Quinoline-3-carboxamide containing sulfones as liver X receptor (LXR) agonists with binding selectivity for LXRβ and low blood-brain penetration

Article abstract of DOI:10.1016/j.bmcl.2009.11.062

A series of quinoline-3-carboxamide containing sulfones was prepared and found to have good binding affinity for LXRβ and moderate binding selectivity over LXRα. The 8-Cl quinoline analog 33 with a high TPSA score, displayed 34-fold binding selectivity for LXRβ over LXRα (LXRβ IC₅₀ = 16 nM), good activity for inducing ABCA1 gene expression in a THP macrophage cell line, desired weak potency in the LXRα Gal4 functional assay, and low blood-brain barrier penetration in rat.

Full text of DOI:10.1016/j.bmcl.2009.11.062

Bioorganic & Medicinal Chemistry Letters 20 (2010) 689–693
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Quinoline-3-carboxamide containing sulfones as liver X receptor (LXR) agonists
with binding selectivity for LXRb and low blood–brain penetration
a
a
a
b
c
Baihua Hu a, , Ron Bernotas , Rayomand Unwalla , Michael Collini , Elaine Quinet , Irene Feingold ,
*
Annika Goos-Nilsson d, Anna Wilhelmsson d, Ponnal Nambi b, Mark Evans b, Jay Wrobel a
a Chemical Science, Collegeville, PA, USA
b Cardiovascular and Metabolic Disease, Collegeville, PA, USA
c Bio Transformation and Disposition, Collegeville, PA, USA
d Karo-Bio, 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 quinoline-3-carboxamide containing sulfones was prepared and found to have good binding
Received 21 September 2009
Revised 10 November 2009
Accepted 16 November 2009
Available online 3 December 2009
affinity for LXRb and moderate binding selectivity over LXR
TPSA score, displayed 34-fold binding selectivity for LXRb over LXR
for inducing ABCA1 gene expression in a THP macrophage cell line, desired weak potency in the LXR
Gal4 functional assay, and low blood–brain barrier penetration in rat.
a
. The 8-Cl quinoline analog 33 with a high
(LXRb IC50 = 16 nM), good activity
a
a
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
LXR agonists
Selectivity in binding assays
It is widely recognized that elevated levels of low density lipo-
protein cholesterol (LDLc) and reduced levels of high density lipo-
protein cholesterol (HDLc) represent major risk factors for
cardiovascular disease.1 Despite the wide use of effective lipid-
lowering drugs, cardiovascular disease is still the leading cause of
morbidity and mortality in the industrialized world. Liver X recep-
by the up-regulation of sterol regulatory element binding protein
1c (SREBP-1c) and fatty acid synthase (FAS) which limits the utility
of these synthetic LXR agonists. Several strategies2,3 have been pro-
posed for improving the therapeutic window of LXR agonists
including LXRb subtype selective agonists, partial agonists, and
gene or tissue specific agonists. The first hypothesis is based on
tors (LXR
a
and LXRb) are members of the nuclear hormone recep-
the observation that LXR
in the liver and that activation of LXR
a
is the predominant subtype expressed
may be responsible for
tor superfamily and are involved in the regulation of cholesterol
and lipid metabolism.2,3 They are ligand-activated transcription
factors and bind to DNA as obligate heterodimers with retinoid X
receptors (RXR). Activation of LXRs induces the expression of sev-
eral genes involved in lipid metabolism and reverse cholesterol
transport including ATP binding cassette transporters A1 and G1
(which drive cellular cholesterol efflux), A5 and G8 (which pro-
mote hepatocyte-biliary and enterocyte excretion of cholesterol),
adipocyte and macrophage-ApoE (which promote cholesterol ef-
flux), and cholesterol ester transfer protein (CETP, which transfer
cholesterol from HDL to non-HDL lipoproteins). The potential to
prevent or even reverse atherosclerotic processes by increasing
the expression of these genes makes LXR an attractive drug target
for the treatment of cardiovascular diseases. A number of LXR ago-
nists (Fig. 1), such as TO901317 (1),4 GW3965 (2),5 and WAY-
254011 (3),6 have been shown to significantly reduced lesion size
in an atherosclerosis mouse model. However, these pan agonists
also caused substantial liver and plasma triglyceride (TG) increases
a
the TG liability in vivo. Therefore, LXRb selective LXR agonists
may have less impact on TG synthesis, but may be effective in mac-
rophage reverse cholesterol transport. A modest level of LXRb
binding selectivity in small molecules has been achieved. A series
of cinnolines/quinolines was reported by Wyeth7 and it was found
that these LXRb binding selective agonists displayed good activity
for inducing ABCA1 gene expression and poor efficacy in the LXR
Gal4 functional assay. However, these cinnolines/quinolines exhib-
ited poor drug-like properties.
