RXR-LXR heterodimer modulators for the potential treatment of dyslipidemia

Article abstract of DOI:10.1016/j.bmcl.2007.01.047

A number of RXR agonists were synthesized and screened in functional assays. The synthesis and the structure-activity relationship (SAR) within the series of compounds will be presented. Some in vivo data in rodent models for dyslipidemia and diabetes wil

Full text of DOI:10.1016/j.bmcl.2007.01.047

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3497–3503
RXR–LXR heterodimer modulators for the potential treatment
of dyslipidemia
Bharat Lagu,* Barbara Pio, Rimma Lebedev, Maria Yang and Patricia D. Pelton
Johnson and Johnson Pharmaceutical Research and Development, Cranbury, NJ 08869, USA
Received 16 November 2006; revised 9 January 2007; accepted 11 January 2007
Available online 24 January 2007
Abstract—A number of RXR agonists were synthesized and screened in functional assays. The synthesis and the structure–activity
relationship (SAR) within the series of compounds will be presented. Some in vivo data in rodent models for dyslipidemia and dia-
betes will also be presented.
Ó 2007 Published by Elsevier Ltd.
Retinoid X receptors are part of the nuclear receptor
superfamily that function as ligand-activated transcrip-
tion factors. RXRs modulate gene transcription through
homodimers (RXR–RXR) or heterodimers such as
RXR–LXRs, RXR–PPARs, RXR–FXR, RXR–TR,
and RXR–VDR.1,2 These receptors impact a number
of metabolic pathways and the modulators of these
receptors have shown efficacy in treating metabolic dis-
orders. These modulators, however, also result in unde-
sired side effects. Agonists of PPARc such as AvandiaTM
and ActosTM improve insulin sensitivity in diabetic
patients but also induce weight gain and edema in many
patients. RXR modulators might provide an alternative
pathway for treating a variety of metabolic diseases such
as dyslipidemia and diabetes.3,4 A pan RXR agonist,
however, may also show untoward side effects in the
clinic including hypertriglyceridemia and suppression
of thyroid hormone.5,6 Recent data with heterodimer
selective RXR agonists such as LG1506 (4) indicate that
it is possible to develop RXR modulators having bene-
ficial metabolic effects without hypertriglyceridemia
and thyroid suppression.7 LG1506 selectively activates
the PPAR subfamily of heterodimers and, unlike the
selective PPARc agonists, does not induce weight gain
in rodents. These data indicate that RXR modulators
with the appropriate tissue and gene selective profiles
may be developed.
Structures of some of the known RXR agonists are
shown in Figure 1.8–13 A few compounds such as 1
and
4 were reported to selectively activate the
RXR–PPARc heterodimer over the RXR–LXR hetero-
dimer.10,13 Similarly, compound 3 was reported to acti-
vate the RXR–RXR homodimer and RXR–PPAR
heterodimers but not the RXR–FXR and the RXR–
LXR heterodimers.12 The data reported for the tetra-
hydrobenzofurans 5a and 5b reveal that the binding
affinity of the compounds increased when the thiazolid-
inedione (TZD) moiety was replaced by the carboxylic
acid (Ki = 6 nM for 5b; Ki = 20 nM for 5a).14 The collab-
orative research program between Johnson & Johnson
PRD and Maxia Pharmaceuticals (now Incyte Corpora-
tion) resulted in the identification of novel TZDs such as
6.13 If a similar trend is observed, it might be possible to
increase the potency of 6 by replacing the TZD moiety
with a carboxylic acid 7. Herein we disclose the synthesis
and SAR for the series of compounds that are analogs of
7 (Fig. 1). Some of the compounds showed an unexpect-
ed selectivity for the RXR–LXR heterodimer partner,
which could have beneficial effects for both cardiovascu-
lar disease and diabetes.14,15
A number of compounds with changes in the left hemi-
sphere and the linker chain (Fig. 1) were synthesized by
using the chemistry shown in Schemes 1 and 2. In all the
analogs except 36 and 37, the methyl group at the C-6-
position was maintained in the left hemisphere. This
methyl group is considered to be necessary for the com-
pounds to attain the necessary L-shaped conformation
(‘a-methyl effect’) thereby imparting selectivity for
RXR over RAR.16 In general, a number of benzo-fused
cyclic amides were synthesized by known synthetic
Keywords: RXR; LXR; Dyslipidemia; ABCA-1; HDL; LDL; Triglyc-
erides; Diabetes.
*
Corresponding author at present address: Novartis Institute for
Biomedical Research, Cambridge, MA 02139, USA. Tel.: +1 617 871
4257; fax: +1 617 871 4081; e-mail addresses: bharat.lagu@
novartis.com; blagu@prdus.jnj.com
0960-894X/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2007.01.047

