Novel Nonsteroidal Progesterone Receptor (PR) Antagonists with a Phenanthridinone Skeleton

Article abstract of DOI:10.1021/acsmedchemlett.8b00058

The progesterone receptor (PR) plays an important role in various physiological systems, including female reproduction and the central nervous system, and PR antagonists are thought to be effective not only as contraceptive agents and abortifacients but also in the treatment of various diseases, including hormone-dependent cancers and endometriosis. Here, we identified phenanthridin-6(5H)-one derivatives as a new class of PR antagonists and investigated their structure-activity relationships. Among the synthesized compounds, 37, 40, and 46 exhibited very potent PR antagonistic activity with high selectivity for PR over other nuclear receptors. These compounds are structurally distinct from other nonsteroidal PR antagonists, including cyanoaryl derivatives, and should be useful for further studies of the clinical utility of PR antagonists.

Full text of DOI:10.1021/acsmedchemlett.8b00058

Letter
Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
Novel Nonsteroidal Progesterone Receptor (PR) Antagonists with a
Phenanthridinone Skeleton
Yuko Nishiyama,† Shuichi Mori,‡ Makoto Makishima,§ Shinya Fujii,† Hiroyuki Kagechika,‡
Yuichi Hashimoto,† and Minoru Ishikawa*,†
†Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
‡Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo
101-0062, Japan
§Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
S
* Supporting Information
ABSTRACT: The progesterone receptor (PR) plays an
important role in various physiological systems, including
female reproduction and the central nervous system, and PR
antagonists are thought to be effective not only as contraceptive
agents and abortifacients but also in the treatment of various
diseases, including hormone-dependent cancers and endome-
triosis. Here, we identified phenanthridin-6(5H)-one deriva-
tives as a new class of PR antagonists and investigated their structure−activity relationships. Among the synthesized
compounds, 37, 40, and 46 exhibited very potent PR antagonistic activity with high selectivity for PR over other nuclear
receptors. These compounds are structurally distinct from other nonsteroidal PR antagonists, including cyanoaryl derivatives,
and should be useful for further studies of the clinical utility of PR antagonists.
KEYWORDS: Progesterone receptor, antagonist, nonsteroid, phenanthridinone
selectivity for PR over other steroid receptors. Some of the
rogesterone receptor (PR) is a member of the nuclear
Preceptor superfamily of ligand-dependent transcription present authors also developed 7−9.10−13 PR antagonists
factors1 and is expressed in female tissues including uterus,
containing a cyanoaryl moiety, a common pharmacophore
motif, found that quite small structural modifications cause
agonist/antagonist activity switching.10,8,9 A concern about
such activity switching is that metabolites of an antagonist act
as agonists. Although we recently reported nonsteroidal PR
antagonist 10, which does not have a cyanoaryl moiety,14 there
is still a need for a new, more robust pharmacophore motif of
PR antagonists to avoid such activity switching.
Here, to obtain nonsteroidal PR antagonists without a
cyanoaryl moiety, we focused on our previously developed liver
X receptor (LXR) and retinoic acid receptor-related orphan
receptor (ROR) ligands 12 and 13, which contain a
phenanthridin-6(5H)-one skeleton as a cyclized carba-analog
of T0901317 (11) (Figure S1).15,16 Because hydroxycholester-
ols are endogenous ligands for both LXR and ROR, we
hypothesized that if the phenanthridin-6(5H)-one scaffold acts
as a steroid surrogate, phenanthridinone derivatives would also
bind to other nuclear receptors that recognize endogenous
steroidal ligands. Based on this idea, we successfully identified
phenanthridinone derivatives with PR-antagonistic activity and
examined their structure−activity relationships (SAR) and
selectivity.
ovary, vagina, fallopian tubes and breast, and brain. It plays an
important role in female reproduction, being associated with
the establishment and maintenance of pregnancy and with
alveolar development in the breast. Recently, there is
increasing evidence suggesting that PR has a role in the
central nervous system.2,3 PR agonists, including the
endogenous agonist progesterone (1, Figure 1), have been
used extensively to treat gynecological disorders, as well as in
female contraception and hormone replacement therapy.
