludes its use in vivo. As such, 17
is a useful chemical probe for LXR in cellular studies only.
LXR GAL4 pEC50 (RE)
compd
LXRR
LXRβ
2
6.1 (1.0)
7.2 (1.1)
8.0 (1.0)
8.2 (1.2)
7.0 (0.9)
7.9 (1.2)
7.1 (0.5)
6.9 (0.2)
6.3 (1.0)
7.0 (1.1)
8.5 (0.9)
9.0 (1.2)
7.7 (1.0)
8.5 (1.0)
7.8 (0.6)
7.0 (0.3)
3
11
12
13
14
15
16
17
18
ia
7.1 (1.0)
ia
7.1 (0.9)
a Abbreviations: RE, relative efficacy compared to first generation
LXR agonist 2; ia, inactive.
Conclusion
In summary, tertiary sulfonamides were identified in a high
throughput screen as dual LXR ligands, and the binding
affinity of the series was increased through iterative analogue
synthesis. A ligand-bound cocrystal structure was determined
which elucidated key interactions for high binding affinity.
Further characterization of the tertiary sulfonamide series led
to the identification of high affinity LXR antagonists.
GSK2033 (17) is the first potent cell-active LXR antagonist
described to date.14-18 17 may be a useful chemical probe to
further define the cell biology of this orphan nuclear receptor.
Experimental Section
Compound solvents and reagents were reagent grade and used
without purification unless otherwise noted. All 1H NMR spectra
were recorded on a Varian 400 MHz spectrometer. Chemical
shifts (δ) are reported downfield from tetramethylsilane (Me4Si)
in parts per million (ppm) of the applied field. Peak multiplicities
are abbreviated: singlet, s; broad singlet, bs; doublet, d; triplet, t;
quartet, q; multiplet, m. Coupling constants (J) are reported in
hertz. LCMS analyses were conducted using a Waters Acquity
UPLC system with UV detection performed from 210 to 350 nm
with the MS detection performed on a Waters Acquity SQD
spectrometer. Purities of compounds 8-18 were >98% as
determined by LCMS.
General Procedure for the Preparation of Tertiary Sulfona-
mides. 4-Iodobenzylamine (3.20 g, 13.7 mmol), triethylamine
(7.65 mL, 104 mmol), and an arylsulfonyl chloride (16.5 mmol,
1.2 equiv) were added to CH2Cl2 (40 mL). After allowing this
reaction mixture to stir overnight, water was added to precipi-
tate the product and the solution was acidified with 10 M
H2SO4. The solids were collected by filtration and triturated
with diethyl ether to yield a secondary sulfonamide. In a
subsequent step, the secondary sulfonamide (4.1 mmol), a
substituted arylboronic acid (4.9 mmol, 1.2 equiv), palladium
acetate (0.4 mmol), tri(o-tolyl)phosphine (0.8 mmol), and so-
dium carbonate (8.2 mmol) were added to a mixture of ethylene
glycol dimethyl ether (8 mL) and water (2 mL). After heating
under a nitrogen atmosphere at 65 °C for 4 h, the reaction
mixture was then diluted with EtOAc and washed with saturated
aqueous NaHCO3. The organics were dried over Na2SO4,
filtered, and concentrated under reduced pressure. Trituration
with diethyl ether afforded the biaryl secondary sulfonamide. In
a subsequent step, the biaryl sulfonamide (0.09 mmol), a
benzylic or heterobenzylic bromide (0.011 mmol), MP-carbo-
nate (0.045 mmol), and DMF (0.4 mL) were combined and
heated at 95 °C overnight with stirring. After cooling to room
Figure 2. (a) Fold induction of LXR target gene expression cells
treated with 50 nM 3 (*,* p < 0.0005); (b) relative induction of LXR
target genes in nonstimulated cells (*,** p < 0.0005); (c) dose-
dependent stimulation (2) and repression (17) of triglyceride accu-
mulation in HepG2 cells (*, ** p < 0.005).

3416 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 8
Zuercher et al.
temperature, the reaction mixture was diluted with CH2Cl2,
filtered, and concentrated under an N2 stream. The residue was
then dissolved in DMF/MeOH and purified on an Agilent 1100
Series HPLC (70 mm ꢀ 30 mm Phenomenex column packed
with Luna 5 μm C18 stationary phase) using 50-100% MeCN/
water þ 0.05% CF3CO2H elution to yield the desired biaryl
tertiary sulfonamide product.
2,4,6-Trimethyl-N-{[30-(methylsulfonyl)-4-biphenylyl]methyl}-
N-{[5-(trifluoromethyl)-2-furanyl]methyl}benzenesulfonamide (17).
1H NMR (400 MHz, DMSO-d6) δ ppm 2.27 (s, 3 H) 2.55 (s, 6 H)
3.29 (s, 3 H) 4.34 (s, 2 H) 4.41 (s, 2 H) 6.39 (d, J = 3.48 Hz, 1 H)
7.03 (d, J = 2.09 Hz, 1 H) 7.07 (s, 2 H) 7.29 (d, J = 8.00 Hz, 2 H)
7.61-7.82 (m, 3 H) 7.91 (d, J = 8.00 Hz, 1 H) 8.01 (d, J = 8.00 Hz,
1 H) 8.13 (s, 1 H). 13C NMR (CDCl3) δ 20.1, 22.8, 41.2, 44.6, 50.0,
110.2, 112.4 (JCF = 2.8 Hz), 117.5, 120.2, 125.8, 126.1, 127.5,
129.5, 129.9, 132.1, 132.2, 132.6, 135.6, 138.7, 140.4, 141.3, 142.1,
143.1, 152.8. 19F NMR (CDCl3) δ -64.7. MS (ESI): m/z 592
(M þ H)þ. HRMS for C29H29F3NO5S2 calcd 592.1426; obsd
592.1439.
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