Phenylbenzenesulfonates and -sulfonamides as 17β-hydroxysteroid dehydrogenase type 2 inhibitors: Synthesis and SAR-analysis

Article abstract of DOI:10.1016/j.bmcl.2017.05.005

17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) converts the potent estrogen estradiol into the weakly active keto form estrone. Because of its expression in bone, inhibition of 17β-HSD2 provides an attractive strategy for the treatment of osteoporosis

Full text of DOI:10.1016/j.bmcl.2017.05.005

Accepted Manuscript
Phenyl benzenesulfonates and -sulfonamides as 17β-hydroxysteroid dehydro-
genase type 2 inhibitors: synthesis and SAR-analysis
Anna Vuorinen, Roger T. Engeli, Susanne Leugger, Christoph R. Kreutz,
Daniela Schuster, Alex Odermatt, Barbara Matuszczak
PII:
S0960-894X(17)30486-9
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.05.005
BMCL 24950
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
31 March 2017
1 May 2017
3 May 2017
Please cite this article as: Vuorinen, A., Engeli, R.T., Leugger, S., Kreutz, C.R., Schuster, D., Odermatt, A.,
Matuszczak, B., Phenyl benzenesulfonates and -sulfonamides as 17β-hydroxysteroid dehydrogenase type 2
inhibitors: synthesis and SAR-analysis, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/
10.1016/j.bmcl.2017.05.005
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Phenyl benzenesulfonates and -sulfonamides as 17β-hydroxysteroid
dehydrogenase type 2 inhibitors: synthesis and SAR-analysis
Anna Vuorinena,b+, Roger T. Engelib+, Susanne Leuggerb, Christoph R. Kreutzc, Daniela
Schustera Alex Odermattb*, Barbara Matuszczaka*
+ These authors contributed equally to the work
Affiliations
aInstitute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences
Innsbruck (CMBI), University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
bDivision of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences,
University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland
cInstitute of Organic Chemistry and Center for Molecular Biosciences (CMBI), University of
Innsbruck, Innrain 80-82, 6020 Innsbruck
*Corresponding authors
Synthesis: Barbara Matuszczak, Institute of Pharmacy / Pharmaceutical Chemistry, University
of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
Tel. +43-512-507-58262
E-mail: Barbara.Matuszczak@uibk.ac.at
Biology: Alex Odermatt, Division of Molecular and Systems Toxicology, University of Basel,
Klingelbergstrasse 50, 4056 Basel, Switzerland
Tel. +41 61 267 15 30
E-mail: Alex.Odermatt@unibas.ch
1

Abstract
17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) converts the potent estrogen estradiol
into the weakly active keto form estrone. Because of its expression in bone, inhibition of 17β-
HSD2 provides an attractive strategy for the treatment of osteoporosis, a condition that is
often caused by a decrease of the active sex steroids. Currently, there are no drugs on the
market targeting 17β-HSD2, but in multiple studies, synthesis and biological evaluation of
promising 17β-HSD2 inhibitors have been reported. Our previous work led to the
identification of phenylbenzene-sulfonamides and -sulfonates as new 17β-HSD2 inhibitors by
ligand-based pharmacophore modeling and virtual screening. In this study, new molecules
representing this scaffold were synthesized and tested in vitro for their 17β-HSD2 activity to
derive more profound structure-activity-relationship rules.
Keywords: 17β-HSD2, Inhibitor, Osteoporosis, Virtual screening, Estrogen
2

The microsomal enzyme 17β-hydroxysteroid dehydrogenase 2 (17β-HSD2) regulates the
intracellular concentrations of the sex steroid hormones estradiol and testosterone. It is
responsible for the oxidative inactivation of estradiol into estrone and inactivation of
testosterone into ∆4-androstene-3,17-dione (androstenedione), respectively (Figure 1)[1, 2].
Additionally, 17β-HSD2 is involved in the inactivation of 5α-dihydrotestosterone into 5α-
androstanedione and conversion of androstenediol into dehydroepiandrosterone[2, 3].
OH
OH
O
O
17 -HSD2
17 -HSD1
H
H
H
H
H
H
H
HO
HO
Estradiol
Estrone
17 -HSD2
17 -HSD3
H
H
H
H
H
O
O
4-Androstene-3,17-dione
Testosterone
Figure 1: Reactions catalyzed by 17β-HSD2.
17β-HSD2 is expressed only in a few tissues: placenta,[4] endometrium,[4, 5] prostate,[6]
small intestine,[7] and bone[1]. Inhibition of 17β-HSD2 is an attractive way to increase local
estradiol concentrations only in the target tissues, without affecting estrogen receptor
signaling in tissues where it is not expressed. This is thought to be especially beneficial in the
treatment of osteoporosis, a condition where reduced bone density increases the fracture risk.
The onset of osteoporosis is often connected with the age-related decrease of estradiol in
women and decrease of testosterone in men[8]. Currently, osteoporosis is treated by estrogen
replacement therapy, bisphosphonates, monoclonal antibodies against receptor activator of
nuclear factor kappa-B ligand (RANKL), and selective estrogen receptor modulators
(SERMs)[9-11]. All of these treatments have their disadvantages: Hormone replacement
therapies and SERMs have been associated with cardiovascular complications and
bisphosphonate therapy suffers from low oral bioavailability[12]. Because of the challenges in
the current treatment options, there is a considerable demand for novel therapies such as 17β-
HSD2 inhibitors. In fact, there is evidence from a study in ovariectomized cynomolgus
3