However, their steroidal skeleton brings with it the potential
to cross-react with other steroid receptors, which can result in
unwanted side effects, potentially limiting the benefits of these
agents. To overcome these issues, nonsteroidal PR agonists
such as tanaproget (2) have been developed4
PR antagonists may be potentially useful for the treatment of
various diseases including hormone-dependent cancers,5
uterine fibroids,6 endometriosis,7 and abortifacient. However,
the steroidal PR antagonist mifepristone (3) is in only limited
clinical use as an abortifacient at present. It is known that 3
demonstrates potent activities against other steroid receptors
such as glucocorticoid receptor (GR). Therefore, development
of selective nonsteroidal PR antagonists is necessary for the
estimation of their clinical utility. Indeed, various nonsteroidal
PR antagonists, including 4,8 5,9 and 6,6 have been synthesized
based on the structure of 2, with the aim of improving the
Received: February 4, 2018
Accepted: June 23, 2018
Published: June 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.8b00058
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ACS Medicinal Chemistry Letters
Letter
Figure 1. Chemical structures of PR agonists 1−2 and antagonists 3−10.
Compounds 12−24 were prepared as described in refs 15
and 16. PR-antagonistic activity was evaluated by assay of PR-
regulated alkaline phosphatase activity in human breast cancer
cell line T47D.17 Under our assay conditions, mifepristone (3)
showed subnanomolar IC50 value with a reproducibility (Table
1). We found that compound 14, a phenanthridin-6(5H)-one
decrease of antagonistic activity. Thus, we concluded that
hydrogen or a methyl group is a suitable substituent on the
nitrogen atom.
Next, the effect of introduction of a methoxy group at every
position (methoxy scanning) was investigated (25−31; Table
2) because many types of nuclear receptor ligands possess a
a
Table 1. SAR at the 2-Position and the Nitrogen Atom
Table 2. SAR at the 4-Position and Other Substitution
Effects
a
compounds
R1
R2
PR IC50 (nM)
Mifepristone (3)
7
9
0.073 0.0047 (N = 19)
123
95.3
107
7100
7900
7800
8300
8600
1200
780
compounds
R1
R2
PR IC50 (nM)
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
45
46
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
H
H
H
H
H
H
H
H
H
Me
Me
1-MeO
3-MeO
4-MeO
7-MeO
8-MeO
9-MeO
10-MeO
4-F
4000
410
560
12000
1100
5800
2700
130
10
14
15
16
17
18
19
12
20
21
22
23
24
H
Me
Et
t-Bu
CH2OH
(CF3)2COH
(CF3)2COH
(CF3)2COH
(CF3)2COH
(CF3)2COH
(CF3)2COH
(CF3)2COH
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
H
Me
Et
n-Pr
n-Hex
n-C9H19
7-F
8-F
9-F
730
310
1000
340
1400
3800
2500
10000
4-MeO
4-Me
4-Et
4-n-Pr
4-Me, 8-F
4-Me
270 20 (N = 2)
150 17 (N = 5)
210 3.7 (N = 2)
360 15 (N = 2)
46 4.4 (N = 4)
180 8.9 (N = 3)
27 16 (N = 2)
a
Alkaline phosphatase assay. Mean IC50 values with standard error of
mean (SEM) from 1 or N times independent experiments.
