Discovery of substituted maleimides as liver X receptor agonists and determination of a ligand-bound crystal structure

Article abstract of DOI:10.1021/jm050532w

Substituted 3-(phenylamino)-1H-pyrrole-2,5-diones were identified from a high throughput screen as inducers of human ATP binding cassette transporter A1 expression. Mechanism of action studies led to the identification of GSK3987 (4) as an LXR ligand. 4 r

Full text of DOI:10.1021/jm050532w

J. Med. Chem. 2005, 48, 5419-5422
5419
Chart 1. Structures of 24(S),25-Epoxycholesterol (1),
GW3965 (2), and T0901317 (3)
Discovery of Substituted Maleimides as
Liver X Receptor Agonists and
Determination of a Ligand-Bound Crystal
Structure
Michael C. Jaye,§ John A. Krawiec,§
Nino Campobasso,† Angela Smallwood,†
Chunyan Qiu,† Quinn Lu,† John J. Kerrigan,†
Maite De Los Frailes Alvaro,† Bryan Laffitte,†
Wu-Schyong Liu,† Joseph P. Marino, Jr.,†
Craig R. Meyer,‡ Jason A. Nichols,† Derek J. Parks,†
Paloma Perez,† Lea Sarov-Blat,‡
Sheila D. Seepersaud,‡ Klaudia M. Steplewski,‡
Scott K. Thompson,§ Ping Wang,† Mike A. Watson,†
Christine L. Webb,§ David Haigh,|
Justin A. Caravella,† Colin H. Macphee,§
Timothy M. Willson,† and Jon L. Collins†,*
GlaxoSmithKline Research and Development,
Research Triangle Park, North Carolina 27709
and synthetic LXR agonists have been shown to increase
the expression of ABCA1.6 Synthetic LXR agonists have
demonstrated efficacy in mouse models of atheroscle-
rosis, presumably as a consequence of upregulated
expression of genes abca1, abcg1, abcg5, abcg8, cyp7a,
and apoE leading to increased RCT.7 Synthetic LXR
agonists inhibit LPS-induced expression of proinflam-
matory genes and decrease inflammation in mouse
models, which may also contribute to the antiathero-
sclerotic activity of LXR agonists.8 Synthetic LXR ago-
nists also regulate the expression of several genes
involved in glucose metabolism and show antidiabetic
activity in rodent models of type 2 diabetes.9 However,
the therapeutic potential of LXR agonists is compro-
mised by LXR-mediated increases in plasma and hepatic
triglycerides, which results from LXR-regulated induc-
tion of lipogenic genes including sterol response element
binding protein-1c (SREBP-1c) and fatty acid synthase
(FAS). There is a clear need for new LXR chemotypes
which retain the antiinflammatory, antidiabetic, or
antiatherosclerotic efficacy of current LXR agonists but
are devoid of lipogenic activity. In this report, we
describe the identification of substituted 3-(pheny-
lamino)-1H-pyrrole-2,5-diones (maleimides) as dual
LXRR/â agonists.
To identify compounds that upregulate the expression
of ABCA1 gene in macrophages, we conducted a high
throughput screen of the GSK compound collection
using human monocytic THP-1 cells stably transfected
with a luciferase reporter construct driven by a 1.5 kb
segment of the human ABCA1 proximal promoter.
Nonspecific transcriptional upregulators were elimi-
nated by examining activity of compounds in an unre-
lated control reporter assay (data not shown). Com-
pounds showing specificity for induction of the ABCA1
reporter gene were further characterized using an in
vitro ligand-sensing assays (LiSA) employing the puri-
fied LXRR and LXRâ ligand binding domains.10 In this
manner, several LXR chemotypes were identified along
with the known LXR agonist 3.
Received June 7, 2005
Abstract: Substituted 3-(phenylamino)-1H-pyrrole-2,5-diones
were identified from a high throughput screen as inducers of
human ATP binding cassette transporter A1 expression.
