Synthesis of 4-(3-biaryl)quinoline sulfones as potent liver X receptor agonists

Article abstract of DOI:10.1016/j.bmcl.2010.03.031

A series of 4-(3-biaryl)quinolines with sulfone substituents on the terminal aryl ring (8) was prepared as potential LXR agonists. High affinity LXRβ ligands with generally modest binding selectivity over LXRα and excellent agonist potency in LXR functional assays were identified. Many compounds had LXRβ binding IC₅₀ values <10 nM while the most potent had EC₅₀ values <1.0 nM in an ABCA1 mRNA induction assay in J774 mouse cells with efficacy comparable to T0901317. Sulfone 8a was further evaluated in LDL (-/-) mice and shown to reduce atherosclerotic lesion progression.

Full text of DOI:10.1016/j.bmcl.2010.03.031

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2903–2907
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of 4-(3-biaryl)quinoline sulfones as potent liver X receptor agonists
a
a
a
a
John W. Ullrich a, , Robert Morris , Ronald C. Bernotas , Jeremy M. Travins , James Jetter ,
Rayomand Unwalla a, Elaine Quinet b, Ponnal Nambi b, Irene Feingold c, Christine Huselton c,
Christofer Enroth 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 Drug Safety and Metabolism, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426, 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-biaryl)quinolines with sulfone substituents on the terminal aryl ring (8) was prepared as
Received 25 January 2010
Revised 4 March 2010
Accepted 5 March 2010
Available online 9 March 2010
potential LXR agonists. High affinity LXRb ligands with generally modest binding selectivity over LXR
a
and excellent agonist potency in LXR functional assays were identified. Many compounds had LXRb bind-
ing IC50 values <10 nM while the most potent had EC50 values <1.0 nM in an ABCA1 mRNA induction
assay in J774 mouse cells with efficacy comparable to T0901317. Sulfone 8a was further evaluated in
LDL (ꢀ/ꢀ) mice and shown to reduce atherosclerotic lesion progression.
Keywords:
Liver X receptor
LXR
Ó 2010 Elsevier Ltd. All rights reserved.
Quinoline
Sulfone
ABCA1
Atherosclerosis
Lipid
Cholesterol
A major cause of mortality in modern societies is atherosclerotic
cardiovascular disease (CVD),1 characterized by the accumulation
of low density lipoprotein (LDL) particles in the arterial wall lead-
ing to the formation of cholesterol-laden foam cells and immune
system activation.2 Important therapeutics directed towards mod-
ification of the HMG-CoA reductase pathway (e.g., statins, LipitorÒ)
have been developed.3 Although these therapies lower circulating
levels of low density lipoprotein (LDL) cholesterol and successfully
reduce the incidence of CVD,4 myocardial infarction events and
ischemic stroke are only reduced by one-third, and many individ-
uals with ‘normal’ LDL levels suffer from atherosclerosis.
High density lipoprotein (HDL) bound cholesterol, sometimes
called ‘good cholesterol’ seems to protect against cardiovascular
diseases.5 The HDL particle contributes to the transport of choles-
terol from lipid-laden macrophages, (foam cells), present in the
atherosclerotic arteries to the liver for secretion into the bile.6 This
pathway has been termed reverse cholesterol transport (RCT) and
is considered as the classical protective function of HDL toward
atherosclerosis. Therapeutic agents that promote RCT and affect
the level of circulating HDL would potentially compliment the
existing LDL-based therapies.
