5-Aryl indanones and derivatives as non-steroidal progesterone receptor modulators

Article abstract of DOI:10.1016/j.bmcl.2009.10.008

Novel 5-aryl indanones, inden-1-one oximes, and inden-1-ols were synthesized and evaluated as progesterone receptor (PR) modulators using the T47D cell alkaline phosphatase assay. Both PR agonists and antagonists were achieved with appropriate 3- and 5-su

Full text of DOI:10.1016/j.bmcl.2009.10.008

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6666–6669
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
5-Aryl indanones and derivatives as non-steroidal progesterone
receptor modulators
Jeffrey C. Kern a, , Eugene Terefenko , Eugene Trybulski , Thomas J. Berrodin , Jeffrey Cohen ,
a
a
b
b
*
b
b
b
b
a
Richard C. Winneker , Matthew R. Yudt , Zhiming Zhang , Yuan Zhu , Puwen Zhang
Chemical Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
a
b
Musculoskeletal Biology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel 5-aryl indanones, inden-1-one oximes, and inden-1-ols were synthesized and evaluated as proges-
terone receptor (PR) modulators using the T47D cell alkaline phosphatase assay. Both PR agonists and
antagonists were achieved with appropriate 3- and 5-substitution from indanones and inden-1-ols while
inden-1-one oximes provided only PR antagonists. Several compounds such as 10 and 11 demonstrated
potent in vitro PR agonist potency similar to that of steroidal progesterone (1). In addition, a number of
compounds (e.g., 12, 13, 17, 18) showed potent PR antagonist activity indicating the indanones and
derivatives are promising PR modulator templates.
Received 10 September 2009
Revised 1 October 2009
Accepted 1 October 2009
Available online 7 October 2009
Keywords:
Progesterone receptor
Nuclear receptor
Ó 2009 Elsevier Ltd. All rights reserved.
Progesterone receptor agonist
Progesterone receptor antagonist
5
5
5
-Aryl indanone
-Aryl indan-1-one oxime
-Aryl indan-1-ols
Progesterone (1) is an endogenous hormone which plays an
tanaproget (3). Recently, we reported the co-crystal structure of
1
2
important role in female reproduction. Synthetic progestins com-
monly used in oral contraceptives achieve efficacy via ovulation
inhibition and thickening of the cervical mucus.1 Progestin/estro-
gen combinations are also used in hormone replacement therapy.
A progesterone receptor (PR) antagonist may be potentially used
the PR ligand binding domain (LBD) and tanaproget. The crystal
structure revealed that tanaproget binds to the same site as steroi-
dal progesterone in the PR LBD with the 3-keto moiety from
progesterone aligning together with the cyano group from tanapr-
oget while the C- and D-rings of progesterone overlay with the
2
12,14
in female contraception and for the treatment of various gyneco-
benzoxazine-2-thione group.
To exploit the findings from the
logical and obstetric diseases including hormone dependent can-
cers and non-malignant chronic conditions such as fibroids and
co-crystal and design structurally novel PR ligands, the carbonyl
motif of the D-ring region of progesterone was combined with
the cyanopyrrole A-ring mimic of tanaproget to produce the more
simplified indanone scaffold, exemplified by compound 4. In this
Letter, we describe the synthesis and in vitro structure–activity
relationship of the indanones and their derivatives.
The preparation of 4, a representative indanone, is shown in
Scheme 1. Friedel–Crafts acylation of anisole with 3-methylbut-
2-enoyl chloride 5 and simultaneous demethylation to give phenol
6 was achieved under microwave conditions. Cyclization of phenol
6 using aluminum chloride was conducted in o-dichlorobenzene
with conventional heating to afford indanone 7, which was con-
verted to triflate 8 with triflic anhydride in pyridine. The target
compound 4 was obtained by palladium catalyzed coupling of 8
with in situ generated N-methyl-2-cyanopyrrole boronate. Further
elaboration of the carbonyl group of indanone is shown in Scheme
3
,4
endometriosis. However, steroidal progestins and antiprogestins
are often associated with undesirable side effects due to the direct
interactions with other steroid receptors such as the glucocorticoid
receptor (GR) and androgen receptor (AR), as well as potential ef-
fects of steroidal metabolites. The only clinically available PR
antagonist, mifepristone, demonstrates activity at other nuclear
receptors with nearly equipotent activity at the glucocorticoid
1
5
5
receptor (GR), which limits its chronic use. In the search for selec-
tive PR modulators, a number of non-steroidal PR scaffolds have
6
–10
been investigated.
We reported several chemical series that
11–13
yielded potent PR modulators.
folds is the 5 -cyanopyrrol-2-yl substituted benzoxazinone (i.e., 2)
One of the most successful scaf-
0
which led to the discovery of the clinically efficacious PR agonist,
2. Conversion of the indanone 4 into inden-1-one oxime 13 was
*
Corresponding author. Tel.: +1 484 865 2901; fax: +1 484 865 9399.
E-mail address: Kernj@wyeth.com (J.C. Kern).
readily achieved with hydroxyl amine. Reduction with sodium
0
960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.10.008

