Computer-Assisted Discovery and Structural Optimization of a Novel Retinoid X Receptor Agonist Chemotype

Article abstract of DOI:10.1021/acsmedchemlett.8b00551

As universal heterodimer partners of many nuclear receptors, the retinoid X receptors (RXRs) constitute key transcription factors. They regulate cell proliferation, differentiation, inflammation, and metabolic homeostasis and have recently been proposed as potential drug targets for neurodegenerative and inflammatory diseases. Owing to the hydrophobic nature of RXR ligand binding sites, available synthetic RXR ligands are lipophilic, and their structural diversity is limited. Here, we disclose the computer-assisted discovery of a novel RXR agonist chemotype and its systematic optimization toward potent RXR modulators. We have developed a nanomolar RXR agonist with high selectivity among nuclear receptors and superior physicochemical properties compared to classical rexinoids that appears suitable for in vivo applications and as lead for future RXR-targeting medicinal chemistry.

Full text of DOI:10.1021/acsmedchemlett.8b00551

Letter
pubs.acs.org/acsmedchemlett
Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
Computer-Assisted Discovery and Structural Optimization of a
Novel Retinoid X Receptor Agonist Chemotype
Pascal Heitel,† Leonie Gellrich,† Lena Kalinowsky,† Jan Heering,‡ Astrid Kaiser,† Julia Ohrndorf,†
Ewgenij Proschak,† and Daniel Merk*,†
†Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany
‡Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology
IME, Theodor-Stern-Kai 7, D-60596 Frankfurt, Germany
S
* Supporting Information
ABSTRACT: As universal heterodimer partners of many
nuclear receptors, the retinoid X receptors (RXRs) constitute
key transcription factors. They regulate cell proliferation,
differentiation, inflammation, and metabolic homeostasis and
have recently been proposed as potential drug targets for
neurodegenerative and inflammatory diseases. Owing to the
hydrophobic nature of RXR ligand binding sites, available
synthetic RXR ligands are lipophilic, and their structural
diversity is limited. Here, we disclose the computer-assisted
discovery of a novel RXR agonist chemotype and its systematic optimization toward potent RXR modulators. We have
developed a nanomolar RXR agonist with high selectivity among nuclear receptors and superior physicochemical properties
compared to classical rexinoids that appears suitable for in vivo applications and as lead for future RXR-targeting medicinal
chemistry.
KEYWORDS: Nuclear receptors, RXR, Neurodegeneration, Inflammation
degenerative diseases such as multiple sclerosis and
Alzheimer’s disease.3,4 However, toxicity, lack of selectivity,5
and unfavorable physicochemical properties of available
rexinoids hamper the full exploration of RXR’s therapeutic
potential.6−10 By pharmacophore-based virtual screening and
subsequent structural optimization, we have identified a new
RXR agonist chemotype to equip medicinal chemistry with
innovative novel rexinoids and potentially overcome the
characteristic issues of RXR ligands.
To identify potential RXR ligands in large screening
collections, we have developed a pharmacophore model
(Figure S1) based on the binding mode of bexarotene (1,
PDB entry 4K6I11) in the hRXRα ligand binding domain
(LBD) considering positive features and excluded volumes.
Screening of a focused library of commercially available fatty
acid mimetics10 on this computational model resulted in 29
primary hits. The 15 most diverse compounds of these
computationally favored molecules (Figure S2) were evaluated
in vitro employing specific Gal4-hybrid reporter gene assays to
determine modulatory potential on the three RXR subtypes. In
these assays, HEK293T cells were transiently transfected with
plasmids coding for a constitutively expressed (CMV
promoter) RXR-LBD-Gal4-DNA binding domain fusion
he fatty acid-sensing ligand-activated transcription factors
Tretinoid X receptors (RXRs, NR2B1−3) stand out among
nuclear receptors by acting as universal heterodimer partners
of numerous members of this protein family.1 Thereby, RXRs
are key regulators of cell proliferation and differentiation and
are involved in metabolic homeostasis as well as inflammation.2
The synthetic rexinoid bexarotene (1, Figure 1) and the
putative endogenous RXR agonist 9-cis-retinoic acid (2) are
the only RXR ligands with market approval and only available
for second line treatment of cutaneous T-cell lymphoma and
Kaposi’s sarcoma, respectively. Recent animal studies have also
demonstrated great potential of RXR modulation in neuro-
Received: November 16, 2018
Accepted: December 27, 2018
Published: January 4, 2019
Figure 1. Chemical structures of bexarotene (1), 9-cis-retinoic acid
(2), and virtual screening hits (3 and 4) confirmed active in vitro.
