Design, synthesis and biological evaluation of hypolipidemic compounds based on BRD4 inhibitor RVX-208

Article abstract of DOI:10.1016/j.bmcl.2019.06.028

Bromodomain-containing protein 4 (BRD4) is a new therapeutic target for the treatment of diseases including cardiovascular diseases, cancer, inflammation and central nervous system (CNS) disorders. In this study, we introduced the pharmacophore of fibrates to a BRD4 inhibitor, RVX-208, to design dual-active hypolipidemic compounds, and found that some of new analogues showed favorable hypolipidemic activities. Synthetic accessibility towards this class of compounds optimized RVX-208 as well as would supply more thoughts on hypolipidemic drugs.

Full text of DOI:10.1016/j.bmcl.2019.06.028

Accepted Manuscript
Digest
Design, synthesis and biological evaluation of hypolipidemic compounds based
on BRD4 inhibitor RVX-208
Ping Yu, Wenjing Liu, Jinghui Ren, Yingying Wang, Yao Ning, Mingqi Huang,
Xinyi Hu, Lili Wei, Min Ji, Jin Cai
PII:
S0960-894X(19)30408-1
https://doi.org/10.1016/j.bmcl.2019.06.028
BMCL 26506
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 April 2019
10 June 2019
19 June 2019
Please cite this article as: Yu, P., Liu, W., Ren, J., Wang, Y., Ning, Y., Huang, M., Hu, X., Wei, L., Ji, M., Cai, J.,
Design, synthesis and biological evaluation of hypolipidemic compounds based on BRD4 inhibitor RVX-208,
Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.06.028
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Design， synthesis and biological evaluation of
hypolipidemic compounds based on BRD4 inhibitor RVX-
208
Ping Yua, Wenjing Liua, Jinghui Rena, Yingying Wanga, Yao Ninga, Mingqi
Huanga, Xinyi Hua, Lili Weia, Min Jib,c, Jin Caia,c,⁎
a
School of Chemistry and Chemical Engineering, Southeast University, Nanjing,
Jiangsu 211189, PR China
b School of Biological Science & Medical Engineering, Southeast University, Nanjing
210096, PR China
c
Suzhou Key Laboratory of Biomaterials and Technologies & Collaborative
Innovation Center of Suzhou Nano Science and Technology, Suzhou 215123, PR China
⁎ Corresponding author at: School of Chemistry and Chemical Engineering, Southeast
University, Nanjing, Jiangsu 211189, PR China. E-mail address: caijin@seu.edu.cn (J.
Cai).
Abstract:
Bromodomain-containing protein 4 (BRD4) is a new therapeutic target for the treatment
of diseases including cardiovascular diseases, cancer, inflammation and central nervous
system (CNS) disorders. In this study, we introduced the pharmacophore of fibrates to
a BRD4 inhibitor, RVX-208, to design dual-active hypolipidemic compounds, and
found that some of new analogues showed favorable hypolipidemic activities. Synthetic
accessibility towards this class of compounds optimized RVX-208 as well as would
supply more thoughts on hypolipidemic drugs.
Keywords: RVX-208; BRD4 inhibitor; phenoxyacetic derivatives; dual-active;
hyperlipoidemia
Cardiovascular disease (CVD) is life-threatening disease with high risks of
disabilities and mortalities. 1-4 17.3 million deaths from CVD a year globally were
reported, and the incidence of CVD is predicted to approximately 25 million in 2030.
5 A study reported that rising mortality of CVD in most Asian and Middle Eastern
countries was the highest in the world. 6 CVD can be caused by various factors, 7
such as hyperlipoidemia, atherosclerosis, hypertension, thrombus, etc.
High density lipoprotein cholesterol (HDL-C), exerting an inverse relationship
8-10
between its circulating levels and atherosclerosis,
is mainly carried by
1

