Aza-retinoids as novel retinoid X receptor-specific agonists

Article abstract of DOI:10.1016/j.bmcl.2005.12.003

A new structurally simple series of potent lipophilic aza-retinoids RXR agonists has been developed. SAR studies for the N-alkyl-azadienoic acids described here demonstrate that the RXR activity profile is sensitive to the N-alkyl chain length. Further, we have expanded the work to include azadienoic acids, which exhibited many accessible conformations leading to a better understanding of the SAR around the series.

Full text of DOI:10.1016/j.bmcl.2005.12.003

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2352–2356
Aza-retinoids as novel retinoid X receptor-specific agonists
Luc J. Farmer,* Kristen S. Marron, Stacie S. Canan Koch, C. K. Hwang, E Adam Kallel,
Lin Zhi, Alex M. Nadzan, Dave W. Robertson and Youssef L. Bennani*
Ligand Pharmaceuticals Inc., 10255 Science Center Drive, San Diego, CA 92121, USA
Received 28 October 2005; revised 30 November 2005; accepted 1 December 2005
Available online 20 December 2005
Dedicated to the memory of David W. Robertson in recognition of his outstanding accomplishments in drug discovery and research.
Abstract—A new structurally simple series of potent lipophilic aza-retinoids RXR agonists has been developed. SAR studies for the
N-alkyl-azadienoic acids described here demonstrate that the RXR activity profile is sensitive to the N-alkyl chain length. Further,
we have expanded the work to include azadienoic acids, which exhibited many accessible conformations leading to a better under-
standing of the SAR around the series.
Ó 2005 Elsevier Ltd. All rights reserved.
The nuclear receptors are members of a superfamily of
eukaryotic transcription factors which regulate gene
expression.1 The retinoid receptors, which belong to this
superfamily, are divided into three retinoic acid receptor
(RARa, b, and c) and three retinoid X receptor (RXRa,
b, and c) subtypes, distinguished by differences in amino
acid sequences, responsiveness toward natural and syn-
thetic ligands, and ability to modulate the expression
of various target genes.2 These receptors function as
ligand-activated transcription regulators, transducing
the pleiotropic effects of various retinoids on morpho-
genesis, differentiation, and homeostasis during develop-
ment of the embryo and postnatal life.3 The RARs are
activated by both endogenous all-trans-retinoic acid 1
and 9-cis-retinoic acid 2, while the RXRs are activated
by 9-cis-RA.4 ATRA 1, 13-cis-retinoic acid 4, and etret-
inate 5 are RAR selective agonists currently marketed
for dermatological applications.5 Widespread use of
these agents has been limited because of undesirable side
effects such as headaches and mucocutaneous toxicity.6
It is hoped that the discovery of selective modulators
of the RXRs will open new opportunities for the devel-
opment of novel retinoids with an enhanced therapeutic
profile. The potential utility of selective RXR activators
may evolve from their ability to induce apoptosis7 or
possibly from regulation through heterodimer forma-
tion with RARs,8 peroxisome proliferator-activated
receptors (PPARs),9 thyroid hormone receptor (TR),10
and vitamin D3 receptor (VDR).11
1
R
2
R
CO
H
2
1 R1 = CO2H, R2 = H; (ATRA)
4 R1 = H, R2 = CO2H; (13-cis--RA)
2 9-cis-RA
CO Et
2
CO
H
MeO
2
3 (Targretin)
5 (Etretinate)
Recently, benzoic acids such as 3 (Targretin) have been
reported as selective synthetic ligands for the RXRs.12
Two retinoids, 2 and 3, are currently in clinical trials
for the treatment of a variety of cancers.13 Most report-
ed RXR selective activators, such as Targretin 3,
LG100268, 6a14 and SR11237 6b,15 are retinoids with
an aromatic acid motif. Vuligonda et al.16 reported that
cyclopropyl dienoic acid 7 is a potent RXR selective
agonist. More recently, potent RXR selective retinoids
with 6–7 locked trienoic acids17 and 9-cis isosteres18
were reported by us. An interesting trienoic acid replace-
ment 8 was also published by Michellys et al.19 which
exhibited good RXR selectivity.
