4-(3-Aryloxyaryl)quinoline sulfones are potent liver X receptor agonists

Article abstract of DOI:10.1016/j.bmcl.2009.10.132

A series of 4-(3-aryloxyaryl)quinolines with sulfone substituents on the terminal aryl ring (7) was prepared as LXR agonists. High affinity LXR ligands with excellent agonist potency and efficacy in functional assays of LXR activity were identified. In general, these sulfone agonists were equal to or superior to previously described alcohol and amide analogs in terms of affinity, functional potency, and microsomal stability. Many of the sulfones had LXRβ binding IC₅₀ values <10 nM while the most potent compounds in an ABCA1 mRNA induction assay in J774 mouse cells had EC₅₀ values <10 nM and were as efficacious as T0901317.

Full text of DOI:10.1016/j.bmcl.2009.10.132

Bioorganic & Medicinal Chemistry Letters 20 (2010) 209–212
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
4-(3-Aryloxyaryl)quinoline sulfones are potent liver X receptor agonists
a
a
a
a
Ronald C. Bernotas a, , Robert R. Singhaus , David H. Kaufman , Jeremy M. Travins , John W. Ullrich ,
Rayomand Unwalla a, Elaine Quinet b, Mark Evans b, Ponnal Nambi b, Andrea Olland c, Björn Kauppi d,
Anna Wilhelmsson d, Annika Goos-Nilsson d, Jay Wrobel a
*
a Chemical Sciences, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426, USA
b Cardiovascular and Metabolic Diseases, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426, USA
c Chemical Sciences, Wyeth Pharmaceuticals, 35 Cambridge Park Dr., Cambridge, MA 02140, USA
d Karo Bio AB, Novum S-141, 57 Huddinge, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 4-(3-aryloxyaryl)quinolines with sulfone substituents on the terminal aryl ring (7) was pre-
pared as LXR agonists. High affinity LXR ligands with excellent agonist potency and efficacy in functional
assays of LXR activity were identified. In general, these sulfone agonists were equal to or superior to pre-
viously described alcohol and amide analogs in terms of affinity, functional potency, and microsomal sta-
bility. Many of the sulfones had LXRb binding IC50 values <10 nM while the most potent compounds in an
ABCA1 mRNA induction assay in J774 mouse cells had EC50 values <10 nM and were as efficacious as
T0901317.
Received 30 September 2009
Revised 28 October 2009
Accepted 29 October 2009
Available online 31 October 2009
Keywords:
Liver X receptor
LXR
Ó 2009 Elsevier Ltd. All rights reserved.
Quinoline
Sulfone
ABCA1
Atherosclerosis
Lipid
Cholesterol
Approaches to the treatment of cardiovascular disease, a lead-
ing cause of death in developed countries, have focused on modi-
fying the HMG-CoA reductase pathway using various statins
including LipitorÒ and blocking the uptake of cholesterol from
the intestines using inhibitors such as ZetiaÒ.1 As an alternative
to these therapies, we have examined interventions using LXRb
agonists to increase expression of cholesterol transporters includ-
ing adenosine-binding cassette transporters (ABCs), a family of
lipid transporters responsible for regulating lipid homeostasis.2 Of
particular importance is ABCA1, a key transporter in macrophages
and other cells.