WAY-252623 (4), the first LXR agonist clinical candidate which
was also reported by Wyeth, possessed potent LXR binding affinity
(LXRb binding IC50 of 23 nM) with a modest ꢀ7-fold binding selec-
tivity for LXRb.8 Compound 4 had acceptable oral bioavailability of
63%, 28%, 35% in mice, rat, and monkey, respectively. It showed
reduction of aortic arch lesion progression in LDLR À/À mice with
much reduced triglyceride elevation over agonists 1 and 3. A single
ascending-dose (SAD) study of 4 in healthy humans was conducted
and it was found that 4 dose-dependently increased LXR target
gene expression (ABCA1 and ABCG1).9 However, central nervous
system (CNS)-related adverse events were observed at the two
a
* Corresponding author. Tel.: +1 484 865 7867; fax: +1 484 865 9399.
E-mail address: hub@wyeth.com (B. Hu).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.11.062

690
B. Hu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 689–693
OH
Y
a, b
Y
Y
O
+
CO2H
EtO2C
O
N
X
S
N
F3C
F3C
HO
OEt
6 Y = CN or CO2Et
5 X = H, F, Cl or CF3
N
O
NH2
X
X
Cl
7
F3C
CF3
c
1 (TO901317)
2 (GW-3965)
OH
Cl
SO2R1
+
Z
d
F
Y
CO2H
N
O
F
N
9
8
X
10 Z = H, F, or Cl;
Cl
F
N
N
Z
SO2R1
CF3
N
e
CF3
Z
SO2R1
4 (WAY-252623)
3 (WAY-254011)
O
X
Figure 1. Reported LXR agonists.
O
h or i or j
R2
Y
N
top doses tested (150 mg and 300 mg). It is not clear whether the
observed adverse effects were a result of an off-target effect of 4
or were related to LXR modulation in the brain. However, for a car-
diovascular drug, a compound that does not penetrate the blood–
brain barrier may offer benefits, particularly with regard to a CNS
side effect profile. Analysis of CNS and non-CNS drugs revealed that
the CNS drugs had lower polar surface areas (PSA) and higher cal-
culated log P(c Log P) values.10 Compound 4 has a low topological
polar surface area (TPSA value of 17) and a high calculated log P va-
lue (c Log P = 7.5). It is widely accepted that compounds with high
c Log P (>4.5) and low TPSA (<80) have much higher chances to
penetrate the blood–brain barrier.10 To avoid CNS-related side
effects, we therefore focused our new efforts on LXRb selective
agonists with low c Log P (<4.5) and high TPSA (>90).
11 R1 = lower alkyl
N
X
14 a R2 = CH2NH2
b R2 = C(=NH)NH2
c R2 = tetrazole
f
Y = CO2Et
SO2R1
Z
SO2R1
Z
O
O
g
O
O
R3HN
HO
N
N
X
13
X
12
R3 = H or Me or Et
Scheme 1. Reagents and conditions: (a) toluene; (b) Dowtherm, total yield 70–90%
for step (a) and (b); (c) POCl3, 85–100%; (d) 3-OH-phenylboronic acid, K3PO4,
Pd(PPh3)4; 50–85%; (e) K2CO3, DMF, 40–80%; (f) LiOH; (g) CDI/NH4OH or NH2Me or
NH2Et, total yield 55–79% for (f) and (g); (h) LAH; MsCl/NEt3; NH4OH; 21%; (i)
NH2HCl/AlCl3, 25%; (j) NaN3/NEt3HCl, 84%.
The preparation of the quinoline-3-carboxamide containing
sulfones is depicted in Scheme 1. Condensation of aniline 5 with
2-(ethoxymethylene)malonate 6 followed by thermal cyclization
provided the phenol 7. Conversion of the phenol 7 to the chloride
8 was accomplished readily with phosphorus oxychloride. Reac-
tion of 8 with 3-hydroxylphenylboronic acid under Suzuki condi-
tions provided 9. Arylation of 9 with fluorobenzene 1011 followed
by aqueous basic hydrolysis of 11 (Y = CO2Et) gave the carboxylic
acids 12. The resulting carboxylic acids were readily converted to
C-3 carboxamide substituted biarylether 13 by reaction with car-
bonyldiimidazole in DMF followed by addition of amines. Reduc-
tion of ester in 11 (Y = CO2Et) with lithium aluminum hydride
followed by treatment with methylsulfonyl chloride and ammo-
nium hydroxide gave the corresponding benzyl amine 14a. The
C-3 amidine analog 14b was obtained by treatment of 11
(Y = CN) with ammonium chloride and trimethylaluminum. The
C-3 tetrazole ring of 14c was formed by cycloaddition of sodium
azide with 11 (X = CN).