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.8b00551
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
1
receptor, a Gal4-responsive firefly luciferase, and a constitu-
tively expressed (SV40 promoter) renilla luciferase for
normalization. In total, four compounds were confirmed active
on RXR at 10 μM (Figure S2) of which two were rejected due
to maximal activations below 10% compared to bexarotene (1,
1 μM). Full dose−response characterization of the remaining
hits 3 and 4 revealed comparably low micromolar potency on
all RXR subtypes (7−18 μM), but 3 possessed markedly
higher activation efficacy and was less toxic (Figure S3).
In silico binding mode inspection of 3 (Figure 2a) suggested
favorable formation of the canonical neutralizing contact with
Scheme 1. Synthetic Route A to Novel RXR Agonists
1
Reagents and conditions: (a) EtOH, H2SO4, reflux, 77−99%; (b)
NBS, AIBN, CHCl3, reflux, 15−86%; (c) K2CO3, DMF, rt−100 °C,
28−94%; (d) LiOH, THF, H2O, rt−50 °C, 31−99%; (e) Ph-B(OH)2
(43), Pd(PPh3)4, Na2CO3, dioxane, H2O, reflux, 40−64%; (f) NBS,
DMF, rt, 80%. n is defined in Table 1; R2 is defined in Tables 3 and 4.
phenols were either purchased or obtained from Suzuki
reaction of the corresponding 2-bromophenols (42o-q) with
phenylboronic acid (43). Bromination of 5-indanol (44)
afforded 6-bromo-5-indanol (42o), whereas the remaining 2-
bromophenols (42p,q) were purchased. Alkaline ester
hydrolysis of 41a−s then yielded test compounds 6−8, 14,
15, 20, 22−28, and 31−36. 4-Formylbenzoic acid (45) and 5-
aminoindane (46) were reacted to 47 by amide coupling and
to secondary amine 11 by reductive amination in Route B
(Scheme 2). Subsequently, aldehyde 47 was oxidized to
carboxylic acid 10, and amine 11 was methylated in an
Eschweiler-Clarke reaction affording 12 (Route B).
1
Scheme 2. Synthetic Route B to Novel RXR Agonists
Figure 2. Molecular docking of 3, 27, and 28 into the ligand binding
domain of RXRα (PDB-ID 4K6I). Crystallized ligand 1 in gray for
comparison. Pocket surfaces are colored according to lipophilicity
with green for lipophilic and red for hydrophilic. (a) 3 as 1 forms a
canonical neutralizing contact with Arg316 but leaves considerable
space for optimization. (b) 28 (pink) in contrast to 27 (orange)
occupies an unexplored subpocket between helices 5, 11, and 12,
which appears essential for stabilizing contacts to helix 12 that result
in high activation efficacy.
1
Ragents and conditions: (a) EDC·HCl, 4-DMAP, CHCl3, reflux,
63%; (b) oxone, DMF, rt, 29%; (c) NaBH(OAc)3, DCE, HOAc, rt,
91%; (d) glacial acetic acid, formaldehyde, reflux, 54%.
Arg316 but also indicated considerable space for structural
optimization. While the lipophilic moieties of 3 and 1 aligned
well, a subpocket close to the methylene group of the
crystallized ligand 1 was not occupied by 3 and further space
seemed available around the indane residue. For this promising
optimization potential and their favorable activity, we system-
atically studied the structure−activity relationship (SAR) of 3
and 4 as RXR agonists with analogues 5−36.