monkeys that 17β-HSD2 inhibition lowered bone resorption, although the effects were
moderate and only observed at the highest dose tested (25 mg/kg/day)[13]. Additionally,
treatment with 17β-HSD2 inhibitor reversed the ovariectomy-dependent decrease in bone
strength at 5 mg/kg and 25 mg/kg. Nevertheless, the selectivity of the inhibitor used as well as
inhibitor concentration reached in the bone needs to be further assessed. To the best of our
knowledge, there are currently no 17β-HSD2 inhibitors in clinical trials or already on the
market. However, there are multiple studies on the discovery and development of 17β-HSD2
inhibitors[14-17].
Our recently published study described 17β-HSD2 inhibitors that were discovered by ligand-
based pharmacophore modeling and virtual screening[18]. In total, three pharmacophore
models representing the common chemical features of 17β-HSD2 inhibitors were developed
and used for virtual screening of the commercial SPECS database (www.specs.net) containing
about 200000 small synthetic chemicals. From the hit molecules, 27 were purchased and
biologically evaluated for 17β-HSD2 inhibition. Seven of these compounds inhibited 17β-
HSD2 by more than 70% at a concentration of 20 µM. Four of these compounds represented
the phenyl benzene-sulfonate and –sulfonamide scaffold and were found by the most
successful model (Figure 2). To further explore the phenylbenzene-sulfonamide- and -
sulfonate scaffold, 16 derivatives and additional 14 virtual hits representing this scaffold were
purchased. From these compounds, six inhibited 17β-HSD2. In total, ten 17β-HSD2 inhibitors
representing phenylbenzene sulfonamides and –sulfonates were discovered. From these
compounds, the most active ones are depicted in Figure 3. The full series has been published
previously[18].
4

Figure 2: (A) Pharmacophore model correctly predicting phenylbenzene-sulfonamides and
-sulfonates as 17β-HSD2 inhibitors. This model consists of six pharmacophore features: two
hydrophobic areas (yellow), two hydrogen bond acceptors (red), of which one was optional
(scattered representation), one hydrogen bond donor (green), an aromatic ring (blue rings),
and 54 exclusion volumes (grey) mimicking spatial restrictions by the binding site. (B)
Compound 1 fitted into the model.
Figure 3: The most active phenylbenzene-sulfonamides and –sulfonates from Vuorinen et al.
[18] with their IC50-values.
5

This follow-up study aims at a more comprehensive structure-activity relationship analysis
(SAR) analysis of this scaffold by synthesis of derivatives of the most active compounds. An
additional aim was to replace the phenolic hydroxy group that is an attractive metabolic site
and toxicologically not favorable[19, 20].
In total, 20 derivatives of the most active compounds shown in Figure 3 were synthesized
(Table 1) from the corresponding 1,2-phenylendiamine or 2-hydroxyaniline and 4-tert.-
butylbenzenesulfonylchloride (see Figure 4). These compounds were tested for 17β-HSD2
inhibition in a cell-free radioligand binding assay using the same test system as reported in
Vuorinen et al.[18]. Ten of them inhibited 17β-HSD2 by more than 70% at a concentration of
20 µM, and IC50 values were determined subsequently. These compounds inhibited 17β-
HSD2 with low micromolar IC50 values, with the most active compound 17 exhibiting an IC50
of 0.80 0.22 µM.
Figure 4. Schematic synthesis of compounds 5-24.
6