Mechanism of action studies led to the identification of
GSK3987 (4) as an LXR ligand. 4 recruits the steroid receptor
coactivator-1 to human LXRR and LXRâ with EC50s of 40 nM,
profiles as an LXR agonist in functional assays, and activates
LXR though a mechanism that is similar to first generation
LXR agonists.
The ATP binding cassette transporter ABCA1 plays
a critical role in cholesterol homeostasis and HDL-c
metabolism. ABCA1 is required for efflux of cellular free
cholesterol to poorly lipidated apoA-I and other apoli-
poprotein acceptors in plasma and is considered to be
the first step in reverse cholesterol transport (RCT).
Genetic deficiency in ABCA1 results in Tangier disease,
a condition that leads to massive cholesterol accumula-
tion in peripheral tissues and extremely low plasma
HDL-c levels. Its critical role in atherosclerosis is
supported by the observation that patients with muta-
tions in one or both ABCA1 alleles have an increased
risk for coronary artery disease.1 Agents that increase
ABCA1 expression, stimulate cellular cholesterol efflux,
and increase RCT should decrease atherosclerotic plaque
cholesterol and decrease the incidence of coronary heart
disease.
Liver X receptors (LXR) R and â are ligand-activated
transcription factors belonging to the superfamily of
nuclear hormone receptors.2 To date, several distinct
structural classes of ligands have been described which
include a natural ligand 24(S),25-epoxycholesterol (1,
EPC) as well as two synthetic, nonsteroidal ligands
GW3965 (2) and T0901317 (3) (Chart 1).3-5 Both natural
* To whom correspondence should be addressed. Address: 3030
Cornwallis Road North-M2134C, Research Triangle Park, NC 27709.
Phone: 919-483-5694. Fax: 919-315-5668. E-mail: jon.l.Collins@gsk.com.
§ Cardiovascular Center for Excellence in Drug Discovery.
† Discovery Research.
Nine maleimide compounds, previously reported as
inhibitors of glycogen synthase kinase-3 (GSK-3), showed
activity in both the ABCA1 reporter and LXRR/â SRC-1
LiSA, with 4 being the most potent and efficacious
‡ Genetics Research.
| Metabolic and Viral Diseases Center for Excellence in Drug
Discovery.
10.1021/jm050532w CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/04/2005

5420 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 17
Letters
Table 1. ABCA1 Reporter Gene, LXRR/â LiSA, and GSK-3â Activity of Substituted Maleimidesa
ABCA1
EC50 (µM)
LXRR-SRC1
EC50 (nM)
LXRâ-SRC1
EC50 (nM)
GSK-3â
compd
R1
R2
RE
RE
RE
IC50 (nM)
2
-
-
0.17 ( 0.01
0.07 ( 0.03
0.08 ( 0.03
1.32 ( 0.3
1.42 ( 0.24
10.17 ( 1.17
1.12 ( 0.06
0.84 ( 0.05
1.79 ( 0.36
4.55 ( 0.55
4.65 ( 2.84
1.0
1.0
0.9
0.6
0.4
0.4
0.7
1.4
0.5
0.4
0.3
80 ( 45
55 ( 15
1.0
1.1
0.9
0.3
0.3
1.1
0.7
0.9
0.7
0.5
0.5
20 ( 10
30 ( 10
1.0
0.8
0.9
0.5
0.4
0.9
0.6
0.9
0.7
0.6
0.6
NT
NT
3
-
-
4
Bn
Bn
Bn
Et
Ph
Me
Et
Et
Me
OMe
H
Cl
OMe
OMe
OMe
H
50 ( 7
40 ( 9
>5000
>5000
>5000
>5000
>5000
>2000
>5000
>5000
>5000
5
100 ( 25
130 ( 30
300 ( 75
275 ( 60
575 ( 130
890 ( 215
725 ( 135
1590 ( 385
70 ( 25
6
110 ( 40
200 ( 50
260 ( 90
300 ( 80
560 ( 155
575 ( 150
850 ( 95
7
8
9
10
11
12
Cl
H
a EC50 ) concentration of compound that leads to half-maximal activity ( standard error, n > 4. RE ) relative efficacy compared to
GW3965 (2). NT ) not tested.
