Novel selective anti-androgens with a diphenylpentane skeleton

Article abstract of DOI:10.1016/j.bmcl.2010.09.011

We have proposed a multi-template approach for drug development, focusing on similar fold structures of proteins, and have effectively generated lead compounds for several drug targets. Modification of these polypharmacological lead compounds is then needed to generate target-selective compounds. In the work presented here, we aimed at separation of the anti-androgen activity and vitamin D activity of previously identified diphenylpentane lead compounds. Based on the determined X-ray crystal structures of androgen receptor and vitamin D receptor, bulky substituents were introduced at the t-butyl group in the lead compounds 2 and 3. As a result of this structural development, we obtained 16c, which exhibits more potent anti-androgen activity (IC ₅₀: 0.13 μM) than clinically used anti-androgen bicalutamide (IC₅₀: 0.67 μM) with 30-fold selectivity over vitamin D activity. This result indicates that lead compounds obtained via the multi-template approach can indeed be structurally modified to generate target-selective compounds.

Full text of DOI:10.1016/j.bmcl.2010.09.011

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6661–6666
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel selective anti-androgens with a diphenylpentane skeleton
⇑
Keisuke Maruyama, Tomomi Noguchi-Yachide, Kazuyuki Sugita, Yuichi Hashimoto, Minoru Ishikawa
Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We have proposed a multi-template approach for drug development, focusing on similar fold structures
of proteins, and have effectively generated lead compounds for several drug targets. Modification of these
polypharmacological lead compounds is then needed to generate target-selective compounds. In the
work presented here, we aimed at separation of the anti-androgen activity and vitamin D activity of pre-
viously identified diphenylpentane lead compounds. Based on the determined X-ray crystal structures of
androgen receptor and vitamin D receptor, bulky substituents were introduced at the t-butyl group in the
lead compounds 2 and 3. As a result of this structural development, we obtained 16c, which exhibits
Received 9 August 2010
Revised 30 August 2010
Accepted 2 September 2010
Available online 9 September 2010
Keywords:
Anti-androgen
Steroid surrogate
Diphenylpentane
more potent anti-androgen activity (IC50: 0.13
lM) than clinically used anti-androgen bicalutamide
(IC50: 0.67 M) with 30-fold selectivity over vitamin D activity. This result indicates that lead compounds
l
obtained via the multi-template approach can indeed be structurally modified to generate target-selec-
tive compounds.
Ó 2010 Elsevier Ltd. All rights reserved.
Nuclear receptors (NRs) are ligand-dependent transcription fac-
tors which regulate the expression of responsive genes and thereby
affect diverse processes, including cell growth, development, dif-
ferentiation, and metabolism.1 Based on the elucidated human
genome sequence, 48 NRs are thought to exist in humans.1 Exam-
ples of NRs and their ligands include androgen receptors (ARs)/tes-
tosterone, vitamin D receptors (VDRs)/1,25a-dihydroxyvitamin D3,
farnesoid receptors (FXRs)/bile acid, and estrogen receptors (ERs)/
estradiol.
androgens are more favorable for clinical applications because of
the lack of cross-reactivity with other NRs and improved oral bio-
availability. Of this structural class of anti-androgens, clinically
used bicalutamide (1) is the most potent and best tolerated
(Fig. 1a).3,4 Bicalutamide (1) has little effect on serum testosterone
and luteinizing hormone levels, at least in an animal model.2
Non-secosteroidal VDR agonists such as LG190178 (2)5,6 with
greater stability, easier synthesis and reduced calcium-raising ef-
fects have also been developed (Fig. 1a). Some of them do not bind
to serum vitamin D binding protein,5 a property that has been cor-
related with lower calcemic potential in vivo.7 However, these
non-steroidal NR ligands were discovered individually, and no
common template for steroid surrogates is known.
The multi-template approach is based on the fact that the num-
ber of three-dimensional spatial structures (fold structures) of hu-
man proteins is much smaller (more than 50 times smaller) than
the number of human proteins (50,000–70,000).8–12 Therefore,
ignoring physical/chemical interactions, a template/scaffold struc-
ture which is spatially complementary to onefold structure might
serve as a multi-template for structural development of ligands
that would interact specifically with more than 50 different human
proteins. In other words, the structures of ligands that bind to one
member of the fold structures may be used for the development of
novel lead compounds for other members of the same fold struc-
ture group. Obtained lead compounds probably possess polyphar-
macologic character when the target proteins share fold structures
with other proteins. Therefore, in order to extend the multi-tem-
plate approach, structural modification of polypharmacological
lead compounds, aimed at optimizing target-selectivity, is
required.
Steroid hormones act via NRs. For example, AR is a receptor of
androgens, typically testosterone and/or its active form, 5a-dihy-
drotestosterone, which are endogenous ligands essential for the
development and maintenance of the male reproductive system
and secondary male sex characteristics. Androgens play diverse
physiological and pathophysiological roles in both males and fe-
males. Among the pathophysiological effects elicited by androgens,
a role as endogenous tumor promoters, especially for prostate tu-
mor, is well known. This action is considered to be mediated by
androgen-binding to AR. Thus, AR antagonists are used for treat-
ment of androgen-dependent tumors, especially prostate tumors.
Steroidal anti-androgens, however, also have progestational prop-
erties with central actions on the pituitary gland. Steroidal anti-
androgens significantly lower the levels of both serum testosterone
and luteinizing hormone, which might reduce libido and sexual
potency.2
To reduce side effects of steroidal NR ligands, non-steroidal NR
ligands have been developed. In the case of AR, non-steroidal anti-
⇑
Corresponding author.
E-mail address: m-ishikawa@iam.u-tokyo.ac.jp (M. Ishikawa).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.09.011

