1-Methyl-1H-pyrrole-2-carbonitrile containing tetrahydronaphthalene derivatives as non-steroidal progesterone receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.06.109

Non-steroidal 1-methyl-1H-pyrrole-2-carbonitrile containing tetrahydronaphthalenes and acyclic derivatives were evaluated as novel series of progesterone receptor (PR) antagonists using the T47D cell alkaline phosphatase assay. Moderate to potent PR antag

Full text of DOI:10.1016/j.bmcl.2010.06.109

Bioorganic & Medicinal Chemistry Letters 20 (2010) 4816–4818
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
1-Methyl-1H-pyrrole-2-carbonitrile containing tetrahydronaphthalene
derivatives as non-steroidal progesterone receptor antagonists
a
a
b
b
Jeffrey C. Kern a, , Eugene Terefenko , Eugene Trybulski , Thomas J. Berrodin , Jeffrey Cohen ,
*
Richard C. Winneker b, Matthew R. Yudt b, Zhiming Zhang b, Yuan Zhu b, Puwen Zhang a,
a Chemical Sciences, Pfizer Global Research and Development, 500 Arcola Road, Collegeville, PA 19426, USA
b Musculoskeletal Biology, Pfizer Global Research and Development, 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:
Non-steroidal 1-methyl-1H-pyrrole-2-carbonitrile containing tetrahydronaphthalenes and acyclic deriv-
atives were evaluated as novel series of progesterone receptor (PR) antagonists using the T47D cell alka-
line phosphatase assay. Moderate to potent PR antagonists were achieved with these scaffolds. Several
compounds (e.g., 15 and 20) demonstrated low nanomolar PR antagonist potency and good selectivity
versus other steroid receptors.
Received 12 March 2010
Revised 17 June 2010
Accepted 21 June 2010
Available online 25 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Progesterone
Antagonist
Modulator
Tetrahydronaphthalene
Nuclear hormone
1-Methyl-1H-pyrrole-2-carbonitrile
Progesterone (1) is an endogenous hormone that plays an impor-
tant role in female reproduction. Synthetic progestins commonly
used in oral contraceptives achieve efficacy via ovulation inhibition
and thickening of the cervical mucus.1 Progestin/estrogen combina-
tions are also used in hormone replacement therapy. A selective pro-
gesterone receptor (PR) antagonist may be potentially used in
female contraception2 and for the treatment of various gynecologi-
cal and obstetric diseases including hormone dependent cancers
and non-malignant chronic conditions such as fibroids and endome-
triosis.3,4 The therapeutic potential of PR antagonists has not yet
been fully realized. Mifepristone (2), the only marketed PR antago-
nist, demonstrated activity at other steroid receptors such as the
glucocorticoid (GR) and androgen (AR) receptors. Mifepristone (2)
was nearly equipotent as an antagonist for both the PR and GR. This
potentially limits its chronic use.5 In the search for selective PR mod-
ulators, a number of non-steroidal PR scaffolds have been investi-
gated.6–10 We reported several chemical series that yielded potent
PR modulators.11–14 Several scaffolds incorporated a cyanopyrrole
moiety which acts as a progesterone A-ring mimic from co-crystal
structure analysis.12 We have recently reported our efforts to
combine the cyanopyrrole A-ring mimic with an indane core (e.g.,
3) that produced low nanomolar PR modulators.15 As a continuation
of this work, we expanded the indane core to that of tetrahydro-
naphthalenes (6–11) and their acyclic analogs (13–25) and exam-
ined the SAR of these new scaffolds as PR modulators. In this
Letter, we describe the synthesis and in vitro structure–activity
relationship of the new 1-methyl-1H-pyrrole-2-carbonitrile
containing tetrahydronaphthalenes and acyclic derivatives.
Me
N
O
Me
Me
OH
Me
H
H
H
O
N
O
1, Progesterone
2, Mifepristone
N
N
N
* Corresponding author. Address: Merck Research Laboratory, West Point, PA
19486, USA. Tel.: +1 610 505 8420.
E-mail addresses: Jkern75@hotmail.com (J.C. Kern), puwen.zhang@pharmaron.
com (P. Zhang).
O
6-11
13-25
X
3
Present address: Pharmaron Inc., 201E Jefferson St., Louisville, KY 40202, USA.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.06.109