Figure 1. Effects of 2 (white bars) and 4 (black bars) on (A) ABCA1 mRNA expression in primary human macrophages, (B)
SREBP-1c mRNA expression in HepG2 cells, (C) 3H-cholesterol efflux to apoA1 in primary human macrophages, (D) IL-6 secretion
in THP-1 cells, and (E) percent triglyceride biosynthesis over basal in HepG2 cells.
compound (Table 1).11 Consistent with the high level of
amino acid identity within the LXRR and LXRâ ligand-
binding pockets, all of the analogues profiled as dual
agonists with no significant subtype selectivity.12 Im-
portantly, maleimide 4 showed >50-fold selectivity
when tested against a panel of nuclear receptors (FXR,
PPARR/γ/δ, PXR, AR, ERR/â, GR, PR). While analogues
containing an N-benzyl moiety were the most potent
analogues in the LXRR/â LiSA, incorporation of this
N-alkyl group dramatically reduced activity at GSK-3
(Table 1). The fact that LXR potency decreased as the
size of the N-benzyl group was reduced suggested that
this substituent occupied a hydrophobic pocket (see
structure discussion below). Interestingly, incorporation
of a methoxy group at the para position of the aniline
ring consistently increased efficacy relative to hydrogen
or chlorine substituents at this position. With the
exception of 7, the general rank order of potencies in
the LiSA paralleled that from the ABCA1 assay, con-
sistent with the role of LXR as a primary transcriptional
regulator of ABCA1 expression.
In line with its activity in the ABCA1 reporter gene
assay, 4 increased the expression of ABCA1 in primary
human macrophages (Figure 1A) and induced cellular
cholesterol efflux to apoA1 particles in a dose-dependent
manner (Figure 1C). 2 has been reported to decrease
the expression of several proinflammatory genes in
stimulated macrophages such as interleukin-6 (IL-6),
inducible nitric oxide synthase, and cyclooxygenase-2.8
We therefore employed an ELISA to determine whether
LXR agonists would affect secretion of IL-6 protein from
activated THP-1 macrophages. In this assay, 2 inhibited
LPS-stimulated IL-6 secretion in a dose-dependent
manner by up to 80%. Maleimide 4 profiled similarly
albeit with reduced efficacy at the highest concentration
tested (Figure 1D). First generation LXR agonists also
increase the expression of genes that control fatty acid
and triglyceride biosynthesis such as SREBP-1c and
FAS. Maleimide 4 increased the expression of SREBP-
1c and induced triglyceride accumulation in human
hepatoma (HepG2) cells in a dose-dependent manner
(Figure 1B and 1E). The activities in the gene expression

Letters
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 17 5421
the coactivator binding groove of its mLXRR hetero-
dimer partner. While the functional relevance of this
interaction is not known, the LXXML residues in the
AF-2 helix of RXRR most likely mimic a natural LXXLL
sequence of known coactivators such as SRC-1.14
The orientation of 4 is guided by multiple interactions
with residues that line the pocket (Figure 2B). The 2-oxo
group is involved in a strong hydrogen bond with His419
which stabilizes the receptor in an active conformation
by promoting an interaction between His419 and Trp441
.
In contrast, the 5-oxo functionality is not involved in
any interaction with the receptor, suggesting that
removal of this group would not be detrimental to LXR
binding. The N-benzyl moiety fills a hydrophobic pocket
near the gem-dimethyl group in 1, the 2-chloro-3-
trifluoromethylbenzyl group in 2, and the bis-trifluoro-
methyl groups in 3. Unlike those ligands, the N-benzyl
group in 4 protrudes much deeper into the hydrophobic
pocket, which expands by a shift in the helix 6-7 loop
(Leu329) and the C-terminus of helix 10/11 (Leu426).