The liver X receptor (LXR) belongs to the nuclear hormone
superfamily and is comprised of two subtypes: LXR
a
and LXRb.7
The LXRs in conjunction with retinoid X receptors (RXRs).8 serve
as intracellular oxysterol sensors and regulate expression of genes
involved in lipid metabolism.9 The LXR target genes include many
of those known to be involved with the RCT pathway, specifically
those regulating cellular cholesterol efflux, HDL metabolism, and
biliary cholesterol excretion.10
We have examined LXR agonists to increase expression of cho-
lesterol transporters including ATP-binding cassette proteins
(ABCs), a family of lipid transporters responsible for regulating
lipid homeostasis (Fig. 1).11 Of particular importance is ABCA1, a
transporter in macrophages and other cells which mediates choles-
terol efflux from peripheral cells to the lipid-poor apo-lipoprotein
acceptors.12
LXR
phages, but especially in liver. In contrast, LXRb is widely distrib-
uted in nearly all cell types. Both LXR subtypes ( and b) form
a is expressed in intestine, lung, kidney, spleen, and macro-
a
heterodimers with RXRs and the resulting complex can be
activated by binding of either an LXR agonist (e.g., endogenous
oxysterols such as 24,25-epoxycholesterol) or an RXR agonist
* Corresponding author. Tel.: +1 484 798 5027.
E-mail address: JWUllrich@comcast.net (J.W. Ullrich).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.03.031

2904
J. W. Ullrich et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2903–2907
L
X
cholesterol
efflux
Y
ABCA1
cholesterol
N
CF3
Oxysterols
(LXR a onists)
5
6
7
X = C(O)NR1R2, L = O
X = CR1R2OH, L = O
X = SO2R1, L = O
9-cis-RA
(RXR a onists)
RXR
ABCA1
LXR
7a X = SO2CH3, Y = H, L = O
8
X = SO2R1, L = direct bond
Macrophage
Figure 4. Modifications of 4-[aryl-linked-Ph]quinolines.
Figure 1. Oxidized cholesterol activates the LXR-RXR heterodimer, upregulating
the ABCA1 transporter and increasing cholesterol efflux.
nists with minimal or no PPAR activation (Fig. 4). Further changes
in the hydrogen bond acceptor led to placement of sulfone groups
on the terminal aryl ring providing a series of potent LXR agonists 7
which did not activate PPAR receptors.22
Ph
Ph
N
Based on docking studies, replacing the oxygen linker in 7
(L = O) with a rigidifying direct bond as in 8 (L = bond) would pro-
vide an acceptable trajectory allowing the sulfone substituent to
interact with key residues in the LXRb ligand binding domain
(LBD). An overlay of docked structure 8a with an X-ray structure
of 7a co-crystallized with LXRb illustrates the key interactions
important for affinity23 (Fig. 5). The His435 residue serves as a dual
hydrogen bond donor with the quinoline nitrogen and the 7-tri-
fluoro methyl group. In addition the critical hydrogen bond inter-
action between a sulfone oxygen and the backbone NH of Leu330
was also observed.
CO2H
F3C CF3
HO
O
O
O
S
N
Cl
F3C
1 T0901317 (Tularik)
CF3
2 GW3965 (GSK)
Figure 2. LXR agonists from Tularik and GlaxoSmithKline.
Sulfones 8 were synthesized starting with preparation of carbi-
nol 9 by directed anion formation at low temperature followed by
addition to 3-bromobenzaldehyde (Scheme 1). Oxidation of 9
afforded phenone 10. Reaction with aqueous ammonia at elevated
temperature and pressure provided aniline 11. Friedlander cycliza-
tion24 of 11 with an appropriately substituted aldehyde (YCH2CHO)
gave quinoline 12. This high yielding sequence allowed introduc-
tion of diversity at the C-3 position of the quinoline core. Suzuki
coupling25 of bromide 12 with substituted phenylboronic acids
provided target quinolines 8.26 Alternatively, 12 was converted
into the corresponding borolane 1327 which was isolated as a
white, room temperature stable solid. Coupling of 13 with to aryl-
bromides or aryliodides gave an alternative approach to 8.