be a potent LXR pan agonist. As can be seen in Table 1 the 3-pri-
mary carboxamide substituted quinoline sulfone 16 showed potent
binding affinity (IC50 = 18 nM) for LXRb, good subtype binding
selectivity against LXRa (a/b 33-fold), lower c Log P (4.0) compared
to 15 (c Log P = 5.6), and a high TPSA (99) value. Analogs incorpo-
rating a 3-methyl (17) or 3-ethyl (18) carboxamide resulted in
>20-fold drop in the LXRb binding affinity. While 3-ethyl ester 19
was a potent LXRb binder with IC50 of 2 nM, poor binding selectiv-
ity was observed for this compound. The corresponding carboxylic
acid 20 showed much reduced binding affinity (hLXRb IC50 > 1 lM).
Similarly, the 3-CN analog 21 showed potent binding affinity to
LXRb (IC50 = 2.2 nM), however, poor binding selectivity was ob-
served (a/b = 6). A few 3-CN derivatives with high TPSA values
(>80), such as, 3-tetrazole 22, 3-methylamines 23, and 3- amidine
24, were prepared and all of them showed reduced LXRb binding
affinity and low binding selectivity against LXRa.
To enhance the LXRb binding affinity and/or selectivity of 16, a
few small alkyl substituted sulfones (25–29) were prepared (Table
2). In general, these compounds had good binding affinity (hLXRb
As stated previously phenyl acetic acid based analogs such as
compound 3 had considerable PPAR activity that needed to be re-
moved.7 The phenyl acetic acid moiety was responsible for the
PPAR activity. To find a polar group as a replacement for the phenyl
acetic acid, a series of amides, alcohols, sulfonamides, and sulfones
were screened by Wyeth.12 The sulfone moiety was a superior
polar group for potent quinoline LXR agonism (see 15 in Table 1).
Compound 15 and analogs had no PPAR activity and lower c Log P
(5.6 for 15) relative to 4 (c Log P 7.8) or 3 (c Log P 7.7). In an effort
to develop LXRb-selective agonists with low brain penetration
potential a series of 3-polar group substituted quinoline sulfones
with low c Log P (<4.5) and high TPSA (>90) was prepared. The
LXR binding affinity of the newly synthesized compounds was
evaluated in radio ligand binding assays.6 As a reference, TO-901317
(compound 1) was tested in the binding assays and was found to
IC50 < 60 nM) and good binding selectivity against LXR
a (a/b > 20.
Isopropyl sulfone 29 was the most selective compound in the
C-8-trifluoromethyl quinoline series which had 57-fold binding
selectivity over LXRa and good binding affinity (hLXRb IC50 = 5 nM).
While a fluorine at the meta position of the sulfone maintained
LXRb binding affinity and selectivity (25 vs 16), chlorine substitu-
tion at the same position resulted in decreased LXRb binding
affinity (26 vs 16).

B. Hu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 689–693
691
Table 1
Quinoline C3 modificationsa
SO2Me
O
Y
N
CF3
Compd
Y
c Log P
TPSA
hLXRb IC50, (nM)
hLXRa
IC50, (nM)
a/b
1
4.2
5.6
4
57
56
99
85
85
82
93
80
111
82
9
1
18
367
730
2
1076
2.2
5294
77
13
2
600
>10,000
6864
6.6
6348
13.4
1
2
33
>4
9
3
6
6
5
1512d
16
Me
CONH2
CONHMe
CONHEt
COOEt
COOH
CN
Tetrazole
CH2NH2
C(@NH)NH2
17
18
19
20
21
22
23
24
4.3
4.9
5.9
4.6
4.9
4.3
4.0
4.4
26,613
445
29,850
6
6
106
5133
a
Results are given as the mean of at least two independent experiments. The standard deviations for these assays were typically 30% of mean or less.