Analogues 3−5, 16−19, 21, and 29 were commercially
available. The synthesis of the remaining derivatives was
accomplished in three different routes (Scheme 1−3). In route
A (Scheme 1), carboxylic acids of different chain lengths with
terminal toluene residues (37a−d) were brominated under
radical conditions as ethyl esters 38a−d to benzyl bromides
39a−d, which were then suitable for Williamson ether
synthesis to esters 41a−s with phenols 40d−s. The required
For the preparation of 9, 13, and 30 (Route C, Scheme 3),
48 was esterified to 49, and arenes 49 and 54 were formylated
in a Duff reaction. The resulting aldehydes (50, 55) were
reduced to the corresponding benzyl alcohols 51 and 56. Then
51, 56, and 59 were transformed to benzyl chlorides 52, 57,
and 60 and used for Williamson ether synthesis with 5-indanol
(44) to 53 or with methyl 4-hydroxybenzoate (62) to
“inverted” ethers 58 and 61, respectively. Saponification
yielded the free carboxylic acids 9, 13, and 30.
For a systematic SAR evaluation, we first studied the favored
position and length of the carboxyl side chain (Table 1). 4-
Benzoic acid 3 possessed balanced low micromolar potency on
RXRs despite lower activation efficacy on RXRγ. Shifting the
carboxyl group to the 2-position (6) significantly reduced
activity on all three RXR subtypes, and 3-substitution (5)
produced a firefly luciferase inhibitor, which rendered 4-
B
DOI: 10.1021/acsmedchemlett.8b00551
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
1
1
Scheme 3. Synthetic Route C to Novel RXR Agonists
Table 2. Structure−Activity Relationship of Linker Moiety
1
i.a., inactive at 30 μM; relative activation efficacy compared to 1 (1
μM) is shown in parentheses. All values are mean SEM; n ≥ 3.
1
Table 3. Modification in the Lipophilic Tail Region
1
Reagents and conditions: (a) EtOH, H2SO4, reflux, 96%; (b)
hexamethylenetetramine, TFA, 100 °C, 18−60%; (c) NaBH4, EtOH,
0 °C → rt, 55−59%; (d) SOCl2, DCM, 0 °C, 41−80%; (e) 5-indanol
(44) or methyl 4-hydroxybenzoate (62), K2CO3, DMF, rt−100 °C,
82−93%; (f) LiOH, THF, H2O, rt−50 °C, 92−99%.
RXRα
RXRβ
RXRγ
no.
R2
EC50 [μM]
EC50 [μM]
EC50 [μM]
14
15
16
Ph
4-Cl-Ph
4-Br-Ph
>30
>30
>30
>30
48 10
(36 15%)
>30
>30
>30
Table 1. Lead Optimization in the Acidic Head Region
40
4
(21 4%)
17
18
19
4
4-I-Ph
4-Et-Ph
4-iPr-Ph
4-tBu-Ph
3-Cl-Ph
2-Cl-Ph
24
1
29
2
>30
i.a.
(19 1%)
(25 2%)
28
3
35
3
(11 1%)
(7.4 0.7%)
no. pos.
n
RXRα EC50 [μM] RXRβ EC50 [μM] RXRγ EC50 [μM]
16
1
16
1
i.a.
3
4
0
6.7 0.6
8.8 0.4
17
2
(11 1%)
(9.5 0.5%)
(29 3%)
(28 1%)
(5.0 0.2%)
7.8 2.4
(16 4%)
8.9 0.4
(15 1%)
>30
1
1
1
5
6
7
3
2
4
0
0
1
-
-
-
>30
>30
>30
20
21
17
1
20
4
44 16
(9.3 3.4%)
(54 3%)
(26 5%)
13 2 (47 5%)
18
1
22
1
(9.9 0.1%)
(8.8 0.1%)
9.9 0.5
(58 2%)
>30
5.0 0.1
(24 1%)
1.1 0.1
(22 1%)
8.3 0.8
(31 2%)
>30
8.6 1.1
(27 2%)
2.1 0.1
(22 1%)
>30
8
4
4
2
3
6.7 0.5
10 1 (29 2%) 21 1 (19 1%)
tox. tox.
(28 1%)
22
23
2-F-Ph
2-CH3-Ph
>30
9
tox.