(e.g., 9-cis-retinoic acid, 9-cis-RA) which activates mRNA transcrip-
tion encoding various genes, including ABCs.9 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.13
Several pharmaceutical companies have been active in develop-
ing LXR agonists. Among the most studied are Tularik’s T0901317
(1)14 and GlaxoSmithKline’s GW3965 (2)15 (Fig. 2) both of which
are high affinity LXR ligands with potent agonism for both LXR
subtypes.
Earlier Wyeth efforts identified potent LXR agonist LXR-623
(3),16 which effectively treated dislipidemia in mice but showed
unacceptable CNS effects at higher doses in a phase I clinical trial
(Fig. 3).17 An alternate series was found which replaced the inda-
zole core with a substituted quinoline leading to WAY-254011
(4).18 Typically quinoline benzyloxyacetic acids such as 4 had
excellent affinity and were potent LXR agonists. Unfortunately, 4
possessed moderate PPAR agonism, activating all three subtypes
of the receptor.19
Modification of the benzyloxyacetic acid by incorporating alter-
nate hydrogen bond acceptors led to a series of biarylether
amides20 (5) and alcohols21 (6) which gave high affinity LXR ago-
F
CO2H
O
N
Cl
F
N
N
CF3
CF3
3 LXR-623
4 WAY-254011
Figure 5. Docked structure of Compound 8a (yellow) overlaid with X-ray structure
of LXRb and 7a (magenta). Only important residues are shown for clarity. Hydrogen
bonds are denoted by cyan dotted lines.
Figure 3. LXR agonists from Wyeth.

J. W. Ullrich et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2903–2907
2905
Z
5
2
6
4
SO2R
Br
Br
X
Y
3
1
g or h
e
Y
c, d
a, b
OH
O
F
F
R1
N
N
CF3
CF3
CF3
CF3
CF3
9
10 R1 = F
12 X = Br
13 X = BPin
8
f
11 R1= NH2
Scheme 1. Reagents and conditions: (a) nBuLi, THF, ꢀ78 to 0 °C, 6 h; (b) 3-bromobenzaldehyde, 0 °C, 2 h; (c) pyridinium chlorochromate, CH2Cl2; (d) DMSO, concd NH4OH,
sealed tube, 100 °C, 4–6 h; (e) YCH2CHO, AcOH, H2SO4 (cat), 120 °C; (f) bis(pinacolato)diborane, Pd(PPh3)4, KOAc, toluene, 100 °C; (g) ArB(OH)2, Cs2CO3, Pd(PPh3)4, DMF, 90 °C;
(h) ArBr or ArI, Cs2CO3, Pd(PPh3)4, DMF, 90 °C.
Final targets 8 were tested to determine binding affinity for the
over LXR
binding selectivity (LXR
a
was only moderate, though a few compounds showed
IC50/LXRb IC50) of 10- to 20-fold.
two LXR subtypes (Table 1).18 The binding assays used recombi-
a
nant human ligand binding domains (LBDs) of the respective LXR
a
The higher affinity compounds were tested in a Gal4b func-
tional assay for LXR activity.18 These LXR transactivation assays
used Huh7 cells transfected with human LXR ligand binding
domains fused to Gal4 DNA binding domains. The positional pref-
erence for meta-sulfone substitution over para in the functional
assay was apparent comparing 8e to 8f, with a 33-fold greater po-
tency favoring the meta over the para isomer. Another SAR point
explored was the importance of the quinoline 3-substituent (Y).
Benzyl and larger alkyl groups typically gave comparable activity
but a methyl or hydrogen at this position had modestly weaker po-
tency (e.g., 8a and 8c). Varying the alkyl group on the sulfone also
slightly reduced potency (compare 8c with 8k and 8a with 8j) in
this assay. The potency was maintained and tracked with the bind-
ing data for additional substituents (Z) on the phenylsulfone ring
and LXRb subtypes measuring displacement of [3H]T0901317 from
the LBD.28 Typically, the meta-methylsulfones had excellent LXR
affinity while the para analogs had an order of magnitude weaker
affinity (compare 8a, 8c, and 8e to 8b, 8d, and 8f, respectively).