Keywords: RXR selective retinoids; RXR-agonists.
*
Corresponding authors at present address: Vertex Pharmaceuticals
Inc., 130 Waverly Street, Cambridge, MA 02139, USA. Fax: +1 617
444 6290; e-mail addresses: luc_farmer@vrtx.com; youssef_
bennani@vrtx.com
Present address: Pfizer, La Jolla, CA, USA.
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.12.003

L. J. Farmer et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2352–2356
2353
( )n
X
3,5-Di-tert-butyl benzoic acid 13 was treated with meth-
yllithium to give the corresponding ketone 14, which
was sequentially reacted with hydroxylamine hydrochlo-
ride in ethanol, and the resulting oxime was converted to
the corresponding N-acyl aniline 15 through a Beckman
rearrangement. Deacetylation to the primary amine 16
was accomplished by acid hydrolysis in ethanol in 85%
yield (Scheme 2).
X
Y
H
R
CO2H
6a
6b
R =Me;
X =CH2;
n = 0;
Y =N
R =H;
X =O;
n = 2;
Y =CH
CO2H
7
(LGD100268) (SR11237)
Aminoindane 20 was prepared starting from tert-butyl-
benzene 17, which was treated with isoprene in the pres-
ence of AlCl3 to give the corresponding indane 18 in
50% yield.20 The latter was acylated under standard Fri-
edel–Crafts conditions to give methyl ketone 19 in 62%
yield. In a sequence similar to that described above, ke-
tone 19 was transformed into amine 20 in two steps and
81% overall yield (Scheme 3).
N
CO2H
S
CO2H
9
8
The RAR and RXR activation and binding abilities
of representative RXR compounds are compiled in
Table 1.
The dienoic acid moiety was prepared from readily
available ethyl 3-methyl-4-oxocrotonate 21, which upon
treatment with triphenylphosphoranylacetaldehyde in
refluxing benzene gave trans-trans-aldehyde 22 in 47%
yield (Scheme 4). Jones oxidation of 22 afforded ethyl
6-mono-carboxylic acid dienoate 23. Both aldehyde 22
and carboxylic acid 23 served as coupling fragments
leading to the desired retinoids.
In efforts to explore the medicinal chemistry and biology
of novel retinoids, we have discovered and wish to re-
port on a new class of structurally simple lipophilic
aza-retinoids which exhibited a potent RXR selective
agonist profile and displayed novel conformational fea-
tures. Thus, in the search for novel isosteres for the tet-
raenoic acid chain and the cyclohexyl moiety in ATRA 1
and 9-cis-RA 2, we investigated the introduction of a
nitrogen atom between a variety of aromatic or bicyclic
groups and side chain bearing a dienoic acid moiety.
The SAR studies consisted of a systematic variation
of the aryl or bicyclic moieties; the N-alkyl groups and
the dienoic acid spacer group. These studies resulted in
the discovery of the substituted indane-derived N-propyl
dienoic acid 9 as a potent and highly selective RXR ago-
nist. In addition, we have found that the dienoic acid
chain flexibility, coupled with the appropriate N-substi-
tuent, provides compounds which expand the definition
of the RXR agonist pharmacophore.
Amines 12a–c, 16, and 20 were coupled with carboxylic
acid 23 in a standard DCC amide coupling to give the
corresponding amides 24a–c, which were subjected to
N-alkylation conditions followed by saponification to
give the corresponding retinoid-like N-alkyl-amidocarb-
oxylic acids of type 25 in good overall yields (Scheme 5).
Alternatively, the amines were coupled via reductive
amination with aldehyde 2221 to give allylic amines of
type 26 in generally good yields. Alkylation with a vari-
ety of alkyl halides under standard conditions gave the
corresponding N,N-dialkyl retinoates, which were
saponified to the desired carboxylic acid of type 27.