3498
B. Lagu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3497–3503
HOOC
HOOC
HOOC
F
N
N
COOH
O
O
S
2
CHF2
1
3
4
F3CO
O
O
NH
6
O
N
S
R =
R
NH
S
COOH
R =
O
5a
O
7
R
COOH
R2O
O
R1
N
5b
O
OH
6
X
O
Y
Analogs of 7
Figure 1. Known RXR ligands and 7.
(HO)2B
R2O
CHO
R2O
R1
N
R1
H
H
O
N
O
N
Br
CHO
11a
b or c
a
O
O
N
Br
d
8
9
10
R2O
12
R2O
R1
N
R1
N
f
e
O
O
CO2tBu
COOH
13
14a-j
(HO)2B
CHO
OH
O
Z
11b
CHO
e, f
O
N
Br
O
N
O
N
Z
Z
g
Z = O, S
10
14k Z = O
14m Z = S
Scheme 1. Reagents and conditions: (a) NBS, CH2Cl2, rt, 12 h, 80–95%; (b) KOH, DMSO, alkyl iodide, rt, 12 h, 65–94%; (c) Boc2O, NaH, THF,
98%; (d) 11a, Pd(PPh3)4, toluene–EtOH, 2M K2CO3, reflux, 47–80%; (e) THF–DMPU (10:1), n-BuLi, dimethyl-tert-butoxycarbonyl-
methylphosphonate, À78 °C to 0 °C, 41–75%; (f) CH2Cl2, TFA, rt, 8 h, >90%; (g) 11b, Pd(PPh3)4, toluene–EtOH, 2M K2CO3, reflux, 47–80%.
routes and brominated by the treatment with NBS.17–19
The amide nitrogen was then alkylated under standard
conditions in high yield. Suzuki coupling with an appro-
priate aryl boronic acid yields aldehyde, which was then
converted into the cinnamate ester using Horner–Em-
mons conditions in good overall yields. The final
carboxylic acids were obtained by the removal of the
tert-butyl group by treatment with TFA (Scheme 3).
HDL-C as potential novel therapy for the treatment of
dyslipidemias characterized by low circulating HDL-C,
we initially screened all the compounds for their ability
to induce expression of ABCA-1 (a member of the
ATP binding cassette protein family), a key gene in-
volved in reverse cholesterol transport and known to
be upregulated by LXR agonists.20,21 Compounds were
screened using branched DNA technology to measure
induction of ABCA1 mRNA in the human monocytic
cell line, THP-1.22 In this assay, the maximal efficacy
of the newly synthesized RXR agonists was about half
In order to identify compounds that would have poten-
tial to increase reverse cholesterol transport and plasma

