SAR studies of 6-aryl-1,3-dihydrobenzimidazol-2-ones as progesterone receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2005.05.082

We have previously reported that the aryl substituted benzimidazolones, benzoxazinones, and oxindoles (e.g., 1-3) are progesterone receptor (PR) antagonists and have recently disclosed that the nature of 5- and 6-aryl moieties played a critical role in PR functional activity in the oxindole and benzoxazinone templates. For example, replacing the phenyl group of PR antagonists 2 and 3 with a 5′-cyanopyrrol-2′-yl moiety switched their functional activity to PR agonist activity (2a and 3a). These findings prompted us to examine if there is a similar effect of the 6-aryl moieties on the PR functional activity for the benzimidazolone template. Numerous analogs, such as 5, showed potent PR antagonist activity with about a 10-fold increase in potency as compared to those reported earlier in the same series. More interestingly, pyrrole-containing benzimidazolones 24-27 remained as PR antagonists in contrast to the PR agonist activity switch for oxindole and benzoxazinone scaffolds when a 5′-cyanopyrrol-2′-yl group was installed as a pendant aryl group.

Full text of DOI:10.1016/j.bmcl.2005.05.082

Bioorganic & Medicinal Chemistry Letters 15 (2005) 3600–3603
SAR studies of 6-aryl-1,3-dihydrobenzimidazol-2-ones
as progesterone receptor antagonistsq
Eugene A. Terefenko,a Jeffrey Kern,a Andrew Fensome,a Jay Wrobel,a Yuan Zhu,b
Jeffrey Cohen,b Richard Winneker,b Zhiming Zhangb and Puwen Zhanga,*
aChemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
bWomenÕs Health Research Institute, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
Received 5 April 2005; revised 10 May 2005; accepted 11 May 2005
Abstract—We have previously reported that the aryl substituted benzimidazolones, benzoxazinones, and oxindoles (e.g., 1–3) are
progesterone receptor (PR) antagonists and have recently disclosed that the nature of 5- and 6-aryl moieties played a critical role
in PR functional activity in the oxindole and benzoxazinone templates. For example, replacing the phenyl group of PR antagonists 2
and 3 with a 50-cyanopyrrol-20-yl moiety switched their functional activity to PR agonist activity (2a and 3a). These findings prompt-
ed us to examine if there is a similar effect of the 6-aryl moieties on the PR functional activity for the benzimidazolone template.
Numerous analogs, such as 5, showed potent PR antagonist activity with about a 10-fold increase in potency as compared to those
reported earlier in the same series. More interestingly, pyrrole-containing benzimidazolones 24–27 remained as PR antagonists in
contrast to the PR agonist activity switch for oxindole and benzoxazinone scaffolds when a 50-cyanopyrrol-20-yl group was installed
as a pendant aryl group.
Ó 2005 Elsevier Ltd. All rights reserved.
The progesterone receptor (PR) is a member of the super-
family of ligand-dependent transcription factors.1 PR
agonists play an important role in female reproduction
and have been used extensively, often in combination with
an estrogen, in contraceptives, and hormone therapy. In
contrast, clinically successful PR antagonists remain
scarce and their therapeutic potential has not yet been ful-
ly realized. A selective PR antagonist may be potentially
used in female contraception2 and for the treatment of
various gynecological and obstetric diseases including
hormone-dependent cancers and non-malignant chronic
conditions, such as fibroids3 and endometriosis.4
identified.6–10 Recently, we have disclosed several series
of novel PR antagonists including 6-aryl benzimidazol-
ones (e.g., 1), 6-aryl benzoxazinones (e.g., 2), and 5-aryl
oxindoles (e.g., 3).10–12 The SAR trends brought out
by these studies indicated that a pendent aryl ring
substituted para to the N–H moiety and a lipophilic
group at the position ortho to the N–H are critical for
the compounds to elicit PR antagonist activity. Further-
more, we discovered that the nature of 6- and 5-aryl
moieties played a critical role in PR functional activity
for the benzoxazinone and oxindole templates in the hu-
man T47D cell alkaline phosphatase assay. For exam-
ple, replacing the phenyl group of PR antagonists 2
and 3 with a 50-cyanopyrrol-20-yl moiety switched their
functional activity from PR antagonism to PR agonist
activity. The corresponding pyrrole-containing com-
pounds 2a and 3a became potent PR agonists in the
T47D cell alkaline phosphatase assay (EC50 values of
1.1 and 2.8 nM, respectively).11 These findings prompted
us to examine if there is a similar effect of 6-aryl moieties
for the benzimidazolone scaffold on their PR functional
activity. Thus, a number of benzimidazolone com-
pounds with various 6-aryl groups, as well as with a
selection of 1-position substituents, were prepared and
these novel 6-aryl benzimidazolones were evaluated for
PR functional activity in the alkaline phosphatase assay.
Clinically available steroidal PR antagonists, namely
mifepristone,5 demonstrated activity at other steroidal
receptors, such as the glucocorticoid receptor (GR).
Mifepristone was nearly equipotent as an antagonist
for both PR and GR, and this potentially limited its
chronic use. To search for more selective compounds,
a number of non-steroidal PR antagonists have been
q Presented in preliminary form at 228th ACS National Meeting,
Philadelphia, PA, USA, August 22–26, 2004.
*
Corresponding author. Tel.: +1 484 865 3856; fax: +1 484 865
9398; e-mail: ZhangP@wyeth.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.05.082