4-Me, 8-F
a
Alkaline phosphatase assay. Mean IC50 values with standard error of
bearing an n-butyl group on the nitrogen atom, showed PR-
antagonistic activity with the IC50 value of 7.1 μM. Although
the activity was not potent, we considered it promising, as this
compound belongs to a different chemical class from other
known PR antagonists. Thus, we focused on 14 as a lead
compound and investigated the SAR of analogs we had
previously synthesized.16 First, we examined SARs at the 2-
position (Table 1). Introduction of alkyl groups (15−17) or a
hydroxymethyl group (18) retained the PR-antagonistic
activity. On the other hand, compound 19 bearing a
hexafluoropropanol moiety showed the strongest activity,
suggesting that trifluoromethyl groups at this position are
favorable for potent activity.
mean (SEM) from 1 or N times independent experiments.
methoxy group(s).18 3-Methoxy and 4-methoxy analogs 26
and 27 showed more than 3-fold and 2-fold enhanced activity
compared with the unsubstituted analog 19, respectively. In
contrast, 9-methoxy analog 30 showed 5-fold weaker activity.
We believe that introduction of a substituent into every
position is favorable in order to investigate substituent effects.
It is important to note that phenanthridin-6(5H)-one analogs
bearing substituent(s) at any position can be quite easily
synthesized, and this represents a considerable advantage
compared to the steroid skeleton. Based on the SARs shown in
Tables 1−3, we proceeded to synthesize new compounds,
aiming to obtain more potent antagonists.
Next, we evaluated substituent effects on the nitrogen atom.
Hydrogen analog 12 and methyl analog 20 increased PR-
antagonistic activity, affording submicromolar IC50 (Table 1).
Introduction of a longer alkyl group (22−24) resulted in a
At this stage, the substituent on the nitrogen atom was fixed
to hydrogen, and we focused on fluoro derivatives to
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DOI: 10.1021/acsmedchemlett.8b00058
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ACS Medicinal Chemistry Letters
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a
antagonistic activity of 4-methyl analog 45 was stronger than
that of unsubstituted 20 as expected but weaker than that of
N−H analog 37. On the other hand, the N,4-dimethyl and 8-
fluoro analog 46 showed very potent antagonistic activity
(Table 2), being more potent than the cyanoaryl,10−13 and
noncyanoaryl14 chemical classes of nonsteroidal PR antagonists
in alkaline phosphatase assay (Table S1). In addition, these
representative compounds did not show PR agonistic activity
at 10 μM. This result suggests that the phenanthridinone
skeleton might be a more robust pharmacophore motif of PR
antagonists to avoid such activity switching. Therefore, we
selected 37, 40, and 46 as representative compounds and
investigated their biological activities in more detail.
The alkaline phosphatase inhibitory activity assay utilized for
SAR analyses may be affected not only by inhibition of PR-
mediated transcription (antagonistic activity) but also by direct
inhibition of the enzymatic activity. Therefore, to validate the
PR-antagonistic activity of representative compounds, we
measured the expression of another PR-regulated protein, the
β1 subunit of Na/K-ATPase,19 in T47D cells by means of
Western blotting. Potent PR antagonists 37, 40, and 46
decreased progesterone-induced β1-Na/K ATPase expression,
whereas the weak antagonist 24 had little effect on the β1-Na/
K ATPase level at the evaluated concentration (Figure 2). The
Table 3. Binding Affinity of Representative PR Antagonists
compounds
PR IC50 (nM)
Mifepristone
5.2 0.53
1500 540
340 150
150 110
37
40
46
a
4 nM [1,2,6,7-3H]progesterone was used.
investigate the effect of the electron withdrawing substituent.
Synthesis of the novel analogs 32−40 is illustrated in Scheme
1. Briefly, ortho-substituted anilines 41 were treated with
a
Scheme 1. Synthesis of the Novel Analogs 32−40
a
Reagents and conditions: (a) CF3COCF3·1.5H2O, p-TsOH·H2O,
toluene, reflux, 8−49%; (b) 2-iodobenzoic acids or 2-bromobenzoic
acids, EDC, DMAP, DMF, 100 °C, 19−91%; (c) SEMCl, NaH, DMF,
0 °C to rt; (d) Pd(OAc)2, PCy3·HBF4, Cs2CO3, DMA, 130 °C, 9−
44% in 2 steps; (e) TBAF, THF, reflux, 30−80%.