Table 2
SAR of C-8 and phenyl sulfone modificationsa,b
Z
SO2R1
O
O
H2N
N
X
Compd
R1
X
Z
c Log P
hLXRb IC50,
(nM)
hLXR
(nM)
a
IC50,
a/b
16
25
26
27
28
29
30
31
32
33
Me
Me
Me
Et
CF3
CF3
CF3
CF3
CF3
CF3
Me
F
H
F
4
18
18
62
11
57
5
28
590
2850
16
600
552
1772
453
1365
286
756
12,700
>10,000
543
33
31
29
41
24
57
27
22
4.3
4.8
4.5
5.1
4.8
3.6
3.3
3.1
3.8
Cl
H
H
H
H
H
H
H
Pr
i-Pr
Me
Me
Me
Me
Figure 2. Docked structure of 16 bound to hLXRb. Hydrogen bonds are shown by
yellow dotted lines. Residue adjacent to Thr316 , that is, Ala317 is highlighted in
yellow and is different between LXRa/LXRb, that is, Ala317(LXRb)/Ser303(LXRa).
H
Cl
34
a
Results are given as the mean of at least two independent experiments. The
standard deviations for these assays were typically 30% of mean or less.
In order to understand the modest LXRb selectivity (a/b 33-fold)
b
All compounds in Table 2 have the same TPSA value of 99.
of 16, we docked this ligand into a previously solved in-house X-
ray structure of compound 3.6 The best scoring pose13 of 16 from
the docking studies is shown in Figure 2. The N1 atom of the quin-
Several less hydrophobic (lower c Log P) replacements (com-
pounds 30–33) for the C-8-trifluoromethyl substituent were then
evaluated. Compared to C-8 trifluoromethyl analog 16 (c Log P
4.0), a small loss of binding activity was seen in the C-8 methyl
analog 30 (c Log P 3.8). Replacing the trifluoromethyl with a fluo-
rine (31, c Log P 3.3) or hydrogen (32, c Log P 3.1) resulted in much
reduced affinity in the binding assays (hLXRb IC50 >500 nM for 31
and 32). Chlorine proved to be a good replacement for trifluoro-
methyl since the 8-chloro quinoline 33 had essentially the same
LXRb binding affinity and binding selectivity as 16. Compared to
4, 8-chloro quinoline 33 had much lower c Log P (7.8 for 4 vs 3.8
for 33) and higher TPSA value (17 for 4 vs 99 for 33), which may
lead to lower blood–brain penetration and therefore may offer
benefits over 4 in term of the CNS related side effects of 4.
oline ring made a hydrogen bond interaction with the Ne atom of
His435 residue. In addition the 8-CF3 group was in close proximity,
that is, d(N–F) = 3.1 Å to make favorable electrostatic interactions
with this residue and provide additional binding affinity. The ben-
zyloxy group further extended towards the b-hairpin loop and
placed the sulfone group in position to make hydrogen bond inter-
action with the backbone NH of Leu330. The C-3 carboxamide group
was twisted slightly out of the plane with respect to the quinoline
ring and the amino group made a weak hydrogen bond interaction,
that is, d(N–O) = 3.2 Å with the Thr316 residue within the helix-5
region. Since all residues in close proximity (<5 Å) of the ligand-
binding pocket of LXRa and LXRb are identical it is possible that
the modest selectivity of 16 comes from perturbations of residues
within the 2nd shell which are different between these two recep-

692
B. Hu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 689–693
Table 3
Functional assaysa,b
Compd
hLXRb IC50 (nM)
a/b
LXRb Gal4 EC50
(lM, % eff)
LXR
a
Gal4 EC50
(l
M, % eff)
ABCA1 (THP1) EC50
(lM, % eff)
TG (HepG2) EC50 (lM, % eff)
18
9
24
18
16
1
7
33
34
0.17 (100%)
3.67 (73%)
1.6 (85%)
0.14 (100%)
6.66 (53%)
4.5 (22%)
3.0 (57%)
0.044 (100%)
0.54 (100%)
0.11 (104%)
0.44 (107%)
0.137 (100%)
1.0 (38%)
0.37 (47%)
1.25 (68%)
48
16
33
0.63 (72%)
a
Results are given as the mean of two to three independent experiments. The standard deviations for functional assays were typically 50% of mean or less. The % of
efficacy is relative to reference compound 1.
b
LXR transactivation assay used Huh7 cells transfected with human LXR LBD fused to Gal4 DBD; ABCA1 gene regulation by LXR ligands was measured in THP1 (human)
cells; LXR-mediated TG accumulation was measured in HepG2 cells.
Table 4
Pharmacokinetic properties of 4 and 33 in long Evans rata,b
Compd
Cmax (ng/mL, plasma)
AUC0-inf (h*ng/mL, plasma)
Cmax (ng/mL, brain)
AUC0-inf (h*ng/mL, brain)
B/P ratio
4
33
2853
1269
13,057
5417
3526
107
15,312
457
1.2
0.08
a
Dose: oral gavage 30 mg/kg for 4 and 10 mg/kg for 33.