Table 1: Structures and activities of the newly synthesized compounds.
Compound X
Y
R
H
H
H
H
R1
H
R2
H
R3
H
H
H
H
Activity1
46 5%
37 1%
33 4%
11 4%
4.65 0.35 µM
58 7%
44 2%
49 3%
36 3%
43 1%
86 3%
NH2
NH
O
5
6
7
8
NH2
NH2
NH2
CH3
H
H
O
H
NH
Cl
Cl
NH2
NH2
NH2
NH2
NH2
NH2
OH
NH
O
H
H
H
H
Bn
H
H
CH3
Cl
CH3
H
H
9
H
10
11
12
13
14
15
O
CH3
H
H
CH3
H
O
CH3
H
O
H
O
Ph
H
H
H
NH
H
H
5
3%
1.23 0.35 µM
13 3%
OH
OH
OH
OH
OH
OH
NH
NH
NH
NH
NH
NH
H
H
CH3
Cl
H
H
H
H
H
16
17
18
19
20
21
4.09 0.49 µM
H
H
6
4%
0.80 0.22 µM
18 7%
CH3
H
H
CH3
H
5.19 0.92 µM
22 1%
CH3
H
4.40 0.79 µM
H
Ph
2
2%
1.25 0.09 µM
3%
2.90 0.69 µM
H
H
Bn
7
7

NH2
NH
H
H
Cl
H
28 6%
22
5.58 1.09 µM
35 4%
NH2
NH2
NH
NH
H
H
Cl
F
H
H
H
H
23
24
36 2%
4 (positive control)
10 3%
1.0 0.2 µM
1Given as remaining enzyme activity at a compound concentration of 20 µM (%) or as IC50
As already observed in the previous publication, the phenolic hydroxyl group is advantageous
for the activity. However, this functionality is an attractive site for metabolic modification
[19, 20] and therefore exchanging this feature with a bioisosteric group would be beneficial
for the in vivo half-life of the molecule and may address possible toxicological concerns.
Nevertheless, replacing the phenolic hydroxy group by an amino group results in the
formation of anilines, which also need to be evaluated for their toxic potential. The previous
work revealed a decreased activity upon methylation of the phenol group, suggesting that a
hydrogen bond donor is needed for the activity. Therefore, the hydroxyl group was replaced
by an amine. Unfortunately, the activity was decreased (compounds 5 and 7). Introducing an
electronegative substituent, such as chlorine or fluorine, to the sulfonamide compounds
increased the activity, as can be concluded from the comparison of activities of the
unhalogenated compound 5 and the corresponding halogenated derivatives 8, 22, 23 and 24.
In the sulfonamide series, methyl substituents in any position of the benzene ring reduced the
inhibitory ability (compounds 16 and 18-19) compared to compound 15, however the activity
was not completely lost. The position of the single methyl substituents did not make a
significant difference in the activity of the compounds, as represented by their IC50 values.
Interestingly, in the sulfonamide series, large aromatic ring substituents were tolerated by the
enzyme (20-21); however, this was not the case in the sulfonate series. Whether the linker
between the benzene rings was a sulfonamide or a sulfonate did not play a major role in the
activity: Compounds 23 and 10 were equipotent. However, the sulfonate-compound 1 was six
times more active than the respective sulfonamide compound 15. Still, compound 15 was
more active than the sulfonamide 5 and the sulfonate 7, respectively.
To demonstrate the observed SAR, a refined pharmacophore model representing the common
chemical functionalities of our lead compound 1 and the most active compound from the new
series (17) was generated. An addition of a phenyl and benzo anellation were tolerated (Figure
8

5A and 5B), however, without significant effect on the potency of the compounds (compare
compounds 7 vs. 13 and 15 vs. 21). Substitution with a phenyl in para position to the amino
group (position R2 in Table 1) was tolerated in the sulfonamide 20. However, in the sulfonate
14, a phenyl in the para position to the linker (R1 in Table 1) led to a loss of activity (Figure
5C). Therefore, the position of the phenyl substituent makes a difference in the activity.
However, this loss of activity in compound 14 could also be caused by the hydroxyl-amino
group exchange and by the different linker. It is speculated that the reason for the activity loss
of 14 may lie in the spatial properties of the binding site in this position. Still, without
structural data for 17β-HSD2, this is rather an assumption. A chlorine substituent at position
R2 in Table 1 is well tolerated, as compounds 15 and 17 are similarly active (Figure 5D), and
they both fit to the model well.
Figure 5: New SAR-pharmacophore model with selected compounds: (A) 19 (light blue) and
20 (orange), (B) 21 (gray), (C) 14 (red) and 20 (green), (D) 15 (blue) and 17 (yellow). The
pharmacophore features are color-coded: hydrogen bond acceptor –red, hydrogen bond donor
green, aromatic ring – blue, hydrophobic – yellow. In case a feature is optional, it is depicted
in a scattered style. Exclusion volumes were not generated.
9