J. C. Kern et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6666–6669
6667
O
dependant upon the 3-position substitution of the indanones.
The unsubstituted indanone 14 is a PR antagonist with an IC50 of
34 nM, and the 3,3-dimethyl substituted indanone 4 is a potent
PR agonist (EC50 = 10 nM). This result indicated that combining
the tanaproget scaffold with progesterone to form the non-steroi-
dal indanone template is a valid approach for novel PR ligands,
however the potency of resultant compound 4 was reduced com-
pared to that of either progesterone (1) or tanaproget (3). Encour-
aged by the findings of indanones 4 and 14, we decided to further
expand this template and explore the SAR of related analogs. The
oxime compounds 13, 15, and 16 were prepared and evaluated.
In contrast to the indanones, the oxime derivatives remained as
PR antagonists regardless of their 3-position substitution
N
H
N
O
H
H
N
O
H
O
1
, EC50 = 0.9 nM
2, EC50 = 1.1 nM
N
N
N
O
N
N
H
S
O
(Table 1). There is, however, an increase in potency in the oxime
derivatives with the installation of 3-methyl groups. The 3,3-di-
methyl analog 13 (IC50 = 14 nM) is fourfold more potent than the
mono-methyl analog 16 and 10-fold more potent than the unsub-
stituted oxime 15. Examination of the functional activity of inden-
1-ols (9, 17, 18) indicated that they follow the same SAR trend as
that of the indanones. Both the unsubstituted and 3-mono-methyl
substituted inden-1-ols (17, 18) are potent PR antagonists with IC50
values of 10 and 18 nM, respectively. Similar to indanone 4, the di-
methyl substituted inden-1-ol (9) resulted in a functional switch to
that of a PR agonist with an EC50 of 19 nM. To further explore the
alcohol template, several 1-position substituted derivatives were
prepared. As shown in Table 2, both methyl and ethyl substituted
4
3
, EC50 = 0.15 nM
borohydride in methanol or addition of an appropriate Grignard re-
agent to indanone 4 provided the corresponding secondary and
tertiary inden-1-ols 9–12. Other analogs reported herein were pre-
pared in a similar fashion.
All compounds were tested in an alkaline phosphatase assay
using the T47D breast carcinoma cell line. The indanones and their
oxime derivatives 4, 13–16 are shown in Table 1. Compounds 4
and 14 demonstrated that the mode of PR functional activity is
O
HO
TfO
NC
O
N
a
b
c
d
Cl
HO
O
O
O
4
5
6
7
8
Scheme 1. Synthesis of 5-(3,3-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile. Reagents and conditions: (a) anisole, AlCl
5 min, microwave, 46%; (b) AlCl , o-dichlorobenzene, 150 °C, 32%; (c) triflic anhydride, pyridine, 0 °C, 85%; (d) N-methyl-2-cyanopyrrole, LDA, B(OiPr)
3
, CH
2 2
Cl , 100 °C,
1
3
3
, THF, 0 °C, N ;
2
Pd(PPh
3
) , Na
4
2
CO
3
, glyme/H
2
O, 80 °C, N
2
, 55%.
NC
NC
N
NC
N
b or c
a
N
OH
N
OH
R
O
9-12
4
13
Scheme 2. Synthesis of inden-1-ol and inden-1-one oxime from indanone 4. Reagents and conditions: (a) NH
1%; (c) RMgBr, THF, 0 °C, 24–50%.
2 2 4
OHꢀHCl, NaOAc, EtOH/H O, 80 °C, 55%; (b) NaBH , MeOH, 0 °C,
5
Table 1
PR alkaline phosphatase activities of indanones and inden-1-one oximes
R1
R2
N
N
Me
X
b
c
Compd
R1
R2
Xa
PR Alk. Phos. EC50 (nM)
PR Alk. Phos. IC50 (nM)
34
1
4
4
5
6
3
H
CH
H
H
CH
H
CH
H
CH
CH
O
O
NOH
NOH
NOH
>3000
10
>3000
>3000
>3000
3
3
3
1
1
1
132
65
14
3
3
a
b
c
Oxime analogs predominantly trans configuration (>90%).
5
5
0% Effective concentration of tested compounds on alkaline phosphatase activity in the human T47D breast carcinoma cell line.
0% Inhibitory concentration of tested compounds on 1 nM progesterone induced alkaline phosphatase activity in the human T47D breast carcinoma cell line. Values
represent the average of at least duplicate determinations. The standard deviation for the assay was typically ±20% of the mean or less. Blanks indicate values not determined.