E. A. Terefenko et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3600–3603
3601
The synthesis and in vitro SAR of novel 6-aryl ben-
zimidazolones (4–27) are the subjects of this report.
and 5-aryl oxindoles.13–15 Similar SAR trends were ob-
served for the benzimidazolone and oxindole scaffolds.
However, the PR functional activities of the 6-aryl ben-
zoxazinones were dependent on the nature of the pen-
dant 6-aryl group and a few analogs showed modest
PR agonist activity in the T47D cell alkaline phospha-
tase assay.14 More recently, we have disclosed that 5-
or 6-(50-cyanopyrrol-20-yl) substituted oxindoles and
benzoxazinones were potent PR agonists when phen-
yl-based pendent aryl groups were replaced by a 50-
cyanopyrrol-20-yl moiety.11 In contrast, the corre-
sponding SAR for the benzimidazolone template has
not been fully examined and only a modest potency
(IC50 ꢀ 30 nM) in the T47D alkaline phosphatase assay
was achieved among the best compounds reported ear-
lier.13 To probe further the SAR of the benzimidazo-
lone scaffold and improve upon the PR potency, a
selection of 1-position substituents and different 6-aryl
moieties was examined. These novel 6-aryl ben-
zimidazolones were evaluated for PR antagonist activ-
ity in the T47D cell alkaline phosphatase assay and the
results are listed in Tables 1 and 2.
Listed in Table 1 are compounds 4–10 substituted with
various lipophilic groups at the 1-position, while main-
taining a consistent 6-aryl group (30-cyano-50-fluorophe-
nyl). Compounds 4 and 7 that were substituted with an
acyclic isopropyl and 3-pentyl, respectively, exhibited a
similar PR antagonist potency and had IC50 values of
about 29 nM. Interestingly, the constrained cyclobutyl
and cyclopentyl analogs 5 and 6 were the most potent
ones with IC50 values of 3.3 and 5.7 nM, respectively,
suggesting that an appropriate rigid ring at the 1-posi-
tion in this series was preferred. Increasing the cyclo-
alkyl ring size to a cyclohexyl moiety (8) caused a
ꢀ20-fold reduction in PR antagonist potency over the
Chemistry
The preparation of the target compounds 4–27, as
shown in Scheme 1, was described previously.12,13 In
brief, alkylation of the BOC-protected benzimidazol-
ones 28 to 29 easily took place by alkylation via a
Mitsunobu protocol or for R1 = Aryl by coupling with
an appropriate aryl boronic acid via a copper (II) cata-
lyzed procedure. Removal of protecting groups from
benzimidazolones 29 under acidic conditions afforded
30, which was cross-coupled with an appropriate aryl
boronic acid to provide the desired 6-aryl benzimidazol-
ones 4–27 in good yield.
Table 1. Inhibition of progesterone induced alkaline phosphatase
activity in T47D cells: SAR at the 1-position
Results and discussion
We have previously reported the preliminary SAR of
the 6-aryl benzimidazolones, 6-aryl benzoxazinones,
Compound
R1
PR Alk. Phos. IC50 (nM)a
4
i-C3H7
c-C4H7
c-C5H9
29.6
3.3
5
6
5.7
7
3-C5H11
c-C6H11
Phenyl
29.0
83.6
137.3
3000
8
9
10
30-Chlorophenyl
a 50% inhibitory concentration of tested compounds on 1 nM proges-
terone 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.
Scheme 1. 6-Aryl-1,3-dihydro-benzimidazol-2-ones. Reagents and
conditions: (a) R1OH, DEAD, Ph3P, THF, rt or Cu(OAc)2,
ArB(OH)2, CH2Cl2, rt, N2; (b) CH2Cl2, TFA, rt; (c) ArB(OH)2,
Pd(Ph3P)4, K2CO3, toluene, EtOH/H2O, 90 °C.

