Design and synthesis of benzofused heterocyclic RXR modulators

Article abstract of DOI:10.1016/j.bmcl.2004.03.073

Benzofused heterocyclic analogs of the RXR selective modulator 1 (LG101506) were synthesized, and tested for their ability to bind RXRα and activate RXR homo and heterodimers. Potency and efficacy were observed to be dependent upon the choice of heterocycle as well as the sidechain employed.

Full text of DOI:10.1016/j.bmcl.2004.03.073

Bioorganic & Medicinal Chemistry Letters 14 (2004) 2759–2763
Design and synthesis of benzofused heterocyclic RXR modulators
b,
a
d
e
D. L. Gernert,b,* D. A. Neel, M. F. Boehm, M. D. Leibowitz, D. A. Mais,
*
P. Y. Michellys,a D. Rungta,e A. Reifel-Millerc and T. A. Greseb
aDepartment of Medicinal Chemistry, Ligand Pharmaceuticals, Incorporated, San Diego, CA 92121, USA
bDiscovery Chemistry Research, Lilly Research Laboratories, Indianapolis, IN 46285, USA
cDivision of Endocrine Research, Lilly Research Laboratories, Indianapolis, IN 46285, USA
dDepartment of Pharmacology, Ligand Pharmaceuticals, Incorporated, San Diego, CA 92121, USA
eDepartment of New Leads Discovery, Ligand Pharmaceuticals, Incorporated, San Diego, CA 92121, USA
Received 13 January 2004; revised 18 March 2004; accepted 25 March 2004
Abstract—Benzofused heterocyclic analogs of the RXR selective modulator 1 (LG101506) were synthesized, and tested for their
ability to bind RXRa and activate RXR homo and heterodimers. Potency and efficacy were observed to be dependent upon the
choice of heterocycle as well as the sidechain employed.
Ó 2004 Published by Elsevier Ltd.
1. Introduction
version to the heterocycle was accomplished by dis-
placement of fluorine with the appropriate nucleophile
and intramolecular condensation to provide 21 and 22.
A Heck coupling with methyl crotonate, followed by
hydrolysis yielded the final compounds 4 and 5.
The retinoid X receptor (RXR) is known to regulate
gene transcription through the formation of hetero-
dimers with other nuclear receptors.1;2 In particular the
heterodimer formed with peroxisome proliferative-acti-
vated receptor c (PPARc) plays a major role in the
regulation of both glucose and lipid metabolism.3
Selective RXR modulators such as 1 (LG101506), have
been described as hypoglycemic agents4 (Fig. 1).
Recently, analogs of this compound in which the 6–7
olefin of the trienoic acid moiety is locked into the cis-
conformation showed potent RXR activity and very
good selectivity.5 As part of our ongoing SAR we re-
placed the trienoic acid portion of these compounds
with benzofused heterocycles in an attempt to increase
the stability of the trienoic acid moiety while maintain-
ing the potent activity.
The remainder of the compounds were synthesized by
coupling of the appropriate heterocyclic triflate or halide
with an aryl boronic acid. For example, in Scheme 2, the
enol triflate of 25 was coupled with aryl boronic acid 26
to provide 27. A subsequent Horner–Emmons reaction
followed by hydrolysis extended ketone 27 to the fully
elaborated butenoic acid.
The synthesis of compound 9, was accomplished as de-
picted in Scheme 3. The known thienopyridine 29,7 was
brominated and coupled with aryl boronic acid 31. The
ketone was converted to the butenoic acid as described
above.
2. Chemistry
In Scheme 4, the butenoic acid methyl ester was at-
tached first through a Heck coupling with 34, followed
by cyclization to the imidazopyridine 36.8 Suzuki cou-
pling with the iodide 37 and subsequent hydrolysis
provided compound 10.
Compounds 4 and 5 were constructed using the same
benzophenone intermediate 20 (Scheme 1). Compound
20 was prepared by adding the aryllithium derived from
176 to aldehyde 18 followed by oxidation of 19. Con-
The indole derivatives were made in a similar fashion
(Scheme 5). The protected indol-5-yl-butenoic acid
methyl ester 40 was iodinated and coupled with a
variety of aryl boronic acids to provide compounds 11–
15.
Keywords: RXR; Heterocycles; Trienoic acid.
* Corresponding authors. Tel.: +1-317-433-0430; fax: +1-317-276-24-
41; e-mail addresses: dgernert@lilly.com; neelda@lilly.com
0960-894X/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2004.03.073