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K. Maruyama et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6661–6666
Figure 1. (a) Chemical structures of representative non-steroidal NR ligands. (b) Diphenylpentane-based ligands of NR and steriod-related enzyme generated by means of the
multi-template approach.
One of the multi-templates that we have adopted is a surrogate
for the steroid skeleton.12–15,11,16 A skeleton that corresponds
structurally to the steroid skeleton would be a potential multi-
template for structural development of ligands for a number of
proteins. For example, we have found that the non-steroidal VDR
Secondly, we utilized X-ray crystal structure data. X-Ray crystal
structures of the complex of VDR with (S,R)-2,18 and the complex of
AR with a bicalutamide analog 419 (Fig. 2a) have been reported. We
compared their X-ray crystal structures and confirmed that AR and
VDR possess very similar fold structures (Fig. 2b). These similar
fold structures are considered to be the basis of not only effective
lead generation based on the multi-template approach, but also the
dual function of 2. Next, we carefully analyzed the active confor-
mation of both ligands. In general, a compound which binds with
the ligand-binding pocket (LBD) but interferes with the folding of
helix 12 (one of the LBD substructures) acts as an antagonist of
the corresponding NR.20 As shown in Figure 2c, the fluorophenyl
group in 4 is located near helix 12 of AR, and is important for AR
antagonism. On the other hand, VDR antagonism is thought not
to be straightforward, because only a few series of secosteroidal
VDR antagonists and no non-steroidal VDR antagonists21–27 have
been created, even though thousands of VDR ligands are known.
Thus, we hypothesized that introduction of substituents into the
t-butyl group in 2 would decrease VDR-agonistic activity and
would not lead to VDR-antagonistic activity. We also speculated
that the designed ketone series would retain selective AR-antago-
nistic activity even if the carbonyl group was metabolized to a hy-
droxyl group. From these two ideas, we designed novel compounds
containing a bulky substituent at the t-butyl group of 2 and 3 with
the aim of both increasing metabolic stability and reducing VDR
affinity. We decided to synthesize (S)-isomers of the diol, because
(S)-isomers of 2 exhibited stronger anti-androgen activity than the
corresponding (R)-isomers (Table 1). On the other hand, there are
no great distinction between the activity of (S,R)-2 and the activity
of (S,S)-2 (Table 1). Therefore, we designed alcohol series as diaste-
reomixtures of the hydroxyl group.
agonist
2
also possesses AR-antagonistic activity,12,13 while
LG190119 possesses VDR-selective agonistic activity.13 We have
also employed the diphenylpentane skeleton as a multi-template
for creation of novel ligands of nuclear receptors and steroid-re-
lated enzymes, such as VDR/AR dual ligands (VDR agonists/AR
antagonists),12,13 FXR agonists,14 and inhibitors of steroid metabo-
lism-related enzymes, including 5a
-reductase15 (Fig. 1b). These re-
sults indicate that the diphenylpentane skeleton can act as steroid
surrogate. However, AR-selective ligands with the diphenylpen-
tane skeleton have not been generated. It has been suggested that
polypharmacological lead compounds generated by means of the
multi-template approach might be difficult to optimize toward tar-
get-selective drug candidates, simply because the multiple target
proteins share similar fold structures. Therefore, we focused here
on separation of vitamin D and anti-androgen activities, and on
the creation of selective anti-androgens. Here, we describe the de-
sign, synthesis and structure–activity relationship study of diphe-
nylpentane derivatives, focusing on generation of selective anti-
androgens.
As a clue for the molecular design, we first reconsidered our
previous findings regarding metabolism.13,17 DPP-0013 (3) has
been designated as a selective AR ligand, based on AR and VDR
binding assay data (Table 1). However, 3 showed both anti-andro-
gen activity and vitamin D activity in cell-based assay, that is, it
inhibited testosterone-induced cell growth of the androgen-depen-
dent cell line SC-3 (anti-androgen activity) and HL-60 cell differen-
tiation-inducing activity (vitamin D activity). Further, a reductive
metabolite of 3, LG190178 (2), showed both anti-androgen activity
and vitamin D activity. Thus, 3 is not a selective anti-androgen in a
cellular system, apparently as a result of metabolism. Therefore,
we designed compounds possessing a bulky group introduced at
the t-butyl group of 3 in order to block metabolism of the carbonyl
group.
Right-hand fragments bearing a bulky moiety were synthesized
as shown in Scheme 1. Nitrile anion was reacted with bromides
5a–d,f to generate 6a–d,f. Methyl lithium was reacted with nitriles
6a–d,f to afford ketones 7a–d,f. Alpha-bromination of ketones 7a–
d,f gave 8a–d,f. Next, benzylpyrroline 9g was reacted with CbzCl in
the presence of KHCO3 to give 9h. Epoxidation28 of 9g–h afforded
racemic epoxides 10g–h.