(e.g., endogenous oxysterols such as 24,25-epoxycholesterol) or
an RXR agonist (e.g., 9-cis-retinoic acid) resulting in mRNA
transcription of various genes, including ABCs.4 In addition to their
role in lipid efflux, LXRs may also have an important anti-inflam-
matory role which may help minimize the development of
athlerosclerosis.5
Several pharmaceutical companies have been active in develop-
ing LXR agonists to treat dislipidemia. Among the most notable
LXR agonists are Tularik’s T0901317 (1)6 and GlaxoSmithKline’s
GW3965 (2)7 (Fig. 1), which are high affinity LXR ligands with
potent agonism for both LXRb and LXR
a subtypes. Wyeth has iden-
Adenosine-binding cassette protein transporter expression is
tightly controlled by liver X receptors (LXRs), members of the nu-
clear hormone receptor superfamily of gene transcription factors,
in conjunction with retinoid X receptors (RXRs).3 There are two
tified an indazole-based LXR agonist WAY-252623 (3),8 which
Ph
Ph
N
subtypes of LXR: LXRa and LXRb. LXRa is expressed in intestine,
CO2H
F3C CF3
HO
O
lung, kidney, spleen, and macrophages, but especially in liver. In
contrast, LXRb is widely distributed in nearly all cell types. Both
O
O
S
LXRa and LXRb form heterodimers with RXRs and the resulting
N
Cl
complex can be activated by binding of either an LXR agonist
F3C
1 T0901317 (Tularik)
CF3
2 GW3965 (GSK)
* Corresponding author.
E-mail address: bernotr@wyeth.com (R.C. Bernotas).
Figure 1. LXR Agonists from Tularik and GlaxoSmithKline.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.10.132

210
R. C. Bernotas et al. / Bioorg. Med. Chem. Lett. 20 (2010) 209–212
effectively treated dislipidemia in monkey but showed unaccept-
able CNS effects at higher doses in a phase I clinical trial (Fig. 2).9
Another Wyeth series incorporated a quinoline as the core hetero-
cycle leading to WAY-254011 (4).10
agent, typically an alkyl bromide or iodide.14 The desired sulfone
was often accompanied by some sulfinate ester, though except
with more hindered alkylating agents, this was a very minor by-
product. An alternative approach for methylsulfones utilized Ma’s
copper iodide mediated coupling procedure15 to prepare arylsulf-
ones directly from aryl iodides and aryl bromides. A third approach
to sulfones was the alkylation of thiophenols followed by OxoneÒ
treatment in one pot. The wealth of starting materials for these
three approaches allowed the incorporation of a variety of substit-
uents and substitution patterns.
The synthesis of several of the quinoline cores (10c–f) has been
described previously10,12,13 and generally utilized a Friedlander
reaction16 with a 2-aminophenone and an aldehyde or acetal. Syn-
theses of the 3-unsubstituted 4-(3-hydroxyphenyl)quinolines in-
volved the conversion of commercial 4-chloro-quinolines 9 by
Suzuki reaction with 3-hydroxyphenylboronic acid into 10a–b
(Scheme 2). Compound 10a was also prepared from 4-bromo-8-
trifluoromethylquinoline.
Two complementary approaches were used to complete the tar-
gets from phenols 10 and halogenated arylsulfones 8. Copper-med-
iated coupling of 10 to an aryl bromide or aryl iodide, typically
employing another Ma procedure, afforded biarylethers 7.17 Alter-
natively, biarylether formation could be effected for ortho, meta or
para substitution patterns by heating 10 with a fluoro or chlor-
ophenylsulfone 8 in the presence of base. Not surprisingly, fluor-
ophenylsulfones tended to react at lower temperatures compared
to chlorophenylsulfones and meta-substitution required longer
reaction times and higher temperatures.
The quinoline-acids such as 4 were generally high affinity LXR
ligands with potent agonist activity. Unfortunately, 4 (and related
analogs) was a moderate PPAR agonist, activating all three sub-
types of the receptor.11 Modification of the benzylacetic acid group
by incorporating other hydrogen bond acceptors while keeping the
4-phenyl-quinoline core led to a series of biarylether amides (5)
which gave high affinity LXR agonists with essentially no PPAR
activation (Fig. 3).12 Aryloxybenzyl alcohols (6) were also potent
LXR agonists.13 To improve the stability of the hydrogen bond
acceptor, we explored sulfone groups which provided a series of
4-(3-aryloxyaryl)quinoline sulfones 7 as potent LXR agonists.