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D. L. Gernert et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2759–2763
HO2C
HO2C
HO2C
HO2C
N
R1
X
S
S
N
O
R2
O
O
R
O
R1
1 R1 = CH3, R2 = -(CH2)3F
2 R1 = H, R2 = -CH2CH3
3 R1 = H, R2 = -(CH2)3CH3
4 X = O
5 X = NH
6 R = H
7 R = -(CH2)3F
8 R = -CH3
9
HO2C
HO2C
HO2C
HO2C
NH
N
N
N
NH
R1
O
O
O
O
R2
R
10
11 R1 = H; R2 = -(CH2)3CH3
12 R1 = CH3; R2 = -(CH2)3CH3
13 R = -(CH2)3CH3
14 R = -(CH2)2CH3
15 R = -CH2CHF2
16
Figure 1. Benzofused heterocyclic analogs.
OH
F
F
O
Br
O
a, b
S
CO2H
c
a
b
O
O
F
+
O
O
23
24
Br
Br
O
18
17
19
Br
S
d
O
F
e
c, X = O
e, f
X
S
O
B(OH)2
N
25
or d, X = N
O
Br
O
O
MOM
O
21 X = O
22 X = N
MOM
HO2C
20
27
26
MeO2C
HO2C
X
N
f, b
4 X = O
5 X = N
O
or
f, g, b
S
S
6 R = H
Scheme 1. Reagents and conditions: (a) t-BuLi, DME, 66%; (b) PCC,
DCM, 94%; (c) acetone oxime, t-BuOK, THF, 21: 40%; (d) (1) benzo-
phenone hydrazone, t-BuOK, THF (2) 5 N HCl, EtOH, reflux, 22:
16%; (e) methyl crotonate, Pd2(dba)3, P(o-tol)3, TEA, DCM, 120 °C,
X ¼ O or N, 32%; (f) 1 N NaOH, MeOH, 4: 80%, 5: 80%.
O
MOM
7 R = (CH2)2CH2F
8 R = CH3
O
R
28
Scheme 2. Reagents and conditions: (a) HSCH2CO2CH3, NaH, DMF,
81%; (b) LiOH, THF/H2O, 94%; (c) S(O)Cl2, AlCl3, DCE, 79%; (d) (1)
LDA, Tf2NPh, THF; (2) 26, Pd(P(Ph3)4), 2 M Na2CO3, toluene,
EtOH, 0 °C, 40%; (e) NaH, methyl diethylphosphonoacetate, DMF,
25%; (f) HCl, MeOH; (g) CeF, alkylhalide, DMF.
In order to further explore indole as a replacement
for the trienoic acid the heterocycle orientation was
reversed, as shown in Scheme 6. Gribble’s methodol-
ogy,9 which takes advantage of the ipso directing ability
of silicon, was used to access the 2-indolyl ketone 46. A
Horner–Emmons reaction resulted in 47 followed by
Suzuki coupling and deprotection to give 16.
3. Biological evaluation
The binding of each compound to RXRa and the reti-
noic acid receptor (RARc), was characterized using
3
3[H]-9-cis-retinoic acid and [H]-all trans-retinoic acid,
respectively, and the data expressed as a Ki (Table 1).10