Focusing on meta-sulfones, the effect of varying the 3-subsituent
on the quinoline (Y) was investigated but little change in affinity
was seen as Y changed from a large lipophilic benzyl group down
to a hydrogen. (see 8a, 8c, 8e, 8g–i). Increasing the size of the alkyl-
sulfone even from methylsulfone to ethylsulfone reduced affinity
suggesting a steric limit to the LBD pocket (compare 8j to 8a and
8k to 8c). Finally, an additional substituent on the sulfone-bearing
ring had little effect on affinity (8l–q) except for methoxy (8m),
again suggesting steric issues. Subtype binding selectivity for LXRb
Table 1
Biarylsulfone quinolines 8a
Z
3
2
4
X
5
6
Y
N
CF3
Compd
X
Y
Z
LXRb IC50 (nM)
LXRa
IC50 (nM)
Gal4b EC50 (nM) (% agonism)
Microsomal stability t1/2 (r, min)
1
—
—
H
H
—
H
H
H
H
H
H
H
H
H
H
H
9
13
68
>1000
9.0
>1000
7.0
372
4.8
7.6
8.2
362
73
12
170 (100 %)
525 (73%)
nt
284 (94 %)
nt
>30 (r, h)
>30 (r, h)
>30 (r, h)
>30 (r)
>30 (r, h)
16 (r)
7 (r), 27 (h)
>30 (r, h)
>30 (r, h)
>30 (r, h)
>30 (r, h)
>30 (r, h)
27 (r), >30 (h)
>30 (h)
19 (r), >30 (h)
>30 (r, h)
12 (r), >30 (h)
>30 (r, h)
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
3-SO2Me
4-SO2Me
3-SO2Me
4-SO2Me
3-SO2Me
4-SO2Me
3-SO2Me
3-SO2Me
3-SO2Me
3-SO2Et
3-SO2Et
3-SO2Me
3-SO2Me
3-SO2Me
3-SO2Me
3-SO2Me
3-SO2Me
4.4
>1000
1.8
355
1.5
109
2.4
3.8
4.1
33
5.2
3.2
629
1.7
3.3
2.6
4.9
Me
Me
CH2Ph
CH2Ph
Et
Pr
iPr
H
Me
Me
Me
Me
Me
H
100 (112%)
3300 (44%)
76 (93%)
106 (98%)
91 (97%)
1080 (30%)
580 (67%)
175 (110%)
nt
161 (80%)
195 (81%)
512 (76%)
565 (76%)
4-Me
4-OMe
4-F
4,6-di F
4-F
>1000
10
10
32
25
H
4,6-di F
a
Results are given as the mean of two independent experiments. The standard deviations for the binding and Gal4b assays were typically 30% of the mean or less. % of
efficacy is relative to 1. nt = not tested. r = rat liver microsomes, h = human liver microsomes.

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J. W. Ullrich et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2903–2907
Table 2
Gene regulation and TG accumulation for 8a
Z
5
6
4
X
3
2
Y
N
CF3
Compd
X
Y
Z
ABCA1b EC50 (nM) (% agonism)
SREBP-1cd EC50 (nM) (% agonism)
TG accume EC50 (nM) (% agonism)
1
—
—
H
Me
CH2Ph
Et
Pr
iPr
H
Me
H
H
—
H
H
H
H
H
H
H
35 (100%)
77 (94%)
36 (100%)
440 (93%)
52 (118%)
571 (101%)
8.0 (121%)
8.0 (129%)
6.0 (117%)
521 (74%)
250 (108%)
nt
107 (100%)
77 (94%)
8a
8c
8f
8g
8h
8i
3-SO2Me
3-SO2Me
4-SO2Me
3-SO2Me
3-SO2Me
3-SO2Me
3-SO2Et
3-SO2Et
3-SO2Me
3-SO2Me
23 (124%)
571 (101%)
0.7 (121%)
0.4 (107%)
0.5 (110%)
156 (80%)
190 (69%)
140 (103%)c
11 (111%)
23 (124%)
571 (101%)
0.7 (121%)
0.4 (107%)
0.5 (110%)
156 (80%)
190 (69%)
41 (43%)
8j
8k
8p
8q
H
4-F
4,6-di F
132 (81%)f
133 (43%)
a
b
c
Results are given as the mean of two independent experiments. % efficacy is relative to 1. nt = not tested. r = rat, h = human.