19
1
(19 1%)
1
Firefly luciferase inhibitor; tox., toxic at 30 μM; pos., position;
24
25
26
27
28
2-CF3-Ph
2-OCH3-Ph
2-OCF3-Ph
2-tBu-Ph
10
1
relative activation efficacy compared to 1 (1 μM) is shown in
parentheses. All values are the mean SEM; n ≥ 3.
(52 1%)
29
1
>30
>30
(21 1%)
1.1 0.1
(26 1%)
0.16 0.01
(11 1%)
0.28 0.01
(70 1%)
1.9 0.1
(18 1%)
0.37 0.03
(12 1%)
0.31 0.01
(44 1%)
4.2 0.1
(25 1%)
1.1 0.1
(21 1%)
1.6 0.1
(94 4%)
substitution as preferred geometry for RXR activation.
Exploration of the side chain length in 4-position revealed
decreased potency for phenylacetic acid 7, which was restored
with phenylpropionic acid 8. On RXRγ, 8 was slightly superior
to 3 in terms of activation efficacy (19%). Further chain
elongation to 9 resulted in toxicity.
In the linker region (Table 2), ether replacement by an
amide moiety (10) was not tolerated, and free amine 11
revealed markedly reduced potency. N-Methylamine 12
recovered the potency of ether 3 in terms of EC50 values but
with diminished activation efficacy. Inverted ether 13 was
active but turned out too toxic for full characterization. Still,
reduced potency of 13 indicated that the linker residue of 3
was superior.
(1,1′-
biphenyl)-
2-yl
1
i.a., inactive at 30 μM; relative activation efficacy compared to 1 (1
μM) is shown in parentheses. All values are mean SEM; n ≥ 3.
only carrying an unsubstituted phenyl ether, which still
activated all RXRs with lower potency. Introduction of halogen
substituents in 4-position (15−17) enhanced potency with
increasing halogen size. Similar SAR was observed for 4-alkyl
derivatives where potency increased from ethyl (18) over iso-
propyl (19) to tert-butyl (4). However, all 4-substituents,
especially alkyl residues, markedly decreased activation efficacy
To systematically study the SAR of the lipophilic ether
substituent, we started with the minimized motif 14 (Table 3)
C
DOI: 10.1021/acsmedchemlett.8b00551
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
and were less potent on RXRγ. When we shifted the chlorine
substituent from 4- (15) to 3-position (20), potency and
activation efficacy were improved, but the highest activity was
achieved with a 2-chlorine substituent (21). Further
exploration of substituents in 2-position revealed that fluorine
(22) was not favored, but small lipophilic residues such as
methyl (23) and especially trifluoromethyl (24) markedly
increased potency. A similar trend was observed for methoxy
(25) and trifluoromethoxy (26) derivatives, where 26
demonstrated balanced high potency and efficacy on all
RXRs. Further improvement was achieved with larger residues
in 2-position with tert-butyl (27) and phenyl (28) analogues
displaying nanomolar activity. While 27 despite high potency
possessed weak activation efficacy, 2-phenyl derivative 28 was
identified as RXR agonist with particularly high efficacy in
RXRγ activation. This trend was not observed for any other
compound in this series rendering 28 as potential starting
point for the development of RXRγ-preferential ligands.
Systematic analysis of the SAR for the individual molecular
building blocks of 3 and derivatives particularly suggested
optimization potential in the lipophilic ether substituent.
Striving to combine the SAR knowledge for further
optimization, we fused the most promising structural elements
identified for each moiety of the lead compound (Table 4).
First, we aimed to enhance the RXRγ-preferential profile of
28 by inverting the linker residue since 3-chlorine-substituted
inverted ether 29 improved balance over all RXR subtypes in
terms of potency and activation efficacy. However, the
resulting compound 30 turned out less potent and toxic. We
then combined bulky, hydrophobic elements in 2- and 4-
position of the phenyl ether since both positions were favored
for high potency (e.g., 4 and 28). 2,4-Di-tert-butyl derivative
31, 6-phenylindane 32, 4-tert-butyl-2-phenyl combination 33,
and 4-methyl-2-phenyl analogue 34 failed to achieve any
additive effect in potency, however, and were significantly less
active than 28. We hypothesized that steric reasons might
explain the inactivity of these bulky combinations and
investigated sterically less demanding combinations in the
hydrophobic tail region with 2,4-bis(trifluoromethyl) deriva-
tive 35 and 4-tert-butyl-2-chloro residue 36. Both molecules
did not achieve as high potency as 28, but 35 provided full-
agonistic activity on RXRα as well as increased maximal
activation of RXRβ compared to single trifluoromethyl
substitution in 2-position (24).