K. Maruyama et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6661–6666
6663
Table 1
Anti-androgen activity and vitamin D activity of DPP-0013 (3) and its metabolite LG190178 (2)
Compound
AR
VDR
VDR/ARc
Binding (Ki nM)
Antiandrogen activitya IC50 (nM)
Binding (Ki nM)
Vitamin D activityb EC50 (nM)
(R)-3
(S)-3
1100
1800
ntd
1000
1100
1000
1100
15
32
ntd
14
68
3.0
13
ntd
ntd
nde
320
740
12
ntd
ntd
90
Racemic-3
(R,R)-2f
(R,S)-2f
(S,R)-2f
(S,S)-2f
26
1.9
1.8
2.9
1.8
120
8.6
23
11
a
b
c
d
e
f
Anti-androgen activity was measured in terms of testosterone-induced SC-3 proliferation-inhibitory activity.
Vitamin D activity was measured in terms of HL-60 differentiation-inducing activity.
Vitamin D activity/anti-androgen activity.
nt: not tested.
nd: not detected.
The first S or R indicates the stereochemistry of the diol, while the second indicates that of the other hydroxyl group.
Figure 2. (a) Chemical structures of bicalutamide analog 4 and (S,R)-2. (b) Superposition of X-ray crystal structures of the complex of AR with 4 (magenta, PDB ID: 2AXA) and
the complex of VDR with (S,R)-2 (green, PDB ID: 2ZFX). (c) Overlay of active conformation of (S,R)-2 (green stick) and 4 (magenta stick), and helix 12 of AR (magenta ribbon).
The images were drawn with PYMOL.
The left-hand common intermediate 13 was synthesized as
shown in Scheme 2. Bisphenol 1112 was reacted with (S)-glycidol
in the presence of CsF29 to give optically pure diol 12. This diol
12 was protected with acetonide to obtain the left-hand frag-
ment 13. The right-hand fragments 8a–f were coupled with opti-
cally pure phenol 13 to give 14a–f (Scheme 2). 1-Adamantyl
bromomethyl ketone (8e) is commercially available. Deprotec-
tion of the acetonide group afforded a series of desired ketones
(S)-15a–f. Reduction of the carbonyl group of 15a–f gave another
series of desired alcohols 16a–f. These alcohols were thought to
be diastereomixtures from the reaction mechanism. However,
they did not be observed as diastereomixtures by means of 1H
NMR.
Vitamin D activity was measured as human promyelocytic leu-
kemia cell line (HL-60) differentiation-inducing activity, as has
commonly been done.12,13,23,31–33 Briefly, HL-60 cells can be in-
duced to differentiate into monocytic cells by 1a,25-dihydroxyvi-
tamin D3. Differentiation of HL-60 cells was quantified in terms
of morphology using nitroblue tetrazolium (NBT) reduction assay.
HL-60 cell differentiation-inducing activity is believed to correlate
well with the binding/activation of VDR by its ligands. Anti-andro-
gen activity was evaluated in terms of inhibitory activity on testos-
terone-induced cell growth of the androgen-dependent mouse
mammary carcinoma cell line SC-3.12,34–37 SC-3 proliferation was
measured by WST-1 assay. Under our assay conditions, the clini-
cally used AR antagonist 1 exhibited an IC50 value of 0.67 lM for
Cyclic compounds 16g–h were synthesized as shown in
Scheme 3. Epoxides 10g–h were coupled with phenol 13,30 fol-
lowed by deprotection of the acetonide group to provide the de-
sired 16g–h.
inhibition of proliferation.
First, ketones 15a–d, containing alkyl phenyl groups introduced
at the t-butyl group of 2, were evaluated (Table 2). Although all
compounds tested showed decreased anti-androgen activity, the