Filling this hydrophobic pocket with the N-benzyl group
appears to make the compounds more potent (Table 1,
compounds 4-6). The 4-phenyl group occupies a similar
hydrophobic pocket as compared to the trifluoroethyl
group in 3 and one of the phenyl rings in the diphen-
ethyl moiety in 2. The aniline NH appears to be involved
in a weak 3.4 Å hydrogen bonding interaction with the
backbone carbonyl of Phe255 in helix 3. A similar
interaction was not observed in the crystal structures
of 1-3 bound to LXR and may constitute a unique
ligand-LXR interaction. The 4-methoxy ether oxygen is
involved in a hydrogen bond interaction with the hy-
droxyl in Ser262. It is not obvious from the cocrystal
structure why replacement of the methoxy group with
chlorine or hydrogen decreases efficacy in the LXRR/â
LiSAs.
In summary, substituted 3-(phenylamino)-1H-pyrrole-
2,5-diones (maleimides) were identified from a high
throughput screen as inducers of ABCA1 with com-
pound 4 proving to be the most potent, dual LXRR/â
agonist. While analysis of the ligand-bound cocrystal
structure reveals unique interactions between 4 and
mLXRR as compared to previously reported structures,
the molecular basis for receptor activation appears to
be conserved. This may, in part, explain the observed
similarities between 4 and 2 in gene expression and
cellular functional assays in human macrophages and
hepatoma cells. While 4 shows a favorable profile in
cellular cholesterol efflux and antiinflammatory assays,
induction of triglyceride accumulation remains a li-
ability. The identification of this new LXR chemotype
facilitated the determination of key interactions which
are required for receptor activation, but also provides
insight into the plasticity of the LBP and highlights
regions to be probed for future development of LXR
modulators with improved therapeutic indices.
Figure 2. X-ray crystal structure of 4 bound to mLXRR. (A)
View of 4-mLXRR (magenta)/9cRA-RXRR (yellow) ligand-
binding domain heterodimer structure. (B) A closeup view
highlighting key recognition elements for binding of 4 to
mLXRR. A hydrogen bond interaction between the 2-carbonyl
of 4 and His419 on helix 10/11 promotes an electrostatic
interaction between His419 and Trp441 on AF-2 which, in turn,
leads to stabilization of AF-2 and activation of LXRR. Figures
made using the program PYMOL.15
and cellular assays are consistent with 4 profiling as a
nonselective LXR agonist.
To date, ligand-bound LXR crystal structures have
been published for 1-3.13 The X-ray structures reveal
ligand-binding pockets that vary in size and shape
depending on the nature of the bound ligand. Whereas
1-3 show different interactions with residues in the
pocket that are distal to AF-2, they each 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.12 Maleimide 4 provided a structurally distinct
LXR chemotype to explore ligand-receptor contacts and
alternative mechanisms for receptor activation. Cocrys-
tallization of 4 with mouse LXRR (mLXRR) in complex
with human retinoid X receptor R (RXRR) and 9-cis-
retinoic acid generated crystals that diffracted to a
resolution of 2.8 Å (Figure 2). The crystals were in a P1
space group with four heterodimers in each asymmetric
unit. The standard three-layered R-helical fold was
observed for both mLXRR and hRXRR, and the receptors
were involved in a heterodimer interaction involving
helices 7 and 10. The AF-2 helix of each LXRR is packed
against the LBP in an active conformation. Interest-
ingly, the AF-2 helix of each RXRR molecule binds in
Supporting Information Available: Experimental pro-
cedures and crystallographic data (PDB ID code ZACL) for the
research described in this letter are available free of charge
via the Internet at http://pubs.acs.org.
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