The simple and efficient preparation of these N-alkyl ret-
inoids was achieved by either the formation of an amide
bond or by reductive amination of an aldehyde. The
amine substrates 12a–c were prepared by Friedel–Crafts
alkylation of the appropriately substituted benzene rings
10a–c with 2,5-dichloro-2,5-dimethyl hexanes to give
tetrahydro naphthalenes 11a–c in good yields (Scheme
1). Nitration of 11a–c followed by palladium catalyzed
hydrogenation afforded the desired bicyclic amines
12a–c in good yields.
The proline-based retinoids, 48 and 49, were prepared
from the bromotetrahydronaphthalene 2822 according
to Scheme 6. Aromatic amination of the aryl bromide
with (R)- or (S)-prolinol in the presence of potassium
carbonate and copper oxide in DMF produced the cor-
responding naphthyl prolinol intermediate 29. The pri-
mary alcohol was oxidized under Swern conditions
with oxalyl chloride/DMSO to afford the aldehyde,
which was used directly without further purification.
Table 1. Cotransfection data in CV-1 cellsa and binding data for known retinoids
Compound
EC50 (nM)/Kd (nM)
RARa
RARb
RARc
RXRa
RXRb
RXRc
1
2
3
7
8
388/15
208/93
NA
87/17
31/97
NA
21/17
50/148
NA
997/53
219/8
28/36
4.5/3
1240/306
131/15
25/21
1100/306
150/14
20/29
NA
NA
NA
NA
NA
NA
3.0/3
2.0/2.5
4.0/3.0
1.0/1.8
1.5/1.5
NA, not active.
a EC50 values were determined from a full dose–response curve ranging from 10À12 to 10À15 M. Retinoid activity was normalized relative to that of
ATRA and is expressed as potency (EC50), which is the concentration of retinoid required to produce 50% of the maximal observed response.

2354
L. J. Farmer et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2352–2356
H
R
NH
2
b
N
CO2Et
N
CO2Et
a
a
b-c
Ar-NH2
Ar
Ar
O
O
R
R
R
24
26
25
10a; R=H
11a; R=H
12a; R=H
12b; R=Me
12c; R=OMe
10b; R=Me
10c; R=OH
11b; R=Me
11c; R=OH
*
H
R
d
c
N
CO2Et
N
CO2Et
Ar-NH2
Ar
Ar
Scheme 1. Reagents and conditions: (a) 2,5-Dichloro-2,5-dimethyl-
hexanes, AlCl3, CH2Cl2 (40–83%); (b) HNO3 (60–99%); (c) H2, Pd/C,
EtOH (quant.). *Nitronaphthol 11c was O-methylated (K2CO3, MeI,
acetone) prior to reduction.
27
NH2
R
NH2
NH2
X
CO2Et
Ar =
O
X
22; X=H
12a; R=H
CO H
NH
2
2
a
c-d
12b; R=Me
23; X=OH
16
20
12c; R=OMe
Scheme 5. Reagents and conditions: (a) DCC, DCM, DMAP cat. 23
(78–90%); (b) NaH, THF, RX then KOH, MeOH (30–83% two steps);
(c) NaCNBH3, ZnCl2, MeOH, 22 (50–94%); (d) K2CO3, DMA, RX
then KOH, MeOH (73–90% two steps).
14 X=O
13
16
b
15 X=NOH
Scheme 2. Reagents and conditions: (a) MeLi (2.2 equiv), THF,
À78 °C (62%); (b) NH2OH–HCl, Py, EtOH (98%); (c) SOCl2, DCM
(62%); (d) HCl, EtOH, reflux (98%).
Br
N
*
a
+
*
HN
OH
OH
28
(R) or (S)
29
R
NH2
a
c-e
N
*
b-d
18 R=H
19 R= C(O)Me
17
20
b
CO2H
Scheme 3. Reagents and conditions: (a) Isoprene, AlCl3, CH3NO2
(50%); (b) AcCl, AlCl3, DCM (62%); (c) NH2OH–HCl, Py, EtOH;
(d) SOCl2, DCM; then (e) HCl, EtOH, reflux (81% three steps).