Building on previously reported syntheses of 5 and 6, the key
step in the preparation of targets 7 was formation of a bond be-
tween a 4-(3-hydroxyphenyl)quinoline core and a halogenated
phenyl ring. The halogenated phenyl sulfones 8 were generally
prepared by three different approaches (Scheme 1). The first relied
on the partial reduction of a sulfonyl chloride to the sodium sulfi-
nate salt which was reacted in the same pot with an alkylating
F
CO2H
O
Final targets 7 were tested to determine binding affinity for the
two LXR subtypes (Table 1).10 The binding assays used the
recombinant human ligand binding domains (LBDs) of the respec-
N
Cl
F
N
CF3
N
CF3
tive LXR
a and LXRb subtypes measuring displacement of
[3H]T0901317 from the LBD.18 We first examined the effects of
regioisomers 7a–c. While para-methylsulfone 7a had good LXRb
affinity (IC50 = 42 nM), meta isomer 7b was over an order of magni-
tude higher affinity (IC50 = 1.0 nM) while ortho isomer 7c had more
than 500-fold weaker affinity for the receptor compared to 7b. This
result led us to focus on meta-sulfones. The effect of the Y-substitu-
ent was investigated using 3-benzyl-, 3-methyl-, and 3-H-quino-
lines. Comparing 7d, 7b, and 7e, there was little change in affinity
despite moving from a large, lipophilic benzyl group to methyl to
hydrogen. The similar affinity, regardless of the quinoline 3-substi-
tuent, was also seen in the related series of 8-chloroquinolines
7f–h, though here the 3-hydrogen analog dropped to an IC50 value
of 7.2 nM. Comparing 8-CF3 quinolines to 8-chloroquinolines (e.g.,
7d to 7f; 7b to 7g; 7e to 7h) also showed comparable affinity. Varia-
tions in the sulfone from methyl to hydroxypropyl (7i to 7q) showed
little change in LXR affinity, though larger groups tended to reduce
affinity. Finally, introduction of an additional substituent on the
sulfone-bearing ring also had little effect on the high affinity of the
meta-sulfone series (compare 7b to 7r–t). Binding selectivity for
3 WAY-252623
4 WAY- 254011
Figure 2. LXR Agonists from Wyeth.
O
X
Y
N
Z
5 X = C(O)NR1R2
6 X = CR1R2OH
7 X = SO2R
Figure 3. Modifications of 4-[3-(ArO)-Ph]quinolines.
LXRb over LXR
7p showed binding selectivity (LXR
However, the in vivo functional implications of this level of binding
a
subtypes was only moderate, though 7e, 7h, and
IC50/LXRb IC50) of >10-fold.
SH
SO2Cl
a
Hal
Hal
Hal
selectivity are unclear.
W
W
The compounds were also tested in a Gal4b functional assay for
LXR activity.10 These LXR transactivation assays used Huh7 cells
transfected with human LXR ligand binding domains fused to
Gal4 DNA binding domains. The preference for meta-sulfone sub-
stitution over para in the functional assay was apparent comparing
7a to 7b, with a 500-fold greater potency favoring meta over para
isomers. Another SAR point addressed was the importance of the
3-substituent on the quinoline. Benzyl and methyl groups typically
gave comparable activity but hydrogen at this position was signif-
icantly weaker (compare 7b to 7d to 7e, and 7f to 7g to 7h). We
focused on the methyl group to minimize molecular weight and
a
c
Br
SO2R
b
Hal
W
W
8
Scheme 1. Reagents and conditions: (a) Na2SO3, NaHCO3, H2O, 95–100 °C, 1 h, then
tetrabutylammonium bromide, R-Br or R-I; (b) NaSO2Me, CuI, -proline, NaOH,
DMSO, 95 °C, 18 h; (c) R-Br or R-I, K2CO3, acetone, then OxoneÒ, aq NaHCO3.