6
668
J. C. Kern et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6666–6669
Table 2
PR alkaline phosphatase activity of inden-1-ols in T47D cells
R1
R2
N
N
Me
R
HO
Compda
R1, R2
R
PR Alk. Phos. EC50 (nM)
b
PR Alk. Phos. IC50 (nM)
c
1
1
7
8
9
0
1
2
H, H
H, CH
H
H
H
CH
>3000
>3000
19
1
2
10
18
3
CH
3
CH
3
CH
3
CH
3
, CH
, CH
, CH
, CH
3
3
3
3
1
1
1
3
C
2
H
5
CCCH
3
>3000
3
a
b
c
Compounds tested as racemates or a mixture of diastereomers.
5
5
0% Effective concentration of tested compounds on alkaline phosphatase activity in the human T47D breast carcinoma cell line.
0% Inhibitory concentration of tested compounds on 1 nM progesterone induced alkaline phosphatase activity in the human T47D breast carcinoma cell line. Values
represent the average of at least duplicate determinations. The standard deviation for the assay was typically ±20% of the mean or less. Blanks indicate values not determined.
Table 3
In summary, combining the cyanopyrrole moiety from tanapr-
oget with the carbonyl motif of the D-ring region of progesterone
to form the indanone template is a valid approach to develop PR
Inhibition of progesterone induced alkaline phosphatase activity in T47D cells. SAR of
phenyl indanones and oximes.
0
modulators. Utilizing this approach, a number of novel 5-(5 -
cyanopyrrol-2-yl) substituted indanones, inden-1-one oximes,
and inden-1-ols were prepared that had modest to potent PR
activity. Both PR agonists and antagonists were achieved with
appropriate choices of 1-, 3-, and 5-substitutions. Notably, in-
den-1-ols 10 and 11 had low nanomolar in vitro potency in the
T47D cell alkaline phosphatase assay similar to that of steroidal
progesterone.
R3
Me
R3
Me
Me
Me
O
N
OH
1
9-22
23-26
Compda
R3
PR Alk. Phos. IC50 (nM)
b
0
19
20
21
22
23
24
25
26
3 -CN
195
66
79
225
317
490
456
316
0
3 -Cl
0
0
0
Acknowledgments
3 -Cl, 4 -Cl
3 -Me
0
3 -CN
We thank Drs. Ronald Magolda, Richard Lyttle, and Magid
Abou-Gharbia for support and the assistance of Department of
Analytical Chemistry for analytical data.
0
3 -Cl
0
0
0
3 -Cl, 4 -Cl
3 -Me
a
Oxime analogs predominantly trans configuration (>90%).
b
5
0% Inhibitory concentration of tested compounds on 1 nM progesterone
References and notes
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line. Values represent the average of at least duplicate determinations. The standard
deviation for the assay was typically ±20% of the mean or less.
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to a propargyl group (12) resulted in a complete PR functional
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5
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1
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0
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0
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3
6
). Not surprisingly, the phenyl substituted indanones (19–22, IC50
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0
14. Williams, S. P.; Sigler, P. B. Nature (London) 1998, 393, 392.
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than the cyanopyrrole derivative 13.
15. Analytical data for 5-(3,3-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1-methyl-
1
1
H-pyrrole-2-carbonitrile (4). A white solid: H NMR (DMSO-d
J = 1.4 Hz, 0.6 Hz, 1H), 7.68 (dd, J = 7.9 Hz, 0.5 Hz, 1H), 7.59 (dd, J = 7.9 Hz,
.6 Hz, 1H), 7.10 (d, J = 4.2 Hz, 1H), 6.53 (d, J = 4.2 Hz, 1H), 3.79 (s, 3H), 2.61 (s,
6
) 7.86 (dd,
1
+
2H), 1.42 (s, 6H). HRMS: calcd for C17H16N O+H , 265.13354; found (ESI
2

J. C. Kern et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6666–6669
6669
+
[
M+H] ), 265.1332; Anal. Calcd for C17
H
16
N
2
O: C, 77.25; H, 6.10; N, 10.60.
17. Zhang, P.; Kern, J. C.; Terefenko, E. A.; Fensome, A.; Unwalla, R.; Zhang, Z.;
Cohen, J.; Berrodin, T. J.; Yudt, M. R.; Winneker, R. C.; Wrobel, J. Bioorg. Med.
Chem. 2008, 16, 6589.
Found: C, 77.16; H, 6.27; N, 10.58.
1
6. Kern, J. C.; Terefenko, E. A.; Fensome, A.; Unwalla, R.; Wrobel, J.; Cohen, J.; Zhu,
Y.; Berrodin, T. J.; Yudt, M. R.; Winneker, R. C.; Zhang, Z.; Zhang, P. Bioorg. Med.
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