B. Lagu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3497–3503
3499
F3CO
As shown in Scheme 1
for synthesis of 14a-j
H
H2N
MeO
H2N
HO
O
N
b
a
O
N
OH
O
O
O
O
15
16
17
18
O
R2
R3
Br
F3CO
H
H2N
HO
O
R2
N
O
R2
N
Br
20
d
O
N
OH
R2
R3
c
O
O
O
R3
O
R3
19
21
22
23 R2 = H, R3 = Me
24 R2 = R3 = Me
F3CO
N
H
H2N
HN
O
N
O2N
F
O
OH
e, f
g
O
N
N
25
26
27
28
F3CO
F3CO
F3CO
h, i
j, k
O
N
O
O
O
N
O
O
N
O
OH
H
O
O
29
30
31
Scheme 2. Reagents and conditions: (a) MeMgBr, THF, À78 °C to 0 °C, 12 h, 58%; (b) phosgene in toluene, THF, Et3N, À0 °C to rt, 3 h, 95%; (c)
CH2Cl2, rt, 3 h; (d) KOH, DMSO, alkyl iodide, rt, 12 h; (e) isopropylamine, CH2Cl2, 80 °C, 12 h; (f) 5% Pd–C (cat.), EtOH, ammonium formate, rt;
(g) DCC, CH2Cl2, bromoacetic acid, rt, 1 h, 7%; (h) MeMgBr, THF, Et2O, À78 °C to rt; (i) Dess–Martin reagent, CH2Cl2, rt, overnight, 46% over
two steps; (j) THF–DMPU (10:1), n-BuLi, dimethyl-tert-butoxycarbonyl-methylphosphonate, À78 °C to 0 °C; (k) CH2Cl2, TFA, rt, 8 h,96%.
O
N
OH
OH
H
N
N
H
N
O
O
O
O
O
O
37
or
33
N
b
a
O
Br
Br
Br
32
35
O
N
34
36
Scheme 3. Reagents and conditions: (a) and (b) Ref. 19.
of that compared to the known LXR agonist TO-
901317.23 In addition, all RXR agonists screened
showed additive activity when screened in combination
with an LXR agonist using the bDNA assay but did
not have LXR agonist activity as evidenced in the
LXR transactivation reporter assays (data not shown).
These data lend additional support that the compounds
activated the RXR/LXR heterodimers through an inter-
action with the RXR receptor. To determine the activity
at the RXR receptor (subtype alpha), the compounds
were tested in a co-transfection assay with the yeast
GAL4 DNA binding domain fused to the ligand binding
domain of RXRa and the yeast promoter driving
luciferase expression. A few selected compounds were
also tested for their ability to induce the adipocyte fatty
acid binding protein (aP2) mRNA in primary human
preadipocytes, which would be indicative of activation
of the RXR–PPARc heterodimer. The results are sum-
marized in Tables 1–3.
As shown in Table 1, compound 14a where the double
bond resided at the para position with respect to the
OCF3 group in the linker phenyl group showed EC50
comparable to that of 6 in the RXR co-transfection
assay (1.8 nM vs 0.9 nM for 6). The compound was sig-
nificantly more potent (EC50 = 3.6 nM) for activating
RXR–LXR heterodimer than 6 (EC50 = 180 nM). In
comparison, 14b where the double bond was attached
at the meta position with respect to the OCF3 group in
the linker phenyl group was not active in the ABCA-1
gene induction assay. Replacement of the trifluorometh-
oxy group with a triflouroethoxy group resulted in 14d