In an attempt to rationalize the high potency of 28 and its
rather strict SAR that prevented any further optimization on
the phenylether moiety, we virtually studied its interaction with
the RXRα ligand binding site compared to bexarotene (1,
Figure 2b). The benzoic acid residues of 1 and 28 aligned well
in the proposed binding mode and participated in the
canonical neutralizing contact with Arg316. The lipophilic
tails of 1 and 28 differently extended to the large lipophilic
pocket of RXRα and deep burial of the central aromatic ring of
28 in a subpocket between helices 5 and 11 illustrated why no
further substituents were tolerated on this ring. Instead, the
calculated binding mode indicated further optimization
potential at the terminal aromatic ring. Similar to previous
observations,12,13 the molecular docking simulation suggested
that lack of direct interaction with helix 12 may explain lower
activation efficacy of 27 compared to 1 and 28. As a result of
the bulkier 2-phenyl substituent, the central aromatic ring of
28 extended to a lipophilic subpocket between helices 5, 11,
and 12. This region appears not to be addressed by 27 after all
and in contrast to 27, the central aromatic ring of 28 provided
a lipophilic surface for stabilizing interactions with helix 12 that
were mediated by lipophilic contacts to the network of Leu436,
Leu451, and Leu455. Overall, the molecular docking suggested
a binding mode for 28 that significantly differed from the
classical rexinoid 1 since it protruded to unexplored regions of
the pocket between helices 5 and 11 and provided a novel
binding geometry rendering 28 as innovative new RXR ligand.
To further evaluate this novel RXR modulator and its
properties, 28 was extensively characterized in vitro (Figure 3).
The interaction of 28 and the RXRα LBD was studied under
cell-free conditions by isothermal titration calorimetry (ITC),
where 28 displayed high affinity binding with an independent
binding constant Kd of 0.095 0.005 μM (Figure S4). Binding
was both driven by enthalpic (ΔH = −25 kJ/mol) and entropic
shares (ΔS = 49 J/mol K). The minor difference between the
Kd and EC50 value may be due to the cellular assay
environment where activity is also affected by cell penetration
and potential degradation.
Table 4. Combinations of Structural Motifs for Enhanced
1
Potency Identified in SAR Studies
Off-target profiling of 28 and the initial screening hit 3 on 12
nuclear receptors in addition to RXRs showed markedly
improved selectivity for 28 (Figure 3b,c). While 3 also strongly
activated RARs at 30 μM concentration, 28 was only active on
RXRs. In addition, 28 possessed favorable properties compared
to classical rexinoid 1 with superior aqueous solubility (28, 1.3
μg/mL; 1, 0.31 μg/mL), experimental logP (28, 2.0; 1, 5.2,
Figure S5), and cytotoxicity (Figure S3).
1
tox., toxic at 30 μM; relative activation efficacy compared to 1 (1
μM) is shown in parentheses. All values are mean SEM; n ≥ 3.
D
DOI: 10.1021/acsmedchemlett.8b00551
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
cally promoted LXR-RXR activation by LXR agonist
T0901317 (1 μM).
As nuclear receptors translate ligand signals into adaptions in
gene expression, we also analyzed RXR modulation by 28 on
mRNA level (Figure 3f). In HepG2 cells, 28 induced the
expression of adiponectin (ADIPOQ), angiopoietin-like 4
(ANGPTL4), and apolipoprotein E (APOE), which are known
to be regulated by RXRs and their heterodimer partners PPAR
and LXR. At 1 μM and 10 μM concentration, 28 induced gene
expression with comparable efficacy as bexarotene (1, 1 μM).
Thus, 28 was confirmed as potent and selective RXR agonist.