Formulation: Methocel 0.5%:Tween 80 2%.
b
tors. Indeed if one looks at the residue adjacent to the Thr316
residue, Ala317 in LXRb is mutated to Ser303 in LXR . We believe
In summary, a series of novel quinoline 3-carboxamide contain-
ing sulfones, with relatively low c Log P (<4.5) and high TPSA scores
(>90) was found to show potent LXRb agonism and indeed this de-
sign led to compounds that showed reduced blood–brain penetra-
tion. This work has produced >30-fold LXRb binding selective
agonists. Some efficacy and potency selectivity in the Gal4 transac-
a
the C-3 carboxamide group of 16 may confer LXRb binding selec-
tivity due to the ability of the carboxamide group to make interac-
tion with Thr316 residue. This conclusion is supported by our SAR
studies which showed that methylation of one of the carboxamide
hydrogens, that is, 17, resulted in loss of potency and selectivity.
Further docking studies on 17 showed that due to steric interac-
tions with the C-4 phenyl group, the carboxamide group was
forced to flip in a different orientation and thereby lost its hydro-
gen bonding ability with the Thr316 residue.
tivation assays between LXRb and LXRa was obtained; however,
low separation between ABCA1 up-regulation in macrophage ver-
sus TG accumulation in HepG2 cells was observed for the series.
Acknowledgments
Binding selective LXR agonists 16 and 33 were tested in the
Gal4 transactivation assays (Table 3, for assay conditions see refer-
ence 6). Like compound 4, these two binding selective compounds
We thank the Wyeth Discovery Analytic Chemistry Department
for the analytical data, and Anita Halpern and Dawn Savio for bio-
logical assay data. We gratefully acknowledge Drs. Ron Magolda
(deceased on June 1, 2008), Magid Abou-Gharbia, Tarek Mansour,
Steve Gardell, and George Vlasuk for their support of this work.
were weak agonists for LXR
potency for LXRb. In contrast, literature compound 1 is a potent
agonist for both LXR and LXRb in the Gal4 assays. An LXR agonist
having lower activity against LXR may have less liability with re-
a, but showed better efficacy and
a
a
spect to triglyceride synthesis. As expected, the compounds in this
References and notes
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(>100%) for stimulating an endogenous LXR target gene ABCA1.
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foam cells and was as nearly potent (EC50 = 10 nM, 71% agonism)
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in plasma but a poor brain AUC0-inf/plasma AUC0-inf (B/P) ratio of
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potency and efficacy against LXRa relative to 1 in the Gal4 assay,
and reduced potency and efficacy in stimulating TG synthesis
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Chen, L.; Liu, Q.; Wilhelmsson, A.; Goos-Nilsson, A.; Ursu, G.; Arnelof, E.;
Sandberg, J.; Wrobel, J. Abstract of Papers, 234th ACS National Meeting, Boston,
MA, Aug 19–23, 2007; Abstract MEDI-154.; (b) 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; (c) Bernotas, R.; Singhaus, R.; Kaufman, D; Ullrich, J.;
Morris, R.; Unwalla, R.; Nambi, P.; Quinet, E.; Wilhelmsson, A.; Goos-Nilsson,
A.; Enroth, C.; Wrobel, J. Abstract of Papers, 238th ACS National Meeting,
Washington, DC, United States, Aug 16–20, 2009, Abstract MEDI-158.; (d)
Bernotas, R.; Kaufman, D.; Singhaus, R.; Ullrich, J.; Unwalla, R.; Quinet, E.;
Nambi P.; Wilhelmsson, A.; Goos-Nilsson, A.; Wrobel J. Bioorg. Med. Chem.
doi:10.1016/j.bmcl.2009.10.132.
13. GLIDE, Version 4.5; Schrodinger, LLC: Portland, OR, USA, 2007.
14. A set of blood brain barrier (BBB) rules by Lobell et al. suggested that CNS
penetrable compounds should have the following: N + O < 6; TPSA < 60–70;
MW < 450; Log D = 1–3; c Log P-(N+O) > 0. Compound 33 with the following
properties: N + O = 6; TPSA 99; MW = 452; Log D = 3.0À4.25 @ pH 2 ꢀ 9;
c Log P-(N + O) = À2.2 may suggest that the compound should have low brain
penetration potential. For the BBB rule details see: Ref. 10b.