J. C. Kern et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4816–4818
4817
NC
NC
HO
TfO
a
b or c, b
d or e
N
N
6 X=O
7 X=NOH
R
OH
O
O
X
4
5
8-11
Scheme 1. Synthesis of 1-methyl-5-(5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrrole-2-carbonitrile and derivatives. Reagents and conditions: (a) triflic anhydride,
pyridine, 0 °C, 92%; (b) N-methyl-2-cyanopyrrole, LDA, B(OiPr)3, THF, 0 °C, N2; Pd(PPh3)4, Na2CO3, Glyme/H2O, 80 °C, N2, 43%; (c) NH2OHÁHCl, NaOAc, EtOH/H2O, 80 °C, 50%;
(d) NaBH4, MeOH, 0 °C, 40%; (e) RMgBr, THF, 0 °C, 60–80%.
NC
NC
NC
R
Br
N
N
N
a
b or c
R
R
R
O
O
N
OH
OH
18-20
12
13-17
21-25
Scheme 2. Synthesis of acyclic ketones and derivatives. Reagents and conditions: (a) N-methyl-2-cyanopyrrole, LDA, B(OiPr)3, THF, 0 °C, N2; Pd(PPh3)4, Na2CO3, Glyme/H2O,
80 °C, N2, 52–78%; (b) NH2OHÁHCl, NaOAc, EtOH/H2O, 80 °C, 46–83%; (c) NaBH4, MeOH, 0 °C, 26–79%.
Table 1
Table 2
PR alkaline phosphatase activities of tetrahydronaphthalene derivatives
PR alkaline phosphatase activity of acyclic ketones and oximes in T47D cells
N
N
N
N
N
N
Me
R
Me
Me
HO
R
X
X
6, 7
8-11
Xa
R
PR alk. phos. IC50 (nM)
b
Compd
c
Compd
Xa
Rb
PR alk. phos. IC50 (nM)
13
14
15
16
17
18
19
20
O
O
O
O
CH3
C2H5
C(CH3)3
Thien-2-yl
Phenyl
CH3
800
115
3
266
300
108
17
6
7
O
NOH
28
33
7
6
10
35
8
9
10
11
H
CH3
CCCH3
Phenyl
O
NOH
NOH
NOH
C2H5
C(CH3)3
3
a
b
c
Oxime analog is of trans configuration.
Compounds tested as racemates.
50% inhibitory concentration of tested compounds on 1 nM progesterone
a
Oxime analogs are of trans configuration.
50% inhibitory concentration of tested compounds on 1 nM progesterone
b
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.
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.
in Table 1. These compounds all displayed PR antagonist functional
activity. The tetrahydronaphthalenone 6 and oxime 7 were equipo-
The preparation of the tetrahydronaphthalenone (6), tetrahydro-
naphthalenone oxime (7), and tetrahydronaphthalenols (8–11) is
shown in Scheme 1. Synthesis of triflate 5 from commercially avail-
able phenol 4 was carried out using triflic anhydride in pyridine.
The target compound 6 was obtained by palladium catalyzed
coupling of 5 with in situ generated N-methyl-2-cyanopyrrole
boronate. Compound 7 was achieved by first reacting trifate 5
with hydroxylamine, followed by palladium catalyzed coupling
with in situ generated N-methyl-2-cyanopyrrole boronate. Treat-
ment of compound 6 with either sodium borohydride or an appro-
priate Grignard reagent gave secondary alcohol 8 or tertiary
alcohols 9–11, respectively. The synthesis of the acyclic derivatives
is shown in Scheme 2. Starting with commercially available aryl
bromides generically represented by 12, palladium catalyzed
coupling with in situ generated N-methyl-2-cyanopyrrole boronate
yielded ketone derivatives 13–17. Treatment of the ketones 13–15
with hydroxylamine provided oxime derivatives 18–20. Addition
of an appropriate Grignard to ketones 13–17 provided benzyl
alcohol derivatives 21–25.
Table 3
PR alkaline phosphatase activity of acyclic benzyl alcohols in T47D cells
N
N
Me
R
OH
Compda
R
PR alk. phos. IC50 (nM)
b
21
22
23
24
25
CH3
C2H5
C(CH3)3
Thien-2-yl
Phenyl
36
27
24
47
118
a
Compounds tested as racemates.
50% inhibitory concentration of tested compounds on 1 nM progesterone
b
All compounds were tested in an alkaline phosphatase assay
using the T47D breast carcinoma cell line. The tetrahydronapht-
halenone and its oxime and alcohol derivatives 6–11 are shown
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.