3602
E. A. Terefenko et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3600–3603
and N-cyclopentyl groups did not increase antagonist
potency over N-isopropyl for 30, 40-disubstituted phenyl
analogs (compare 18–21 with 14 and 15). These six com-
pounds had similar PR antagonist potency with IC50
values in the range of 96–206 nM. The 6-(thien-20-yl)
analog 23 had PR antagonist potency comparable to
its 6-(30-cyano-50-fluorophenyl) analog 4 (IC50 24.8 nM
vs 29.6 nM, respectively).
Table 2. Inhibition of progesterone induced alkaline phosphatase
activity in T47D cells: SAR of 6-aryl groups
Interestingly, the 50-cyano-10-methylpyrrol-20-yl group
that led to the PR agonist activity in the benzoxazinone
and oxindole templates did not execute the same for the
corresponding benzimidazolones 24–27.16 The 50-cyano-
pyrrol-20-yl containing benzimidazolones remained as
potent PR antagonists. For example, benzimidazolone
24 was about 5-fold more potent than its 6-(30-cyano-
50-fluorophenyl) and 6-(thien-20-yl) analogs 4 and 23.
Other 6-(50-cyanopyrrol-20-yl) containing compounds
25–27 also showed good PR antagonist potency (IC50
5.6–12 nM). In addition, these compounds had high
binding affinity in a progesterone receptor competition
binding assay using T47D cells. For example, compound
25 had an IC50 value of 7 nM in this assay.
Compound R1
i-C3H7
R2
PR Alk. Phos. IC50 (nM)a
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
20-F
412.3
77.9
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
c-C4H7
c-C4H7
c-C5H9
c-C5H9
30-F
40-F
295.4
206.6
105.6
60.3
30-F, 40-F
30-Cl, 40-F
30-CN, 40-F
30-Cl, 50-Cl 100.0
30-F, 40-F
30-Cl, 40-F
30-F, 40-F
30-Cl, 40-F
175.4
106.0
96.8
In summary, we have examined a selection of 1-position
substituents and different 6-aryl moieties for the benzim-
idazolone scaffold. Numerous analogs, such as 5, showed
potent PR antagonist activity in the T47D cell alkaline
phosphatase assay with a 10-fold increase in PR antago-
nist potency as compared to those reported earlier in the
same series. Furthermore, pyrrole-containing ben-
zimidazolones 24–27 remained as PR antagonists in con-
trast to the PR agonist functional activity switch for
oxindole and benzoxazinone scaffolds when a 50-cyano-
pyrrol-20-yl group was substituted at the 6-position.
134.7
425.6
24.8
3-C5H11 30-Cl, 40-F
i-C3H7
i-C3H7
4.7b
c-C4H7
c-C5H9
3-C5H11
10.9b
5.6b
11.7b
a 50% inhibitory concentration of tested compounds on 1 nM proges-
terone 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 In this assay, compounds 24–27 showed weak agonist activity in the
absence of 1 nM progesterone (agonist mode) at 3000 nM.
Acknowledgments
We thank Drs. Ron Magolda and Magid Abou-Gharbia
for support and encouragement, Dr. Eugene Trybulski
for scientific suggestions, and the assistance of the
Department of Analytical Chemistry for analytical data.
1-cyclobutyl congener 5. The 1-phenyl analog 9 was
marginally less potent than its cyclohexyl analog 8.
However, introducing an extra 3-chlorine atom on the
1-phenyl moiety (10) caused a drastic reduction in PR
potency when compared to its des-chlorine analog 9.
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1H, J = 4.0 Hz), 6.31 (d,1H, J = 4.0 Hz), 4.76 (q, 1H,
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