J774 cell line.
THP-1 cells.
Huh7 cells.
HepG2 cells
d
e
(cf. 8a to 8p, and 8q, and 8c to 8l–o). The biaryl-sulfones typically
showed no agonism when tested in Gal4-PPAR transactivation as-
says reported earlier.20
gression (33%, 59% and 60% at 3, 10 and 30 mg/kg/day, respec-
tively) but with an undesired increase in triglyceride levels.
In summary, a series of 4-(biaryl)quinolines 8 was prepared in
which a bond replaced an oxygen atom in an earlier biarylether
series 7. An efficient, convergent synthesis allowed variation at
key positions on the molecules furthering SAR studies. A meta-sul-
fone on the terminal aryl ring gave particularly high affinity LXR li-
gands, typically with excellent agonist potency for upregulating
the ABCA1 transporter in macrophage cells. Among these com-
Most compounds were further tested for efficacy for upregulat-
ing ABCA1 mRNA in a J774 mouse macrophage cell line (Table 2).28
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, larger alkyl sub-
stituents Y on the quinoline core such as ethyl, propyl, and isopro-
pyl gave very potent, fully efficacious compounds (8g–i). With
smaller groups such as hydrogen and methyl, the potency dropped
off (8a, 8c) although the efficacy was maintained. Larger alkylsulf-
ones reduced both affinity and potency (8a to 8j and 8c to 8k).
Additional phenyl sulfone ring substituents maintained activity
and typically showed an increase in mRNA levels (8p and 8q).
Out of this series, 8a, 8c, and 8g–i were the most potent and were
all essentially as efficacious as 1. Unfortunately compound 8a also
increased expression of SREBP-1c in Huh7 cells with an EC50 value
of 440 nM and an efficacy of 93% relative to 1, demonstrating a lack
of desired gene selectivity.
pounds, 8a had 15-fold binding selectivity for LXRb over the LXR
a
subtype and excellent oral bioavailability in mice. While 8a dis-
played in vivo efficacy in LDLr knockout mice for lesions, the unde-
sired SREBP-1c agonism as well as the TG accumulation, both in a
cellular assay and in vivo, hindered further development of this
series.
Acknowledgments
We thank Discovery Analytical Chemistry for analytical data,
and Anita Halpern and Dawn Savio for biological data. We
acknowledge the support of Drs. Li Di, Ronald Magolda (deceased
June 1, 2008), Magid Abou-Gharbia, Steven Gardell, and George
Vlasuk.
Compound 8a and several analogs were examined in a func-
tional assay which measured changes in TG levels in a human he-
patic cell line (HepG2). It was found that the most potent
compounds for up regulating ABCA1 mRNA also increased intracel-
lular TG levels. The increase in TG concentrations may relate to
undesired accumulation of lipids, particularly in the liver.
In an assay testing for stability in rat and human microsomes,29
the majority of compounds were stable in both rat and human
microsomes. Typically, larger alkyl groups and benzyl substitution
at C3 of the quinoline core provides less stable compounds. The
pharmacokinetics of 8a was characterized by a very long terminal
t1/2 of 13.9 h and excellent bioavailability (ꢁ100%) following
10 mg/kg po (gavage) dosing in 0.5% methylcellulose/2% Tween
in water in male C57 mice, with a Cmax of 106 ng/mL, AUC0–1 of
3009 ng h/mL, and a Tmax of 1.0 h.30
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