Figure 2. Western blot analysis of β1-Na/K-ATPase in T47D cells in
the presence of test compounds.
hexafluoroacetone trihydrate to give 1,1,1,3,3,3-hexafluoro-2-
hydroxypropyl derivatives 42. Anilines 42 were condensed
with o-bromo-/iodobenzoic acids to give amides 43. After
protection of the amide and hydroxyl group with SEM,
palladium-catalyzed intramolecular cyclization afforded 44.
Compounds 32−40 were obtained by deprotection of the
SEM groups. The 4-fluoro analog 32 and 8-fluoro analog 34
were 6-fold and 3-fold more potent than the unsubstituted
analog 12, respectively (Table 2). These preferences of
fluorine-substitution position are roughly consistent with the
results of the methoxy scanning, that is, 4- and 8-substituted
analogs showed enhanced activity whereas 9-substituted
analogs showed weaker activity.
We next focused on the 4-position because 4-fluoro analog
32 showed the most potent activity among the methoxy- and
fluorine-substituted compounds, and 4-substituted analogs are
easier to synthesize than 3-substituted analogs; in the course of
synthesis of the 3-substitued analog, the 1-substitued analog is
also obtained. 4-Methoxy analog 36 was more potent than the
unsubstituted analog 12, in accordance with the results for the
n-butyl analog 19 and 27 (Table 1). 4-Alkyl analogs 37−39
showed greater activity than the unsubstituted analog 12. In
particular, 4-methyl analog 37 had around 0.1 μM IC50 value
(Table 2).
activity of 1 μM 40 and 46 was equal to or greater than 0.3 μM
mifepristone, indicating that these nonsteroidal antagonists are
very potent, at least under these assay conditions.
We next investigated whether the representative compounds
bind directly to PR, using human PR ligand-binding domain
3
(LBD) and H-labeled progesterone (1) (Table 3). Com-
pounds 37, 40, and 46 all exhibited strong binding affinity.
These results, together with the results of alkaline phosphatase
assay, Western blotting of β1-Na/K ATPase, and PR binding
assay, indicate that compounds 37, 40, and 46 bind directly to
the progesterone-binding pocket of PR and inhibit expression
of PR-regulated genes; thus, they function as PR antagonists.
Some of the analogs shown in Tables 1 and 2 were identified
as RORs inverse agonists or LXRs antagonists. And PR, GR,
and androgen receptor (AR) all belong to the class I steroid
receptor family. Thus, selectivity of PR antagonists toward AR
and GR is an important concern, and selectivity of PR
antagonists over AR and GR has been investigated8 (3: PR
IC50: 0.3 nM, AR IC50: 5 nM, GR IC50: 0.8 nM; 4: PR IC50: 16
nM, AR IC50: 1300 nM, GR IC50: 1800 nM). Here, the
activities of the representative PR antagonists toward other
nuclear receptors, including RORα/β/γ inverse agonistic
activities, and LXRα/β, GR and AR antagonistic activities,
were evaluated by means of reporter gene assays.20 Among
these compounds, 37 showed more than 100-fold selectivity
for PR over all the NRs evaluated (Table 4). Compounds 40
and 46 also showed more than 300-fold selectivity over these
Next, we planned to introduce a fluorine atom at the 8-
position of 37, because the 8-fluoro analog 34 showed
enhanced antagonistic activity. Indeed, the 4-methyl and 8-
fluoro-substituted analog 40 showed even more potent activity
than 37. Finally, based on the SARs shown in Table 2, we
investigated N-methyl analogs 45−46 (Scheme S1). The
C
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ACS Medicinal Chemistry Letters
Letter
Table 4. Selectivity of Representative Compounds for PR over other NRs
ab
,
ac
,
ac
,
ac
,
ac
,
ac
,
ac
,
ac
,
compounds
PR
RORα
RORβ
RORγ
LXRα
LXRβ
AR
GRα
d
d
d
37
40
46
0.15
0.046
0.027
NA
NA
NA
>20
>20
>20
>20
>20
>20
>20
>20
NA
>20
>20
1.8
0.3
>20
>20
>20
d
d
NA
NA
d
a
b
c
d
IC50 (μM). Alkaline phosphatase assay. Reporter gene assay. No activity at 20 μM. T0901317 (0.3 μM), T0901317 (0.1 μM),
dihydrotestosterone (0.3 nM), and dexamethasone (1 nM) were used as agonists for LXRα, LXRβ, AR, and GR, respectively.