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K. Maruyama et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6661–6666
Scheme 3. Reagents and conditions: (a) Cs2CO3, 18-crown-6, EtOH, reflux, 22–29%;
(b) TsOH, MeOH, THF, rt, 78–80%.
Scheme 1. Reagents and conditions: (a) LDA, isobutyronitrile, THF, 0 °C to rt, 67–
97%; (b) MeLi, THF, 0 °C to rt, 35–94%; (c) Br2, 1,4-dioxane, 0 °C to rt, quant.; (d)
CbzCl, KHCO3, CHCl3, rt, 48%; (e) mCPBA, H2SO4, acetone, H2O, rt, 12–40%.
was 16c > 16b > 16a > 16d. Among these compounds, 16c, possess-
level of anti-androgen activity varied depending on the linker
ing a propyl linker, showed the strongest anti-androgen activity
length:
15b > 15c > 15a > 15d. Among them, 15b showed the strongest
anti-androgen activity with an IC50 value of 1.1 M. In the case
of vitamin D activity, 15a–d all showed very weak activity (EC50
>30 M), indicating that introduction of alkyl phenyl groups leads
to reduced affinity for VDR, as expected. Concerning the selectivity
of ketones 15, 15b–c showed improved selectivity for anti-andro-
gen activity over vitamin D activity. Among them, 15b is the most
selective anti-androgen (21-fold selectivity). On the other hand,
another bulky compound possessing the adamantyl group, 15e,
completely lacked both anti-androgen activity and vitamin D activ-
ity at the concentration tested.
the
order
of
anti-androgen
potency
was
with the IC50 value of 0.13
lM, being more potent than bicaluta-
mide (IC50: 0.67 M). The butyl linker compound 16d lacked
l
l
anti-androgen activity. This result indicates that the butyl phenyl
group in 16d might be too bulky to be accommodated in the pocket
around helix 12 in the AR. Concerning vitamin D activity, 16a–e
showed decreased vitamin D activity compared to 2, as expected.
The order of potency is the same as that of the anti-androgen activ-
ity, that is, 16c > 16b > 16a > 16d. However, this structural devel-
opment changed the selectivity, also as expected. Specifically,
16a–c showed better selectivity than 2, and the propyl linker com-
pound 16c showed the best selectivity, that is, 28-fold selectivity
for anti-androgen activity over vitamin D activity. However, ada-
mantyl analog 16e completely lacked anti-androgen activity, sug-
gesting that bulky cyclic alkyl ring is unfavorable for the
interaction with AR.
:
l
In the case of alcohols 16a–e, all compounds showed decreased
anti-androgen activity. However, the anti-androgen activity varied
depending on the linker length: the order of anti-androgen potency
Scheme 2. Reagents and conditions: (a) (S)-glycidol, CsF, DMF, 85 °C, 47%; (b) acetone dimethyl acetal, CSA, MeCN, rt, 87%; (c) K2CO3, DMF, rt or 90 °C, 21–71%; (d) TsOH,
MeOH, THF, rt, 30–69%; (e) NaBH4, MeOH, rt, 37–83%.