D. L. Gernert et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2759–2763
2761
b
MeO2C
b
S
a
S
N
MeO2C
a
N
I
I
B(OH)2
O
29
Br
O
30
O
N
N
N
41
31
SO2Ph
SO2Ph
40
MeO2C
SO2Ph
39
O
HO2C
HO2C
H3CO2C
c
N
d
d
N
c
N
R1
B(OH)2
N
SO2Ph
S
R1
NH
R1
O
R2
S
S
42
43
O
O
32
O
R2
R1
R2
O
O
33
9
R1
R1
11 R1 = H, R2 = -(CH2)3CH3
HO2C
Scheme 3. Reagents and conditions: (a) Br2, CCl4/H2O, 36%; (b) 31,
Pd(P(Ph3)4), 2 M Na2CO3, toluene, EtOH, 90 °C, 91%; (c) NaH,
methyl diethylphosphonoacetate, DMF, 61%; (d) 1 N NaOH, MeOH.
13 R1 = CH3, R2 = -(CH2)3CH3
14 R1 = CH3, R2 = -(CH2)2CH3
15 R1 = CH3, R2 = -CH2CHF2
e, f
N
R1 = H
R2 = Bu
NH2
N
O
NH2
a
b
N
N
N
Br
12
MeO2C
MeO2C
35
36
34
Scheme 5. Reagents and conditions: (a) methyl crotonate, TEA,
Pd(OAc)2, DMF, 40%; (b) NIS, p-TsOH, CH2Cl2, Florosil pad, 44%;
(c) 42, Pd(P(Ph3)4), 2 N Na2CO3, toluene, 80 °C, 31–58%; (d) 2.5 N
KOH, EtOH, dioxane, 60 °C, 54%; (e) MeI, Cs2CO3, DMF, 40 °C,
86%; (f) 1 N NaOH, MeOH, dioxane, 60 °C, 52%.
H3CO2C
N
N
d
e
c
I
N
N
MeO2C
37
38
O
Br
HO2C
Br
Br
b
a
O
N
SiMe3
N
N
PhO2S
46
SO2Ph
N
N
SO2Ph
44
45
Br
MeO2C
O
10
d
c
SO2Ph
CO2Me
N
N
B(OH)2
Scheme 4. Reagents and conditions: (a) methyl crotonate, Pd2(dba)3,
P(o-tol)3, TEA, DCM, 120 °C, 41%; (b) BrCH2CH(OCH3)2, Na2CO3,
H2O, 31%; (c) NIS, CH3CN, 50%; (d) 31, Pd(P(Ph3)4), 2 M Na2CO3,
toluene, EtOH, 90 °C, 76%; (d) 1 N NaOH, MeOH, 78%.
PhO2S
47
OBu
48
HO2C
49
O
NH
e, f
Most of the benzofused heterocycles showed significant
reduction in binding to RXR. Only three scaffolds (5, 8,
and 11) were below 100 nM. Of these only the indole
scaffold showed binding similar to its corresponding
acyclic analog (compound 3).
16
O
The RXR homodimer transcriptional activation profile
of each compound was determined in CV-1 cells and
efficacy is reported relative to all-trans-retinoic acid.11
All the compounds showed similar agonist and anta-
gonist profiles to the corresponding acyclic analogs.
While these compounds maintained similar efficacy to
their acyclic counterparts, only the indole compound 11
had similar potency.
Scheme 6. Reagents and conditions: (a) (1) LDA, THF, )73 °C; (2)
TMSCl, 67%; (b) AlCl3, CH2Cl2, Ac2O, 51%; (c)
(EtO)2P(O)CH2CO2CH3, KOt-Bu, DMF, 50 °C, 28%; (d) 48,
Pd(P(Ph3)4), 2 N Na2CO3, toluene, 75 °C, 48%; (e) 1 N NaOH, MeOH,
dioxane, 60 °C, 58%; (f) 2.5 N KOH, EtOH, dioxane, 60 °C, 53%.
cious concentrations of PPARc (e.g., BRL49653) or
RAR (e.g., TTNPB) ligands.11 Compound 1 was shown
to synergize with BRL49653 to enhance activation at the
RXR:PPARc heterodimer but did not synergize with
We have previously demonstrated that RXR homo-
dimer antagonists can exhibit selective profiles of RXR
heterodimer activation in combination with sub-effica-