NRs except for AR. For AR, 40 and 46 showed over 30- and
10-fold selectivity, respectively. Compounds 37 demonstrated
medium Caco-2 permeability, sufficient human liver micro-
somal stability, and acceptable LogP value (Table S2).
(KAKENHI Grant No. 17H03996 (Y.H.), No. 17H03997
(S.F.), and No. 25293027 (M.I.)).
ABBREVIATIONS
■
In summary, we have identified a series of PR antagonists
with a phenanthridin-6(5H)-one skeleton and investigated
their SARs by means of alkaline phosphatase assay using T47D
cells. Among them, 37 exhibited potent PR-antagonistic
activity with the IC50 value of around 0.1 μM and showed
more than 100-fold selectivity over other NRs examined.
Compounds 46 and 40 showed very potent PR-antagonistic
activity, with IC50 values of 0.01 μM order. These compounds
showed over 100-fold selectivity for PR over RORs, LXRs, and
GR and about more than 10-fold selectivity over AR. The PR-
antagonistic activity of these representative compounds was
validated by means of Western blot analysis of a PR-regulated
protein (β1-Na/K-ATPase) and PR-binding assay. Com-
pounds 37, 40, and 46 are PR antagonists belonging to a
novel chemical class distinct from other PR antagonists, and
their activity is similar to or stronger than those of reported PR
antagonists, including cyanoaryl compounds. The phenanthri-
dinone skeleton might be a more robust pharmacophore motif
of PR antagonists to avoid activity switching. Thus, these
compounds should open up new possibilities for exploitation
of the pharmaceutical potential of PR antagonists.
PR, progesterone receptor; GR, glucocorticoid receptor; AR,
androgen receptor; LXR, liver X receptor; ROR, retinoic acid
receptor-related orphan receptor; Ts, p-toluenesulfonyl; EDC,
N-ethyl-N′-(3-(dimethylamino)propyl)carbodiimide; DMAP,
4-(N,N-dimethylamino)pyridine; DMF, dimethylformamide;
SEM, 2-(trimethylsilyl)ethoxymethyl; Cy, cyclohexyl; DMA,
dimethylacetamide; TBAF, tetrabutylammonium fluoride;
THF, tetrahydrofuran.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.8b00058.
Structures of phenanthridinones and their lead com-
pound, synthesis of 45 and 46, tables of PR antagonistic
activity and physicochemical and pharmaceutical
potential of PR antagonists, experimental section, and
purity of the synthesized compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: m-ishikawa@iam.u-tokyo.ac.jp.
■
ORCID
Makoto Makishima: 0000-0002-4630-905X
Hiroyuki Kagechika: 0000-0002-6747-1013
Minoru Ishikawa: 0000-0002-3937-2261
Notes
The authors declare no competing financial interest.
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Marella, M. a.; et al. Design, Synthesis, and SAR of New Pyrrole-
Oxindole Progesterone Receptor Modulators Leading to 5-(7-Fluoro-
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ACKNOWLEDGMENTS
■
The work described in this Letter was partially supported by
Grants-in Aid for Scientific Research from The Ministry of
Education, Culture, Sports, Science and Technology, Japan,
and the Japan Society for the Promotion of Science
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