L

R. C. Bernotas et al. / Bioorg. Med. Chem. Lett. 20 (2010) 209–212
211
lipophilicity while retaining potency. Similarly, larger R groups on
the sulfone generally did not improve potency in the assay. As in
the binding assay, 8-chloro and 8-trifluoromethyl quinolines were
comparable in the Gal4b assay. Additional substituents on the
phenylsulfone ring reduced potency (cf. 7b to 7r–t). Essentially
none of the sulfones had PPAR agonism when tested in PPAR func-
tional assays reported earlier.12
Most compounds were further tested for upregulation of ABCA1
mRNA in a J774 mouse macrophage cell line (Table 1).18 Efficacy
was measured relative to 1 with the maximum increase in mRNA
using 1 taken as 100% efficacy. Overall, the same SAR trends in
the Gal4b assay were seen here. For example, 8-chloro and 8-tri-
fluoromethyl were similar to each other, while both benzyl and
methyl at the 3-position of the heterocycle had comparable activ-
ity but were significantly more potent compared to hydrogen at
that position. Larger R groups on the sulfone and additional phen-
ylsulfone ring substituents did not help activity and often gave
weaker compounds. Based on increased mRNA levels, sulfones
7b, 7d, 7i, and 7k were the most potent compounds and essentially
as efficacious as 1.
In an assay testing for stability in rat and human microsomes,
many of the compounds had greater than 50% remaining after
O
OH
Y
SO2R
Cl
W
Y
a or b
c or d
N
N
N
Z
Z
Z
9a Z = CF3
9b Z = Cl
10a Y = H, Z = CF3
10b Y = H, Z = Cl
10c Y = Me, Z = CF3
10d Y = Me, Z = Cl
10e Y = CH2Ph, Z = CF3
10f Y = CH2Ph, Z = Cl
7 R = alkyl, benzyl
Y = CH2Ph, Me, H
Z = Cl, CF3
Scheme 2. Reagents and conditions: (a) 3-(HO)PhB(OH)2 (2 equiv), Pd(PPh3)4 (0.3 equiv), 2M aq Na2CO3 (4 equiv), toluene, EtOH, reflux, 18 h (9a); (b) 3-(HO)PhB(OH)2 (1
equiv), Pd(PPh3)4 (0.07 equiv), K3PO4, 1,4-dioxane, reflux, 16 h (9b); (c) Hal-ArSO2R (Hal = Br or I, 1.5 equiv), CuI (0.2 equiv), Me2NCH2CO2H hydrochloride (0.3 equiv), Cs2CO3
(3 equiv), 1,4-dioxane, 100-110 °C, 16-24 h (d) Hal-ArSO2R (Hal = F or Cl, 1.1–1.5 equiv), K2CO3 (2 equiv), DMF or DMA, 120-150 °C, 18–24 h.
Table 1
Biarylether sulfone quinolines 7a
2
1
3
O
X
4
6
5
W
Y
3
N
8
Z
Compd
W
X
Y
Z
LXRb IC50
(nM)
LXR
(nM)
a
IC50
Gal4b EC50 (nM)
(% agonism)
ABCA1 EC50 (nM)
(% agonism)
Microsomal Stability t1/2
(min)
1
—
—
—
Cl
9
9
3
42
13
125
12
153
2.4
>1000
2.0
40
3.3
3.4
129
6.1
23
7.9
4.0
61
118
4.7
121
19
170 (100%)
800 (66%)
1,510 (73%)
1,550 (30%)
31 (78%)
Not tested
11 (78%)
214 (44%)
30 (85%)
44 (103%)
382 (45%)
55 (73%)
251 (50%)
56 (49%)
299 (44%)
592 (55%)
1030 (56%)
70 (68%)
962 (62%)
274 (48%)
688 (43%)
90 (79%)
35 (100%)
276 (80%)
555 (108%)
453 (76%)
6 (91%)
Not tested
5 (108%)
70 (87%)
Not tested
Not tested
81 (70%)
3 (100%)
10 (99%)
>30 (r, h)
4 (r), 21 (h)
>30 (h)
>30 (r, h)
>30 (r, h)
8 (r)
16 (r), 12 (h)
>30 (r, h)
3 (r), 11 (h)
8 (r)
>30 (r, h)
>30 (r)
6 (r)
23 (r)
12 (r), 18 (h)