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D. L. Gernert et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2759–2763
Table 1. In vitro evaluation of RXR modulators in CV-1 cells
Compound
RXRa binding Ki,
nMa
RXRa agonist
%efficacy
(EC50, nM)b
RXRa antagonist
%efficacy
(EC50, nM)b
RXRa:PPARc
agonist %efficacy
(EC50, nM)c
RARc binding Ki,
nMd
RAR agonist
synergye
1
2.7
2
4
84 (6.4)
7
91 (4)
60 (3.1)
38 (8)
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
NTf
1.4
5
2
58 (2)
2
3
4
12 (1894)
65 (306.4)
168 (118)
1
4
648.0
69.2
131.0
394.7
29.6
NTf
2078.3
7.4
36 (1024)
43 (235)
37.4 (1438)
1.78
24
7
1.7
2.4
3.5
1.5
2.7
2.0
1.5
1.3
2.5
2.3
3.4
3.0
1.1
5
6
0
112 (383.54)
123.1 (1481)
114.0 (224.25)
127.34 (347.3)
81.82 (424.86)
256.1 (15.03)
49 (611.9)
105 (8.9)
7
48 (4154)
0
8
65.41 (914)
15.1 (1442)
7.93
9
9
10
11
12
13
14
15
16
9
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
NTe
1.7
2.52
87 (21.1)
86 (1533)
93 (26.4)
81 (30.1)
41 (66.3)
64 (3976.3)
740.0
3.2
1.6
1
7
173 (7.0)
233 (21.9)
24.9 (892.94)
1.6
NTe
15 (65)
0.51
Each data point represents the mean of two measurements.
a Calculated using [3H]-9-cis-RA.
b LGD1069 was used as reference.
c Calculated using 100 nM of BRL49653, efficacy relative to BRL49653.
d Calculated using [3H]-ATRA.
e Calculated using 3 nM of TTNPB.
f Not tested.
TTNPB to enhance activation at the RXR:RAR hetero-
dimer. All of the benzofused heterocyclic compounds
showed better efficacy than their acyclic comparator,
with many compounds showing greater than 100% (5, 6,
7, 8, 9, and 11).
on the homo and heterodimer activity. Compound 16
was made to test whether the orientation of the indole
made a difference in the activity of the compounds and it
was less efficacious and potent than compound 11.
In summary, we have demonstrated that benzofused
heterocycles can be substituted in place of the trienoic
acid moiety, and can maintain the desired in vitro pro-
file. We have also demonstrated that the RXR homo-
dimer activity can be altered by the type of heterocycle
employed. The data suggests that the increased bulk of
the heterocycle, as compared with the trienoic acid
scaffold, changes the orientation of these compounds in
the RXR ligand binding domain slightly so that they
require less bulk on the pendant benzene ring. Further
studies to examine the potential of heterodimer selective
RXR modulators for the treatment of NIDDM and
other metabolic disorders are ongoing.
The indole compound (11) was particularly interesting.
It had slightly reduced binding affinity, and was less
efficacious and less potent in the homodimer profiling
assay than its acyclic comparator (3). However, it was
much more efficacious (256% for 11 compared to 12%
for 3) and much more potent in the heterodimer assay
(15 nM for 11 compared to 1894 nM for 3). Based on
this data, more analogs of the indole compound 11 were
synthesized.
It was quickly recognized that changes similar to those
used to optimize the trienoic acid series (resulting in
compound 1) were also effective in enhancing the RXR
binding of the benzofused compounds, as compounds
13, 14, and 15 all are more potent than the initial
compound 11. These changes did not result in
improvement in the homodimer activity and in the case
of compound 15 (the compound most like 1) the
antagonist efficacy and potency was significantly
decreased and some agonist activity was noted. This
change was also noted in the heterodimer assay as the
efficacy of compounds 13, 14, and 15 was reduced while
the change in potency was marginal. In addition,
enhanced synergy with RAR was noted with com-
pounds 13, 14, and 15 over 11.
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Design and Synthesis of New Locked-Dienoic Acid RXR
Modulators. J. Med. Chem., in press.
6. Procedures for making the di-isopropyl or di-t-butyl aryl
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