The previous report also depicted a predictive SAR-model for this scaffold [18]. The new
compounds were fitted into this model as well. In fact, when the tolerance area of the
hydrogen bond donor (HBD) functionality of the model was slightly increased by 0.15 Å, the
following compounds could fit into the model: 15-17, 19-20, and 22 (Figure 6A). Our
previously published predictive SAR-model found most of the active compounds, but most
remarkably, it was able to exclude the weakly active ones. The newly synthesized and
biologically evaluated compounds were also fitted to our previously established
pharmacophore model, the one that initially identified the scaffold. If screened without the
exclusion volume spheres, three of the compounds: 15, 16, and 20 fitted into that model
(Figure 6B).
Figure 6: (A) 15 (purple), 16 (green), 17 (blue), 19 (red), 20 (yellow), and 22 (grey) with the
predictive SAR-model described previously [18]. (B) Compounds 16 (green), 17 (cyan), and
20 (yellow) fitted into the original pharmacophore model. The pharmacophore features are
color coded: hydrogen bond acceptor –red, hydrogen bond donor green, aromatic ring – blue,
hydrophobic – yellow. In case a feature is optional, it is depicted in a scattered style.
Exclusion volumes are not shown for clarity.
Additionally, the most active compounds were also tested against other HSDs (Table 2) that
are structurally and functionally close to 17β-HSD2. Unfortunately, four of the new 17β-
HSD2 inhibitors were also active on 17β-HSD1, the enzyme that is responsible for the
reductive activation of estrone into estradiol[21]. Two of the compounds (17 and 20) also
potently inhibited 11β-HSD2. This enzyme converts cortisol into cortisone in kidneys and is
considered as an antitarget because its inhibition causes cardiovascular complications such as
hypokalemia and hypertension[22]. Therefore, these compounds should be optimized for
better selectivity. Compounds 19, 21, 22 and 24 inhibited 11β-HSD1, which activates
10

cortisone to cortisol. Importantly, compound 15 could be considered as a relatively selective
17β-HSD2 inhibitor, indicating the feasibility to develop potent and selective compounds
from this class.
Table 2: Qualitative selectivity assessment of the active compounds represented as % of
control at the inhibitor concentration of 20 µM.
Compound 17β-HSD2 17β-HSD1
SI 11β-HSD1
2.1 74 4%
8.2 37 5%
2.9 46 2%
2.5 35 3%
1.1 43 2%
1.6 24 4%
6.5 62 5%
8.6 21 4%
2.1 28 7%
1.6 26 8%
SI 11β-HSD2
6.7 21 11%
7.4 83 9%
3.5 63 12%
5.8 7 4%
SI
11 4%
3%
13 3%
4%
23 3%a
41 6%
38 6%
15 6%
19 8%
35 9%
13 3%
46 7%
46 10%
56 11%
11 3%
(apigenin)[23]
1.9
16.6
4.8
1.2
2.1
2.8
1.5
3
8
5
15
16
6
17
18 7%
22 1%
2.4 37 10%
1.1 62 9%
18
19
2
7
2%
3%
31
3
3
3%
20
21
21 4%
22 6%
36 2%
10 3%
(4)
1.3 75 8%
0.7 97 4%
3.4
2.7
22
24
positive
controls
5
1%
7
2%
(glycyrrhetinic
acid)[24]
(glycyrrhetinic
acid)[24]
a % residual enzyme activity compared to non-inhibited control at 20 µM concentration. SI =
selectivity index (residual HSD activity / residual 17β-HSD2 activity)
In this study, 20 phenylbenzene-sulfonamides and -sulfonates were synthesized and tested for
17β-HSD2 inhibition. In total, nine of them inhibited the enzyme with low micromolar IC50
values. Even though none of these new compounds was more active than the parental
compound 1, they allowed for establishing more comprehensive SAR-rules for this scaffold.
In addition, these compounds provide also valuable information on the selectivity towards
related enzymes.
11

Acknowledgements
This study was supported by the Swiss National Science Foundation (31003A-159454 to
A.O.) and the Novartis Research Foundation (A.O.).
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13