apolipoprotein A-I (ApoA-I) and have been studied for the development of the
therapeutics of CVD. Moreover, it was proved that the protective ability of HDL-C
11
or ApoA-I against atherosclerosis might be contributed by many factors, and
making HDL-C and ApoA-I attractive for the CVD therapeutics development. 12
Inhibitors of the bromodomain and extra terminal (BET) family proteins
recently revealed a prospective activity in diverse disease models. 13-17 Moreover,
BRD4 is the most widely studied member of the BET family proteins. Apabetalone
1 (RVX-208, Fig. 1) is a novel BET inhibitor, 18,19showing a strong inhibitory
activity against BRD4 BD2, and currently in a phase III clinical trial as an active
small molecule drug candidate for the treatment of CVD. It is supported that
increasing the levels of ApoA-I and high-density lipoprotein cholesterol (HDL-C),
thereby potentially reducing the risk for CVD. 20-22 After taking RVX-208 orally,
risks in the major adverse cardiovascular events (MACE) were reduced by 57 % in
patients with diabetes mellitus (DM) and CVD. 23
Fibrates are activators of peroxisome proliferator-activated receptor α(PPARα)
24 and play an important role in lipid metabolism so that they are clinically widely
25-27
used for the treatment of the hyperlipoidemia and atherosclerosis.
The
mechanism of action relies on activation of intracellular receptor PPARα, 11 which
leads to several changes in metabolism, then results in improvements in lipid profile
and leads to many pleiotropic effects.
It was reported that a series of phenoxyacetic acid derivatives based on the
resveratrol 2 (Fig. 1) scaffold showed a good hypolipidemic activity in vivo, 28 and
the structure of RVX-208 was similar to resveratrol. Herein, we introduced the
pharmacophore of fibrates gemfibrozil 3 and clofibrate 4, (Fig. 1) with efficiency
of reducing serum triglyceride (TG) to the active moiety of RVX-208 to explore the
dual activity on hyperlipidemia (Fig. 2). For our study, RVX-208 and eight target
compounds 5a-5h (Fig. 3) were synthesized and evaluated in vitro as well as in vivo.
2

OH
O
OH
HO
O
N
O
NH
OH
Resveratrol (2)
O
RVX-208 (1)
O
O
O
OH
O
O
Cl
Clofibrate (4)
Gemfibrozil (3)
Figure 1. Structures of compounds with anti-hyperlipoidemia activity.
O
OH
O
O
N
O
O
OR4
NH
R1
R3
R2
O
Phenoxyacetates
RVX-208
O
N
X
NH
O
O
Target Compounds
Figure 2. A design for compounds expected with dual activity
3

O
N
X
NH
O
O
5a-5h
O
O
O
O
OH
OH
O
5a, X=
5b, X=
5d, X=
O
O
O
O
Br
Br
5c, X=
5e, X=
5g, X=
O
O
Cl
Cl
O
O
O
O
O
O
5f, X=
5h, X=
O
O
O
O
O
O
O
O
O
O
O
OH
OH
O
O
O
Figure 3. Structures of target compounds (5a-5h).
The synthetic route of RVX-208 and its analogue is shown in Scheme 1. As
29,30
reported,
the lead compound RVX-208 was synthesized by the methylation,
rearrangement and amino group protection of 3,5-dihydroxybenzoic acid (6), as a
starting material. Moreover, we optimized the experimental method while preparing
compounds 10 and 11, and found that the molar ratio of 9 and N-bromosuccinimide
(NBS) was 1:1.2 leading the highest yield 75 %, and 1:7 10/copper(І) cyanide was
generating product 11.
The phenyl moiety of compound 5a was introduced into two methoxy groups
while 5b was replaced the ether functionality of the phenyl moiety with the ester to
4

investigate
the
roles
of
the
methoxy
groups
and
the
ester.
HO
OH
O
O
O
O
O
O
b
a
c
F3C
NH
HO
O
NH2
HO
O
O
6
7
8
9
O
O
O
O
O
O
O
e
d
f
H2N
Br
F3C
NC
NH
NH2
NH2
O
10
11
12
O
OH
O
OH
O
N
O
OH
g
h
H
H
NH
O
O
O
RVX-208
14
13
O
O
O
OH
O
OH
O
O
N
i
O
j
O
OH
H
NH
H
O
O
O
O
O
15
16
5a
O
OH
O
O
O
OH
O
N
O
k
OH
l
H
NH
O
H
O
O
O
5b
18
17
Scheme 1. Synthetic route for the preparation of the RVX-208. Reagents and conditions: (a)
Me2SO4, K2CO3, acetone, 55 °C, overnight, 98 %; (b) 1. DPPA, Et3N, toluene, 80 °C, overnight; 2.
NaOH, THF, 2 h, 43 %; (c) trifluoroacetic anhydride, Et3N, CH2Cl2, rt, 2 h, 98 %; (d) NBS, CH2Cl2,
0 °C, 2 h, 75 %; (e) 1. CuCN, DMF, N2, 120 °C, 16 h; 2. 1,6-hexanediamine, H2O, 55 °C, 4 h, 78 %;
(f) MeSO3H, 120 °C, 2 h, 75 %; (g) ethylene carbonate, K2CO3, DMF, overnight, 96 %; (h) 7,
NaHSO3, TsOH·H2O, DMF, 120 °C, 16 h, 75 %. (i) ethylene carbonate, K2CO3, DMF, overnight,
96 %; (j) 7, NaHSO3, TsOH·H2O, DMF, 120 °C, 16 h, 75 %;(k) 2-bromoethanol, NaHCO3, DMF,
12 h, 125 °C, 96 %; (l) 7, NaHSO3, TsOH·H2O, DMF, 120 °C, 16 h, 75 %
Next, we synthesized the hybrid compounds containing the scaffold of RVX-208
5