3500
B. Lagu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3497–3503
Table 1. Modifications in the linker chain in 14
O
F3CO
S
NH
O
N
X
OH
O
N
O
O
6
14
a
ABCA-1 EC50 (nM)
a
RXRa co-trans EC50 (nM)
Compound
X
6
N/A
180 (100%)
0.9 (100%)
F3CO
14a
14b
14c
3.6 (81%)
>3000
975
1.8 (115%)
F3CO
MeO
F3C
ND
ND
O
14d
14k
296 (60%)
67.3 (76%)
>3000
>3000
>10,000
1200
O
14m
S
ND, not determined.
a The numbers in parentheses represent % maximal activation in comparison to compound 6.
with decreased potency and efficacy while replacement
of the OCF3 group with a methoxy (14c) dramatically
decreased the activity. The compounds 14k and 14m
where the phenyl ring was replaced by a furan or a thi-
ophene were found to be weakly active in the functional
assays Table 4.
testing concentration, however compound 24 was found
to have reasonable potency in the RXR co-transfection
(EC50 = 173.1 nM) and the ABCA-1 (EC50 = 39.7 nM)
assay. Both 36 and 37 were found to be inactive at the
testing concentration in the ABCA-1 assay, but 37 was
found to be substantially more potent (EC50 = 96 nM)
than 36 (EC50 = 1600 nM) in the RXR transactivation
assay.
We next turned our attention to the dihydro-[1H]-quin-
olin-2-one core of the compounds. The results are
shown in Table 2.
As previously mentioned, some reported compounds
such as 1 and 4 selectively activated the RXR–PPARc
heterodimer. A few compounds from this series were
screened for their ability to activate RXR–PPARc het-
erodimer (induction of aP2) using the bDNA assay22
and the results are shown in Table 3. The maximal activ-
ity for compound 6 in this assay was 25–35% compared
to the PPARc agonist Rosiglitazone.
The presence and the nature of an alkyl group on the
nitrogen of the dihydro-[1H]-quinolin-2-one core were
found to be important in the functional assays for com-
pounds 14a and 14f–i. The absence of an alkyl group in
14e resulted in loss of activity. Interestingly, the presence
of ethyl, propyl or trifluoroethyl gave compounds with
high and comparable potency (EC50 = 1–2 nM) in the
RXR transactivation assay but a wider range of potency
observed in the ABCA-1 gene induction assay. The pres-
ence of methyl or an isopropyl group on the nitrogen
gave compounds with lower potency in the co-transfec-
tion assay. However, 14h was significantly more potent
in the ABCA-1 gene induction assay (EC50 = 10 nM)
than 14f (EC50 = 200 nM) suggesting that the com-
pounds may be showing some degree of selectivity.
The compounds 18, 23, and 28 where the dihydro-quin-
olin-2-one core was modified showed no activity at the
While 6 was equipotent for activating RXR–LXR and
RXR–PPARc heterodimers, compounds 14d, 14j, and
31 were found to be more specific for the activation of
RXR–LXR over RXR–PPARc heterodimers. Com-
pounds 14j, and 31 had low potency but high efficacy
for the induction of aP2 as evidenced by the high
maximal activation values relative to compound 6.
To the best of our knowledge, these are the first
reported examples of RXR agonists that show greater
selectivity in the in vitro assay for the activation of

B. Lagu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3497–3503
3501
Table 2. Modifications in the left hemisphere
R
F3CO
F3CO
O
N
OH
OH
or
X
O
O
a
ABCA-1 EC50 (nM)
a
RXRa co-trans EC50 (nM)
Compound
R or X
14e
14f
14a
14g
14h
14i
H
Me
>3000
NA
24.3
200 (56%)
3.6 (81%)
>3000
Et
1.8 (94%)
2.1 (83%)
16.3
n-Pr
i-Pr
CH2CF3
10 (70%)
>3000
1.8 (94%)
O
N
18
>3000
ND
O
O
N
O
23
24
>3000
ND
O
O
N
O
39.7 (79%)
173.1(78%)
N
N
28
>3000
ND
O
O
N
N
36
37
>3000
>3000
1600
96.6 (125%)
NA, not active. ND, not determined.
a The numbers in parentheses represent % maximal activation in comparison to compound 6.
the RXR–LXR heterodimer complex over RXR–
PPARc complex.
typically induces a fivefold increase in serum cholesterol
after 14 days. Compound 14d was orally administered
(0.3, 1, 3, and 10 mpk) after 6 days on the diet in 15%
hydroxylpropyl b-cyclodextrin at pH 10) for a total of
8 days. Serum cholesterol, HDL-C, LDL-C, and triglyc-
eride levels were determined. Treatment with compound
14d elicited a statistically significant increase in HDL-C
and a small decrease in LDL-C levels as compared to the
vehicle control animals. Serum triglycerides were not in-
creased to a statistically significant level. The Cmax con-
centrations ranged from an average of 61 ng/ml (0.3 mg/
kg) to 2124 ng/ml (10 mg/kg). On the other hand, the
compound failed to lower blood glucose in the db/db
mouse model for diabetes following 11 days of
treatment (data not shown). These results seem to be
While the origin of such selectivity is not well under-
stood at the present time, one of the compounds, 14d,
was evaluated in rodent models of diabetes and dyslipi-
demia. The compound showed a satisfactory pharmaco-
kinetic profile in Sprague–Dawley rats when dosed at
3 mg/kg (10% hydroxypropyl b-cyclodextrin (pH 10)
with an oral bioavailability of 51%, Cmax = 844 ng/mL,
AUC = 5519 ng h/mL; T1/2 = 4.6 h).
As a model of dyslipidemia, Sprague–Dawley male rats
were fed a high cholesterol, atherogenic diet (C13002
Research Diets, New Brunswick, NJ) ad libitum, which