48 (R)
49 (S)
Scheme 6. Reagents and conditions: (a) K2CO3, (R) or (S)-prolinol,
CuO, DMF, reflux (23%); (b) oxalyl chloride, DMSO, DCM, TEA;
(c) 3-ethoxycarbonyl-2-methylpropenylphosphonate, n-BuLi, THF/
DMPU (1:1), À78 °C (35% two steps); (d) 2 M LiOH, EtOH, 60 °C
(82%).
a
CO Et
2
OHC
X
b
CO Et
2
22; X=CHO
23; X=CO H
21
variable activation of the RXRs (EC50 = 151–
1000 nM). The initial results prompted us to examine
the n-alkyl series of compounds further. It is clear that
the presence of the amide carbonyl is either not tolerated
in the binding pocket of these receptors or does not
allow for sufficient chain flexibility of the ligand. We
reasoned that the reduction of the amide carbonyl group
would create a more flexible dienoic acid chain which
could adopt a favourable conformation. We prepared
secondary and tertiary N-alkyl aminoretinoids-derived
from 3,5-di-tert-butyl aniline 16. The biological results
for six selected compounds 33–38 in this series are dis-
played in Table 2. While we investigated many N alkyl
groups (some data not shown), the N-propyl retinoid
36 displayed the most potent RXR-specific profile with
Ki = 17–38 nM and EC50 = 63–99 nM in the three
RXRs. In this series, activation of RXRs is sensitive
to N-alkyl chain length, with the three-carbon chain
being the best. Elaboration with longer alkyl chains
resulted in analogues with only weak RXR binding. We
also investigated the effects of aromatic group variation,
maintaining the N-alkyl chain length at 2–5 carbons
long. A series of 6-tert-butyl-1,1-dimethylindane-based
2
Scheme 4. Reagents and conditions: (a) Ph3CHCHO, PhH, cat.
benzoic acid, reflux (38%); (b) Jones oxidation (98%).
Horner–Wadsworth–Emmons olefination of the alde-
hyde with 3-ethoxycarbonyl-2-methyl-2-enyl phospho-
nate in THF/DMPU mixture gave the dienoate ester,
which was hydrolyzed under standard conditions to give
the corresponding aza-retinoids 48 and 49.
Cotransfection potency23 (EC50, nM) and binding affin-
ity24 (Ki, nM) for the described aza-retinoids (9, 30–49)
on each of the RXR isoforms (a, b, and c) are compiled
in Table 2. The new aza-retinoids are RXR-specific ago-
nists, thus RAR data are not shown for clarity. All of
the reported compounds shown in Table 2 have RAR-
binding affinities >1000 nM. The secondary amide 30
and various N-alkylated dienoic amides (N-methyl,
-benzyl, -heptyl, etc.); some data shown, such as 34,
did not bind to or activate the retinoid X receptors; with
the exception of N-propyl amide 32, which displayed
moderate RXR-binding affinity (Ki = 299–644 nM) and

L. J. Farmer et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2352–2356
Table 2. Cotransfection potency and binding affinity data for amido- and aza-retinoids
2355
Structure
Compound
R
EC50 (nM); Ki (nM)
RXRb
RXRa
RXRc
R
N
CO H
30
31
32
H
CH
NA; NA
NA; NA
1000; 644
NA; NA
NA; NA
151; 605
NA; NA
NA; NA
669; 299
2
2
Ph (benzyl)
O
C3H7 (n-propyl)
33
34
35
36
37
38
H
NA; 529
378; 37
221; 31
99; 17
NA; NA
95; 88
NA; NA
322; 131
231; 35
63; 38
R
N
CH3
C2H5
CO H
2
235; 24
69; 34
C3H7 (n-propyl)
CH2Ph (benzyl)
C8H17 (n-octyl)
NA; 121
NA; 122
NA; 238
NA; 126
NA; 207
35; 221
R
N
CO H
2
9
39
40
41
42
C3H7 (n-propyl)
C4H9 (n-butyl)
22; 8
53; 21
21; 12
52; 60
19; 10
50; 31
C3H7 (iso-propyl)
C4H7 (methylcyclopropyl)
C5H8 (prenyl)
252; 67
123; 63
NA; 254
216; 301
98; 105
NA; 327
262; 121
100; 150
NA; 309
R
N
CO2H
43
44
45
46
47
C2H5; R1 = H
C2H5; R1 = CH3
C3H7; R1 = H
216; 103
64; 42
239; 185
117; 152
206; 72
128; 162
125; 99
R1
152; 47
231; 18
400; 257
170; 110
223; 211
NA; 576
C3H7; R1 = CH3
C3H7; R1 = OCH3
212; 161
169; 721
N
R
48 (R)-
49 (S)-
H
NA; 103
179; 21
1291; 188
161; 63
1263; 202
147; 100
CO2H
compound were prepared; the biological results on
the most active analogues (9, 39–42), are compiled in
Table 2.