and the pharmacophore of fibrates following the synthetic route shown in Scheme 2.
The compounds 5c-5h were synthesized from intermediates 19 and 20. Compounds 5c
and 5d were obtained by the esterification of 2-bromoisobutyric acid with 19 and 20,
respectively, 5e and 5f by the esterification of 2-(4-chlorophenoxy)-2-methylpropionic
acid with 19 and 20, separately. Compounds 5g and 5h were prepared by the
esterification of propanedioic acid with 19 and 20, respectively, followed by the
reaction with 2-(4-chlorophenoxy)-2-methylpropionic acid.
OH
O
O
O
OH
O
N
a
H2N
H
+
NH
O
N
O
X
b-e
NH2
O
O
O
NH
19
7
13
O
O
5c-5h
OH
O
O
O
N
O
O
O
OH
a
NH
H2N
+
H
O
O
O
NH2
O
7
15
20
Scheme 2. Synthetic route for the preparation of compounds 5c-5h. Reagents and conditions: (a)
NaHSO3, TsOH·H2O, DMF, 120 °C, 16 h, 75 %;(b) 2-bromoisobutyric acid, carbodiimide, DMAP,
DMF, rt, 16 h, 50 %;(c) 2-(4-chlorophenoxy)-2-methylpropionic acid, carbodiimide, DMAP, DMF,
rt, 16 h, 40 %; (d) propanedioic acid, carbodiimide, DMAP, DMF, rt, 16 h, 45 %; (e) 2-
bromoisobutyric acid, K2CO3, DMF, 50 °C, overnight, 40 %.
The synthetic compounds were evaluated against the BRD4 BD2 using the
enzyme linked immunosorbent assay (ELISA). In brief, the reaction system contained
enzyme standard reagent, distilled water, cleaning solution (0.01mol/L pH=7.4 PBS,
0.05% Tween-20), developer (25μL H2O2 and 25μL TMB), testing samples. The
reaction was conducted at 37 ℃ and terminated by addition of H2SO4 (2mol/L). The
optical density (OD) at 450 nm was measured within 15 min of the termination of the
reaction.
Since the mechanism of the hypolipidemic activity of RVX-208 is via inducing
the expression of ApoA-I mRNA in liver cells, we quantified the amount of ApoA-I
6

mRNA in liver cells in vitro to determine whether ApoA-I transcription was induced
by the synthetic compounds. We supposed that when the concentration of the
compounds is less than or equal to 100 μM, the transcriptional up-regulation of ApoA-I
mRNA is more than 15%, then compounds are active.
To test if these compounds (5a-5h) are valid in an vivo model， male
hyperlipidemic Sprague-Dawley rats, whose serum total cholesterol (TC) and
triglyceride (TG) were all higher than in normal rats, were orally administrated
synthetic compounds, twice a day and last for a week, contrasted with gemfibrozil,
clofibrate and RVX-208. Finally, changes of HDL-C and TG contents before and after
administration were analyzed by HPLC and GPO-PAP, respectively.
The test results (IC50) of synthetic compounds are shown in Table 1. RVX-208
and compounds 5a, 5d and 5f showed higher inhibitory activities than other compounds,
whereas 5c and 5e retained comparable activities to RVX-208 and surpassed 5b.
Considering the X-ray crystal structure of RVX-208 combined with protein BD2, 31,32
a water-mediated hydrogen bond is formed between the methoxy group on the RVX-
208 phenyl ring and the protein, and the methoxy groups on the right of the compounds
5a, 5d, and 5f might enhance this interaction, indicating that the right benzene ring with
methoxy groups would be more effective than that with methyl group or hydrogen. We
also found that the inhibitory activity of 5g and 5h were worse than RVX-208, which
might be caused by the extended chain with carbonxylic acid that was not conductive
to entering the binding pocket.
The data (in Supporting Information) of synthetic compounds influencing on liver
cells in vitro indicated all these compounds were active, suggesting that derivatives of
RVX-208 could upregulate the expression of ApoA-I mRNA after introducing a
pharmacophore of phenoxyacetic acid on a phenolic hydroxyl group.
The serum cholesterol (TC) index range of normal male SD rats is 2.20±0.07 mM
and TG index 0.88±0.13 mM. In our study rats, the measured average TC and TG
indexes were 20.13 mM and 1.56 mM, respectively, which were significantly higher
than the normal rats and indicated that the rats were with hyperlipidemia. The results
7