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B. Lagu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3497–3503
Table 3. Selectivity for the RXR agonists
a
ABCA-1 EC50 (nM)
a
RXRa co-trans EC50 (nM)
Compound
aP2 EC50 (nM)
O
F3CO
S
NH
O
N
N
180 (100%)
139
0.9 (100%)
1.8 (94%)
2.1 (83%)
O
6
F3C
F3CO
O
O
OH
OH
>3000
>3000
126
131
O
14i
F3CO
N
O
14g
14d
F3C
O
296 (60%)
>3000
67.3 (80%)
O
N
OH
O
F3C
O
44 (32%)
>3000b
18.3 (64%)
O
O
N
OH
OH
O
O
14j
F3CO
>3000c
61.2 (86%)
N
O
163 (76%)
31
a The numbers in parentheses represent % maximal activation in comparison to compound 6.
b 149% maximal activation compared to 6.
c 240% maximal activation compared to 6.
Table 4. Effects of 14d and 6 on serum cholesterol and triglycerides following 8 days of treatment in Sprague–Dawley rats fed a high cholesterol diet
Dose (mg/kg)
HDL-C (mg/dL)
LDL-C (mg/dL)
Total cholesterol (mg/dL)
Triglycerides (mg/dL)
Vehicle
0.3
15
16
38 4*
34 2*
41 2**
41 2**
3
5
144 14
134 17
421 26
382 38
440 24
302 27
349 26
371 38
227 36
341 31
182 24
249 38
175 28
1
151
102
8
9
3
10
126 13
126 13
1 (mpk) 6
216
9
Data are expressed as means SEM and were analyzed using one way ANOVA and Dunnet’s multiple comparison test (*p < 0.05, **p < 0.001). All
comparisons are made relative to the vehicle controls.
consistent with the in vitro finding that 14d did not acti-
vate the RXR–PPARc heterodimer but did activate the
RXR–LXR heterodimer. In contrast, 6 was found to
potently activate both RXR–LXR and RXR–PPARc
heterodimers and showed glucose-lowering effects in
addition to the beneficial effects on the cholesterol levels
(data not shown). These observations suggest that it
may be possible to synthesize RXR modulators that
selectively activate different permissive heterodimers
other than RXR–PPARc. While these results are
intriguing, one would need to study a large number of
RXR agonists with different selectivity profiles (in the
in vitro assays) in these models of dyslipidemia and dia-
betes before a firm conclusion is reached.
We have synthesized analogs of 6 where the TZD group
was replaced with a carboxylic acid. The SAR in the ser-
ies suggest a possibility of finding RXR modulators that

B. Lagu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3497–3503
3503
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Acknowledgments
The authors thank Dr. Keith Demarest and Dr. William
Murray for their encouragement and support.
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