analogue has moderate RXR activity (EC50 = 147–
179 nM, Ki = 21–100 nM). In light of previously report-
ed variations of RXR activity for cyclopropane-based
retinoids 7 and its enantiomer by Vuligonda et al.16,
and for the diastereomeric pairs of cyclopentane-based
retinoids reported by us,25 these results strongly suggest
that the chirality of prolines 48 and 49 played a role in
the 7- to 9-fold discrepancy in potency for RXRs ob-
served. These analogues confirm that the receptor spec-
ificity is dependent on the spatial configuration of the
dienoic acid chain. Based on new insights into the role
of helix H12 in hRXRb–LG268 complex26 and the spec-
ificity for retinoid X receptor, structural information on
complex with the ligand binding domain of hRXRb
with retinoids such as 9 and 49 would certainly be infor-
mative to further improve RXR selectivity and activity
of these novel modulators.
Our results show that the substituted indane is a suitable
isosteric replacement for the dialkylaryl group. N-Alkyl
substituent modification is again a significant element
for retaining RXR activity, with N-propyl indane
9 and N-butyl indane 39 being the most potent
compounds of the series. Chain branching from N-iso-
propyl 40, N-methylcyclopropyl 41 to N-prenyl 42
resulted in a systematic decrease in receptor activation
and binding affinity. It appears that the N-propyl substi-
tution, as exemplified by indane-based retinoid 9, com-
bines the best structural elements in terms of
pharmacophore requirements for potent activation of
the RXRs. Further variation of the aromatic moiety uti-
lizing the classic 3-substituted 5,5,8,8-tetramethyl-tetra-
hydronaphthyl group gave compounds 43–47, which
display overall diminished RXR activity when com-
pared to retinoid 9. This class of compounds, however,
showed less dependence on N-alkyl substitution for
RXR activity with both N-ethyl 44 and N-propyl 46
analogues displaying moderate activities. The proline-
derived cycloazaretinoids 48 and 49 were synthesized
to evaluate the configurational restrictions for RXR
activity.
In conclusion, we have developed a new and structurally
simple series of lipophilic aza-retinoids. The 6-tert-
butyl-1,1-dimethylindanyl-N-propylazadienoic acid
9
exhibits a potent RXR-specific profile. Other N-alkyl
chain substituents (longer alkyl, branched and unsatu-
rated alkyl, benzyl, etc.) on this indanyl series do not re-
tain potent RXR agonist profiles. The RXR-specific
agonist activity can also be extended to the other classes
of azadienoic retinoids prepared in this study (for exam-
ple, compounds 36 and 44). The SAR studies for the
N-alkyl chain length (small alkyl, i.e., ethyl and propyl,
being the best). Further, we have expanded the RXR
The (R)-proline analogue has very little activity on
the retinoid receptors, while the (S)-proline-derived

2356
L. J. Farmer et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2352–2356
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including azadienoic acids which exhibit many accessible
conformations.
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Acknowledgments
The authors thank Laura J. Dardashti for supplying
amine 12a, Karen S. Flatten for performing competitive
binding assays, and Glenn E. Croston for conducting
the cotransfection experiments.
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to each of the six receptors which is reported as (kd).
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