from the in vivo study are shown in Table 1. Gemfibrozil and clofibrate mainly reduced
the content of TG and weakly upregulate HDL-C, indicating that their effect on
reducing TC was not obvious. Conversely, RVX-208 effectively raised HDL-C but
exerted little effect on reducing TG. RVX-208 was reported as a selective bind to the
bromodomain protein (BD2) 32 and increased the ApoA-I content through an epigenetic
mechanism, then increased the level of HDL-C. 31 In our vivo study, we found that 5a
and 5b induced the upregulation of HDL-C by approximately 20 %, similar to RVX-
208. While compounds 5c, 5d, 5e, and 5f upregulated and downregulated HDL-C and
TG, respectively, better than reference compounds, gemfibrozil, clofibrate, and RVX-
208, showed that introduction the pharmacophore of fibrates to the hydroxyethoxy
group of RVX-208 could exert the efficacy of reducing TG, and the pharmacophores
of both gemfibrozil and clofibrate were effective. In view of the structure-activity
relationship of fibrates, the aromatic group on the left side of the 5c, 5d, 5e, and 5f
ensured the lipophilicity of the drug, and the right ester group was essential for the
activity of the lipid-lowering drug. Although the HDL-C improvement of 5g and 5h
were not outstanding, their ability to lower TG was better than others, due to their
carboxyl and ester groups on the right.
Table 1. Bioactivity and Vivo Activity Data of Compounds
Compounds
Gemfibrozil
Clofibrate
RVX-208
5a
X
IC50 (nM)[a] HDL-C (%)[b]↑
TG (%)[b]↓
39.66
NT[c]
NT
7.03
5.92
41.35
43.8
27.5
23.84
20.61
3.13
O
5.07
O
O
OH
O
5b
5c
71.0
53.8
16.51
19.33
11.94
36.21
OH
O
O
Br
O
8

O
O
5d
5e
5f
20.9
39.6
32.74
22.50
29.39
16.46
21.58
41.63
34.85
37.34
48.59
50.36
O
O
Br
O
O
Cl
Cl
O
O
O
9.7
O
O
O
O
5g
5h
>100.0
>100.0
O
O
O
OH
OH
O
O
O
O
O
O
O
O
[a] Biological activity data of inhibition of BRD4 BD2, and IC50 values are reported as the mean
derived from three independent measurements.
[b] HDL-C and TG changes of hyperlipidemia rats after oral administration drugs and synthetic
compounds; values are reported as the mean derived from four independent measurements, and each
measurement based on one group rats (8 rats in each group).
[c] NT: not tested.
A series of RVX-208 derivatives were synthesized efficiently and evaluated
activities on anti-hyperlipoidemia, and several target compounds revealed higher
activities than RVX-208. The results are well exhibited that the introduction of different
phenoxyacetic acid groups to lead compound RVX-208 could help obtain a dual role
of increasing HDL-C and reducing TG, and the structure or group changes of the parent
structure also would have a certain influence on the activity of the phenoxyacetic acid
pharmacophore. To avoid complex pharmacokinetic problems during a combined drug
administration, BRD4 inhibitor RVX-208 could potentially provide a good preference
for the further development of CVD therapeutics.
Acknowledgments
This work was supported by Jiangsu Natural Science Foundation (No.
BK20161438); and the Southeast University's Basic Research Business Fee Innovation
Foundation (No. 3207048416).
9

Declaration
We declare that all animal experiments have been conducted in accordance with
ethical procedures.
10

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12

Graphical Abstract
Design，synthesis and biological evaluation
of hypolipidemic compounds based on BRD4
inhibitor RVX-208
Ping Yu, Wenjing Liu, Jinghui Ren, Yingying Wang, Yao Ning, Mingqi Huang, Xinyi Hu, Lili Wei, Min Ji, Jin
Cai
O
OH
O
O
O
N
O
O
O
O
OR4
Br
NH
R1
R3
R2
O
N
O
O
Phenoxyacetates
NH
RVX-208
O
O
O
5d
Cl
O
O
O
O
N
X
O
N
O
O
optimization
NH
NH
O
O
5f
O
13