10 (r)
8 (r)
5a
6a
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
7t
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3-C(O)NHMe
3-CH2OH
4-SO2Me
3-SO2Me
2-SO2Me
3-SO2Me
3-SO2Me
3-SO2Me
3-SO2Me
Me
Me
Me
Me
Me
CH2Ph
H
CH2Ph
Me
H
Me
Me
Me
H
Me
Me
Me
Me
Me
Me
Me
Me
CF3
CF3
CF3
CF3
CF3
CF3
Cl
1.0
560
0.92
2.8
1.2
1.1
7.2
1.6
2.6
1.8
2.4
8.1
13
1.4
8.2
3.2
8.2
1.9
3.0
Cl
Cl
3-SO2Me
3-SO2Et
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
3-SO2-1-Pr
3-SO2-2-Pr
3-SO2-2-Pr
3-SO2CH2CHMe2
3-SO2CH2CH2CHMe2
3-SO2CH2CH2CH2OH
3-SO2CH2CH2CMe2OH
3-SO2CH2CH2CH2OMe
3-SO2Me
3 (88%)
22 (77%)
55 (107%)
154 (135%)
24 (112%)
636 (96%)
Not tested
256 (112%)
14 (114%)
162 (135%)
H
H
H
>30 (r)
>30 (r)
1 (r)
11 (r), >30 (h)
>30 (r, h)
>30 (r, h)
4-OMe
5-F
5-Cl
56
6.6
28
3-SO2Me
3-SO2Me
445 (89%)
a
Results are given as the mean of two independent experiments. The standard deviations for the binding assays were typically 30% of the mean or less. The standard
deviations for the Gal4b assay were typically 30% of the mean or less. % of efficacy is relative to 1. r = rat liver microsomes, h = human liver microsomes.

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R. C. Bernotas et al. / Bioorg. Med. Chem. Lett. 20 (2010) 209–212
pounds had potency and efficacy comparable to 1, with a few com-
pounds having greater potency. Structure–activity relationships for
the two functional assays were generally consistent. Stability in rat
and human microsomes was high for many analogs, especially
those with smaller alkyl groups. 4-(3-Aryloxyaryl)quinolines with
a meta-sulfone group are high affinity LXR ligands, often with
excellent agonist potency for upregulating ABCA1 mRNA and no
PPAR activity.
Acknowledgments
We thank the Wyeth Discovery Analytical Chemistry Depart-
ment for analytical data, Anita Halpern and Dawn Savio for biolog-
ical assay data and Weixin Xu for technical assistance. We
acknowledge the contributions and support of Drs. Li Di, Ronald
Magolda (deceased June 1, 2008), Magid Abou-Gharbia, Tarek
Mansour, Steven Gardell, and George Vlasuk.
References and notes
Figure 4. Overlay of X-ray structures of hLXRb/3 complex (blue) and hLXRb/7e
complex (magenta). Only key residues and helices are shown. Hydrogen bonds to
key Leu330 and His435 residues are shown by dotted yellow lines.
1. For an overview of LipitorÒ therapy, see: Bybee, K. A.; Lee, J. H.; O’Keefe, J. H.
Curr. Med. Res. Opin. 2008, 24, 1217.
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30 min. However, longer alkyl groups on the sulfone tended to
shorten the half-life in a rat microsomal preparation, especially
when the linear chain length exceeded two carbons. Typically, ben-
zyl substitution at Y gave less stable compounds. Methoxy substit-
uents, either as part of R (7q) or on the phenylsulfone ring (7r), also
reduced stability. 8-Chloro compounds were somewhat less stable
compared to 8-trifluoromethyl.