Potential therapeutic applications for RXR modulators are
versatile. RXR agonists appear to contribute to β-amyloid
clearance in Alzheimer’s disease4 and accelerate central
nervous system remyelination in multiple sclerosis.3 Apart
from these neurodegenerative diseases, rexinoids also hold
potential in cancer where 1 is approved for cutaneous T-cell
lymphoma and 2 represents a therapeutic option in Kaposi’s
sarcoma. Current research also focuses on other cancer
types.6,14 Furthermore, RXR ligands showed beneficial effects
in a multitude of disorders linked to the metabolic syndrome
such as diabetes15 and cardiovascular diseases.16 However,
several side-effects, among them hypertriglyceridemia,16
hepatomegaly,17 and hypothyroidism,18 hinder further explora-
tion of RXRs as therapeutic targets illustrating the high unmet
need for novel RXR modulators that can overcome these
obstacles.
Here we report the computer-assisted discovery and
structural optimization of a new RXR activator chemotype
culminating in the development of nanomolar RXR agonist 28.
In vitro characterization confirmed high affinity of 28 to the
RXR LBD and effective induction of RXR-regulated gene
expression by 28. The compound’s reduced lipophilicity, as
well as improved solubility and beneficial toxicity profile, is
clearly superior to the classical rexinoid 1, which suffers from
poor physicochemical properties and pronounced toxicity.
Furthermore, recent reports12,13,19 suggest that RXR modu-
lators with partial agonistic activity offer preferable safety
compared to full RXR agonists but retain therapeutic efficacy.
Thus, the high potency of 28 combined with its intermediate
RXR activation efficacy constitutes a very favorable pharma-
codynamic profile.
Molecular docking of 28 to the RXRα LBD suggested a
significantly different binding mode for 28 compared to 1,
which might enable this new RXR ligand scaffold to overcome
the characteristic challenge of poor subtype selectivity in RXR
targeting. Especially the slight RXRγ-favoring activity of 28 in
terms of activation efficacy appears promising and might open
a new avenue toward subtype selectivity. Despite its high RXR-
agonistic potency, 28 has a small, rather fragment-like size
(304 g/mol) and a modular architecture that will allow broad
further structural variation. Therefore, the new RXR ligand
scaffold of 28 contributes to the SAR of RXR modulators and
can provide access to innovative RXR activators that help
further explore the therapeutic potential of RXR modulation in
neurodegeneration, inflammation, and cancer.
Figure 3. (a) Structure and key properties of compound 28. (b,c)
Selectivity profile of 3 and optimized derivative 28 on 12 nuclear
receptors related to RXRs at 30 μM. Although 3 also activates RAR,
28 gained full RXR selectivity. n ≥ 3. (d, e) 28 activated permissive
RXR heterodimers with (d) PPAR and (e) LXR in full-length assays
showing synergistic effects with the respective partner agonists
rosiglitazone (Rosi) and T0901317 (T090); (d) n = 3, (e) n = 4.
(f) 28 induced RXR-regulated gene expression (qRT-PCR) of
adiponectin (ADIPOQ), angiopoietin-like 4 (ANGPTL4), and
apolipoprotein E (APOE) with similar efficacy as bexarotene (1,
Bex). n = 4. All values are mean SEM; ∗ p < 0.05; ∗∗ p < 0.01; ∗∗∗
p < 0.001.
To further evaluate the RXR-modulatory activity of 28, we
studied its effect on the RXR heterodimers (Figure 3d,e) in
reporter gene assays employing human full-length hetero-
dimers to govern reporter gene expression (Figure 3d,e). 28
was capable of activating PPARγ-RXR with an EC50 value of
ASSOCIATED CONTENT
■
S
* Supporting Information
1.0
PPARγ agonist rosiglitazone (1 μM) with an EC50 value of
0.47 0.12 μM. LXR-RXR activation by 28 alone was too
weak to reach statistical significance, but 28 again synergisti-
0.2 μM and synergistically promoted its activation by
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.8b00551.
E
DOI: 10.1021/acsmedchemlett.8b00551
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
(7) Eshagh, K.; Romero, L. S.; So, J. K.; Zhao, X. F. Late-Onset
Bexarotene-Induced CD4 Lymphopenia in a Cutaneous T-Cell
Lymphoma Patient. Cutis 2017, 99 (2), E30−E34.