K. Maruyama et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6661–6666
6665
Table 2
Anti-androgen activity and vitamin D activity of synthesized compounds
NR
OH
S
S
S
R
R
HO
O
O
HO
O
O
HO
O
O
OH
O
OH
OH
OH
(S)-15a-f
16a-f
Anti-androgen activitya
16g,h
Vitamin D activityb
Compound
R
VDR/ARc
IC50 M)
(
l
EC50
(lM)
15a
15b
15c
15d
Me
Me
Me
Me
>10d
21
<2.1
21
1.1
9.8
23
>30
>30
Me
Me
Me
Me
>3.1
—
>30
15e
15f
16a
>30
>30
>30
>30
11
—
Me
Me
—
Me
Me
Me
Me
1.7
6.5
16b
16c
16d
0.88
0.13
7.1
8.1
28
Me
Me
Me
Me
3.6
>10d
>30
—
16e
16f
16g
>10d
>10d
>10d
22
>30
>30
<2.2
—
Me
Me
—
O
O
16h
>30
>30
—
a
b
c
Anti-androgen activity was measured in terms of testosterone-induced SC-3 proliferation-inhibitory activity.
Vitamin D activity was measured in terms of HL-60 differentiation-inducing activity.
Vitamin D activity/anti-androgen activity.
d
Cytotoxicity at 30 lM.
Alcohols 16a–e showed stronger anti-androgen activity and
phenyl group of 16c, because the terminal phenyl group is ex-
pected to be important for the interaction with helix 12 in AR.
Thus, ketone 15f and alcohols 16f–h were designed and synthe-
sized. All these cyclic analogs completely lacked vitamin D activity.
However, they also lacked anti-androgen activity. This result sug-
gests that the flexibility of the propyl linker might be important
for the interaction with AR, or the space occupied by the terminal
phenyl group might be different from that occupied by the fluoro-
phenyl group in bicalutamide.
vitamin D activity than the corresponding ketones 15a–e. This re-
sult indicates that the hydroxyl group in the right part is important
for both anti-androgen activity and vitamin D activity. On the other
hand, the vitamin D activity of ketone 15c was more than eight
times weaker than that of the corresponding alcohol 16c, whereas
3 and its metabolite 2 possess similar vitamin D activity. Thus,
introduction of the alkyl phenyl group into 3 might lead to in-
creased metabolic stability.
The structure–activity relationships mentioned above, that is,
the finding that the propyl linker 16c is the best for anti-androgen
activity, prompted us to restrict the space occupied by the terminal
Overall, the propyl linker compound 16c exhibited the best pro-
file, showing six times stronger anti-androgen activity than bicalu-
tamide, and 28-fold selectivity for anti-androgen activity over

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K. Maruyama et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6661–6666
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vitamin D activity. The androgen activity and antivitamin D activ-
ity of 16c were further evaluated to confirm these results. Com-
pound 16c did not show growth-promoting activity on the
androgen-dependent cell line SC-3 at 10
does not possess androgen activity. In addition, it did not inhibit
differentiation of 1 ,25-dihydroxyvitamin D3-induced HL-60 cells
lM, suggesting that it
a
at 30 lM, suggesting that it is also not a VDR antagonist. Thus,
16c38 is considered to be a selective anti-androgen.
In summary, we aimed to separate the anti-androgen activity
and vitamin D activity of the lead compounds 2 and 3 identified
by means of the multi-template approach. Bulky substituents were
introduced at the t-butyl group in 2 and 3 with the aim of (1)
increasing the metabolic stability of 3 and (2) decreasing the affin-
ity for VDR. This structural development afforded ketone 15c with
increased metabolic stability. In addition, alcohols 16a–c showed
improved selectivity for anti-androgen activity over vitamin D
activity. Among them, 16c possessed stronger anti-androgen activ-
ity (IC50: 0.13 lM) than bicalutamide (IC50: 0.67 lM), with about
30-fold selectivity for anti-androgen activity over vitamin D
activity.
Our results demonstrate that target-selective compounds can
be derived from multi-target lead compounds generated via the
multi-template approach. We have also obtained LXR
a-selective
antagonists by structural development of a lead compound pos-
sessing LXRs dual antagonistic activity and
a-glucosidase-inhibi-
tory activity.39 Thus, we believe that the multi-template
approach is a useful method for not only generating lead com-
pounds, but also creating target-selective drug candidates.
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Acknowledgments
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The work described in this Letter was partially supported by
Grants-in-Aid for Scientific Research from The Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan, and the Japan
Society for the Promotion of Science.
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