4818
J. C. Kern et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4816–4818
Table 4
Nuclear receptor antagonist cross-activities of 2, 15, and 20
N
N
N
N
Me
Me
O
N
OH
15
20
a
b
b
b
b
Compd
PR IC50 (nM)
ER IC50 (nM)
AR IC50 (nM)
GR IC50 (nM)
MR IC50 (nM)
2
15
20
0.2
3
3
5000
NAc
NA
6.9
100
165
0.6
NA
NA
590
NA
NA
a
50% 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.
b
Experimental values represented the average of at least duplicate determinations. The standard deviation for these assays was typically 30% of mean or less. See
reference for details.
c
Not active up to 10 lM concentration.
tent with an IC50 of 28 nM and 33 nM, respectively. The tetrahydro-
naphthalenols also displayed good PR antagonist potency. Unsub-
stituted (8) or 1-methyl (9) or 1-propargyl (10) analogs showed
good PR antagonist potency with an IC50 of 6–10 nM. Compound
11, with a phenyl substitution resulted in several fold reduction
in potency.
strated good in vitro selectivity for the PR over other steroid
receptors with an improved selectivity profile compared to
mifepristone.
Acknowledgment
In an effort to examine the SAR of acyclic analogs, the saturated
ring was excised to yield compound 13. Compared to the tetrahy-
dronaphthalenone analog 6, the acyclic methyl ketone 13 was
nearly 30-fold less potent. Additional ketone analogs were pre-
pared and demonstrated a broad range of PR antagonist potency
(Table 2). The ethyl, thienyl, and phenyl substituted ketone analogs
were weaker PR antagonists with IC50 values of 115–300 nM. Sur-
prisingly, the t-butyl group (15) substantially increased PR antago-
nist potency with an IC50 = 3 nM which was over 30-fold more
potent than the methyl and ethyl analogs (Table 2).16 Conversion
of ketones 13–15 into oximes gave compounds 18–20 which were
also PR antagonists. The oximes exhibited a similar SAR trend as
that of their ketone analogs with the t-butyl analog being most po-
tent. However, the methyl and ethyl oxime analogs 18 and 19 were
more potent than the corresponding ketones 13 and 14. The PR
antagonist potency of benzyl alcohols 21–25 is listed in Table 3.
These compounds showed moderate PR antagonist potency (IC50
24–118 nM). In contrast to the SAR of their ketone and oxime ana-
logs, 1-substitution (R) in the alcohol series did not significantly
impact the PR antagonist potency. The t-butyl analog 23 was sim-
ilar in potency to the methyl (21) and ethyl (22) derivatives.
Compounds 15 and 20 were evaluated for their selectivity
against other steroid receptors by using a Gal4-DNA binding do-
main (DBD)-hormone receptor ligand binding domain (LBD) one-
or two-hybrid assay for each receptor17 (Table 4). Compared to
the steroidal PR antagonist mifepristone (2), both compounds 15
and 20 are more selective for the PR over other steroid receptors.
Although these compounds showed moderate antagonist activity
at the AR, they displayed no activity at the ER, GR, or MR in this as-
say. This suggests that these novel PR antagonists will likely have
less GR-related side effects.
We thank Drs. Ronald Magolda, Richard Lyttle, and Magid
Abou-Gharbia for support and the assistance of Department of
Analytical Chemistry for analytical data.
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16. Analytical data for 5-[4-(2,2-dimethylpropanoyl)phenyl]-1-methyl-1H-
In summary, 1-methyl-1H-pyrrole-2-carbonitrile containing
tetrahydronaphthalenones and analogs were evaluated as PR
antagonists. From these scaffolds, a number of PR antagonists with
low nanomolar in vitro potency were identified, most notably acy-
clic ketone 15 and oxime 20. Compounds 15 and 20 also demon-
pyrrole-2-carbonitrile (15).
A
white solid: 1H NMR (DMSO-d6) 7.83 (d,
J = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.07 (d, J = 4.0 Hz, 1H), 6.47 (d,
J = 4.0 Hz, 1H), 3.77 (s, 3H), 1.31 (s, 9H). HRMS: calcd for C17H18N2O + H+,
267.14919; found (ESI, [M+H]+), 267.1494.
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