Synthesis and analytical characterization of compounds
6−61, assay protocols, computational methods (PDF)
́
(8) Vaz, B.; de Lera, A. Advances in Drug Design with RXR
Modulators. Expert Opin. Drug Discovery 2012, 7 (11), 1003−1016.
(9) Dominguez, M.; Alvarez, S.; de Lera, A. R. Natural and
Structure-Based RXR Ligand Scaffolds and Their Functions. Curr.
Top. Med. Chem. 2017, 17 (6), 631−662.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: merk@pharmchem.uni-frankfurt.de. Phone:
+496979829327.
(10) Proschak, E.; Heitel, P.; Kalinowsky, L.; Merk, D.
Opportunities and Challenges for Fatty Acid Mimetics in Drug
Discovery. J. Med. Chem. 2017, 60 (13), 5235−5266.
ORCID
Pascal Heitel: 0000-0001-5187-6342
Ewgenij Proschak: 0000-0003-1961-1859
Daniel Merk: 0000-0002-5359-8128
(11) Boerma, L. J.; Xia, G.; Qui, C.; Cox, B. D.; Chalmers, M. J.;
Smith, C. D.; Lobo-Ruppert, S.; Griffin, P. R.; Muccio, D. D.;
Renfrow, M. B. Defining the Communication between Agonist and
Coactivator Binding in the Retinoid X Receptor α Ligand Binding
Domain. J. Biol. Chem. 2014, 289 (2), 814−826.
(12) Kawata, K.; Morishita, K.; Nakayama, M.; Yamada, S.;
Kobayashi, T.; Furusawa, Y.; Arimoto-Kobayashi, S.; Oohashi, T.;
Makishima, M.; Naitou, H.; et al. RXR Partial Agonist Produced by
Side Chain Repositioning of Alkoxy RXR Full Agonist Retains
Antitype 2 Diabetes Activity without the Adverse Effects. J. Med.
Chem. 2015, 58 (2), 912−926.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the DFG (PR1405/2-2,
SFB1039/A07). P.H. was supported by the Else-Kroener-
Fresenius-Foundation funding the graduate school ‘Transla-
tional Research Innovation − Pharma’ (TRIP). E.P. was
supported by the DFG (PR1405/4-1).
(13) Ohsawa, F.; Yamada, S.; Yakushiji, N.; Shinozaki, R.;
Nakayama, M.; Kawata, K.; Hagaya, M.; Kobayashi, T.; Kohara, K.;
Furusawa, Y.; et al. Mechanism of Retinoid X Receptor Partial
Agonistic Action of 1-(3,5,5,8,8-Pentamethyl-5,6,7,8-Tetrahydro-2-
Naphthyl)-1 H -Benzotriazole-5-Carboxylic Acid and Structural
Development To Increase Potency. J. Med. Chem. 2013, 56 (5),
1865−1877.
ABBREVIATIONS
■
ADIPOQ, adiponectin; AIBN, azobis(isobutyronitrile);
ANGPTL4, angiopoietin-like 4; APOE, apolipoprotein E;
CAR, constitutive androgen receptor; CMV, cytomegalovirus;
DBD, DNA binding domain; DCE, 1,2-dichloroethane; DCM,
dichloromethane; DMAP, 4-dimethylaminopyridine; DMF,
dimethylformamide; EC, effective concentration; EDC, 1-
ethyl-3-(3-(dimethylamino)propyl)carbodiimide; FXR, farne-
soid X receptor; ITC, isothermal titration calorimetry; LBD,
ligand binding domain; LXR, liver X receptor; NBS, N-
Bromosuccinimide; Pos, position; PPAR, peroxisome prolifer-
ator-activated receptor; PXR, pregnane X receptor; qRT-PCR,
quantitative real-time polymerase chain reaction; THF,
tetrahydrofuran; TFA, trifluoroacetic acid; RAR, retinoic acid
receptor; rt, room temperature; RXR, retinoid X receptor;
SAR, structure−activity relationship; SEM, standard error of
the mean; VDR, vitamin D receptor
(14) Uray, I. P.; Dmitrovsky, E.; Brown, P. H. Retinoids and
Rexinoids in Cancer Prevention: From Laboratory to Clinic. Semin.