7. Collins, J. L. et al J. Med. Chem. 2002, 45, 1963.
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Compound 7e was cocrystallized with LXRb to examine the
ligand binding mode and understand which residues are important
for affinity (Fig. 4).19 An overlay of the previously disclosed8 X-ray
structure of the ligand binding domain of hLXRb/3 with hLXRb/7e
is also shown. Ligand recognition was achieved by hydrogen bond
interaction between the His435 residue in the active site and the
quinoline nitrogen and the N-1 indazole nitrogen in 7e and 3,
respectively. The trifluoromethyl groups in both structures were
in close proximity to His435 residue (d(N–F) = 3.0 Å) and may have
a favorable electrostatic interaction with the histidine. The N2-ben-
zyl group in 3, positioned in a hydrophobic pocket surrounded by
three Phe residues (329, 340 and 349), is replaced by a hydrogen.
In 7e the loss of these hydrophobic interactions was apparently
compensated for by a strong hydrogen bond interaction between
a sulfone oxygen and the backbone NH group of Leu330. However,
the loss in potency in both the Gal4b and ABCA1 assays suggests at
least a methyl group is needed for good functional activity.
Replacement of alcohols and amides with sulfones led to a ser-
ies of high affinity LXR ligands 7. Efficient synthetic approaches
allowed variation at key positions on the molecules furthering
the SAR. Some of the compounds showed modest binding selectiv-
9. Katz, A.; Udata, C.; Ott, E.; Hickey, L.; Burczynski, M. E.; Burghart, P.;
Vesterqvist, O.; Meng, X. J. Clin. Pharmacol. 2009, 49, 643.
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Halpern, A.; Basso, M.; Keith, J.; Clerin, V.; Chen, L.; Resmini, C.; Liu, Q.-Y.;
Feingold, I.; Huselton, C.; Azam, F.; Farnegardh, M.; Enroth, C.; Bonn, T.; Goos-
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11. Hu, B.; Quinet, E.; Unwalla, R.; Collini, M.; Jetter, J.; Dooley, R.; Andraka, D.;
Nogle, L.; Savio, D.; Halpern, A.; Goos-Nilsson, A.; Wilhelmsson, A.; Nambi, P.;
Wrobel, J. Bioorg. Med. Chem. Lett. 2008, 18, 54. and Ref. 12.
12. Bernotas, R.; Singhaus, R.; Kaufman, D.; Ullrich, J.; Fletcher, H.; Quinet, E.;
Nambi, P.; Unwalla, R.; Savio, D.; Wilhelmsson, A.; Goos-Nilsson, A.;
Farnegardh, M.; Wrobel, J. Bioorg. Med. Chem. 2009, 17, 1663.
13. Bernotas, R.; Kaufman, D.; Singhaus, R.; Ullrich, J.; Unwalla, R.; Quinet, E.;
Nambi, P.; Wilhelmsson, A.; Goos-Nilsson, A.; Wrobel, J. Bioorg. Med. Chem., in
press. doi:10.1016/j.bmc.2009.10.001.
14. New compounds gave satisfactory 1H NMR, MS, and HRMS data. Compounds
were generally >95% pure by HPLC analysis. Further experimental details are
given in patent application WO 2008049047.
15. Zhu, W.; Ma, D. J. Org. Chem. 2005, 70, 2696.
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E.; Samadi, A.; Carreiras, M. C.; Soriano, E. Chem. Rev. 2009, 109, 2652.
17. Ma, D.; Cai, Q. Org. Lett. 2003, 5, 3799; For alternative biarylether synthesis
procedures, see: Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
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18. Quinet, E.; Savio, D. A.; Halpern, A. R.; Chen, L.; Miller, C. P.; Nambi, P. J. Lipid
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19. X-ray coordinates for the protein–ligand crystal structure were deposited in
the RCSB Protein Data Bank, PDB deposition code 3KFC.
ity for LXRb over LXRa. Many of the compounds had potent LXRb
agonist activity in a Gal4b functional assay. A second functional
assay using mouse J774 cells demonstrated increases in mRNA
for ABCA1, a key protein for lipid transport. Several of the com-