Oncol. 2016, 43 (1), 49−64.
(15) Altucci, L.; Leibowitz, M.; Ogilvie, K.; de Lera, A.;
Gronemeyer, H. RAR and RXR Modulation in Cancer and Metabolic
Disease. Nat. Rev. Drug Discovery 2007, 6 (10), 793−810.
́
(16) Lalloyer, F.; Fievet, C.; Lestavel, S.; Torpier, G.; van der Veen,
J.; Touche, V.; Bultel, S.; Yous, S.; Kuipers, F.; Paumelle, R.; et al. The
RXR Agonist Bexarotene Improves Cholesterol Homeostasis and
Inhibits Atherosclerosis Progression in a Mouse Model of Mixed
Dyslipidemia. Arterioscler., Thromb., Vasc. Biol. 2006, 26 (12), 2731−
2737.
(17) Kapetanovic, I. M.; Horn, T. L.; Johnson, W. D.; Cwik, M. J.;
Detrisac, C. J.; McCormick, D. L. Murine Oncogenicity and
Pharmacokinetics Studies of 9- Cis -UAB30, an RXR Agonist, for
Breast Cancer Chemoprevention. Int. J. Toxicol. 2010, 29 (2), 157−
164.
(18) Sherman, S. I.; Gopal, J.; Haugen, B. R.; Chiu, A. C.; Whaley,
K.; Nowlakha, P.; Duvic, M. Central Hypothyroidism Associated with
Retinoid X Receptor−Selective Ligands. N. Engl. J. Med. 1999, 340
(14), 1075−1079.
(19) Kakuta, H.; Yakushiji, N.; Shinozaki, R.; Ohsawa, F.; Yamada,
S.; Ohta, Y.; Kawata, K.; Nakayama, M.; Hagaya, M.; Fujiwara, C.;
et al. RXR Partial Agonist CBt-PMN Exerts Therapeutic Effects on
Type 2 Diabetes without the Side Effects of RXR Full Agonists. ACS
Med. Chem. Lett. 2012, 3 (5), 427−432.
REFERENCES
■
(1) Germain, P.; Chambon, P.; Eichele, G.; Evans, R. M.; Lazar, M.
A.; Leid, M.; De Lera, A. R.; Lotan, R.; Mangelsdorf, D. J.;
Gronemeyer, H. International Union of Pharmacology. LXIII.
Retinoid X Receptors. Pharmacol. Rev. 2006, 58 (4), 760−772.
(2) Yamada, S.; Kakuta, H. Retinoid X Receptor Ligands: A Patent
Review (2007 - 2013). Expert Opin. Ther. Pat. 2014, 24 (4), 443−452.
(3) Huang, J. K.; Jarjour, A. A.; Oumesmar, B. N.; Kerninon, C.;
Williams, A.; Krezel, W.; Kagechika, H.; Bauer, J.; Zhao, C.;
Evercooren, A. B.-V.; et al. Retinoid X Receptor Gamma Signaling
Accelerates CNS Remyelination. Nat. Neurosci. 2011, 14 (1), 45−53.
(4) Cramer, P. E.; Cirrito, J. R.; Wesson, D. W.; Lee, C. Y. D.; Karlo,
J. C.; Zinn, A. E.; Casali, B. T.; Restivo, J. L.; Goebel, W. D.; James,
M. J.; et al. ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and
Reverse Deficits in AD Mouse Models. Science 2012, 335 (6075),
1503−1506.
(5) Heitel, P.; Achenbach, J.; Moser, D.; Proschak, E.; Merk, D.
DrugBank Screening Revealed Alitretinoin and Bexarotene as Liver X
Receptor Modulators. Bioorg. Med. Chem. Lett. 2017, 27 (5), 1193−
1198.
(6) Liby, K.; Sporn, M. Rexinoids for Prevention and Treatment of
Cancer: Opportunities and Challenges. Curr. Top. Med. Chem. 2017,
17 (6), 721−730.
F
DOI: 10.1021/acsmedchemlett.8b00551
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX