Novel 3-aryl indoles as progesterone receptor antagonists for uterine fibroids

Article abstract of DOI:10.1021/ml100220b

We report the synthesis and characterization of novel 3-aryl indoles as potent and efficacious progesterone receptor (PR) antagonists with potential for the treatment of uterine fibroids. These compounds demonstrated excellent selectivity over other steroid nuclear hormone receptors such as the mineralocorticoid receptor (MR). They were prepared from 2-bromo-6-nitro indole in four to six steps using a Suzuki cross-coupling as the key step. Compound 8f was orally active in the complement 3 model of progesterone antagonism in the rat uterus and demonstrated partial antagonism in the McPhail model of progesterone activity.

Full text of DOI:10.1021/ml100220b

pubs.acs.org/acsmedchemlett
Novel 3-Aryl Indoles as Progesterone Receptor
Antagonists for Uterine Fibroids
Timothy I. Richardson,* Christian A. Clarke, Kuo-Long Yu, Ying K. Yee,
Thomas J. Bleisch, Jose E. Lopez, Scott A. Jones, Norman E. Hughes, Brian S. Muehl,
Charles W. Lugar, Terry L. Moore, Pamela K. Shetler, Richard W. Zink, John J. Osborne,
Chahrzad Montrose-Rafizadeh, Nita Patel, Andrew G. Geiser, Rachelle J. Sells Galvin, and
Jeffrey A. Dodge
Lilly Research Laboratories, Eli Lilly & Co., Lilly Corporate Center, Indianapolis, Indiana 46285, United States
ABSTRACT We report the synthesis and characterization of novel 3-aryl indoles
as potent and efficacious progesterone receptor (PR) antagonists with potential for
the treatment of uterine fibroids. These compounds demonstrated excellent selec-
tivity over other steroid nuclear hormone receptors such as the mineralocorticoid
receptor (MR). They were prepared from 2-bromo-6-nitro indole in four to six steps
using a Suzuki cross-coupling as the key step. Compound 8f was orally active in the
complement 3 model of progesterone antagonism in the rat uterus and demon-
strated partial antagonism in the McPhail model of progesterone activity.
KEYWORDS Progesterone, progesterone receptor, NR3C3, progesterone receptor
antagonist, uterine fibroids, Suzuki cross-coupling reaction
terine fibroids (leiomyomas) are benign tumors that
develop from smooth muscle cells and fibrous con-
nective tissues of the uterus.1-3 Although most are
subsequently reduces the production of the ovarian hor-
mones estrogen and progesterone. Withdrawal of ovarian
hormone stimulation reduces uterine volume and fibroid
size.11 Unfortunately, this benefit is accompanied by side
effects, most notably bone loss, which limits treatment dura-
tion. Once therapy is discontinued, fibroids usually return.
As a result, GnRH agonists are primarily used to reduce
fibroid size prior to surgical removal.
Clinically, fibroids enlarge in women treated with norethy-
nodrel, a steroidal progesterone agonist.12 Progestins also
block the decrease in uterine size associated with GnRH
agonists.13 Furthermore, it has been demonstrated preclini-
cally that progestins increase the mitotic index of myomas
and myometrial cells both in vitro and in vivo.14 Conversely,
clinical studies with the steroidal antiprogestin mifepristone
have demonstrated a decrease in fibroid volume by 50%
after 12 weeks of therapy.15 Another steroidal antiprogestin,
Proellex (CDB-4124), has been in clinical trials for uterine
fibroids, associated anemia, and endometriosis.16-19
The progesterone receptor (PR, NR3C3) is a member of
the nuclear receptor superfamily of ligand-dependent tran-
scription factors. Two isoforms, PR-A and PR-B, have been
described.20 The PRs can be modulated by a wide variety of
ligands, ranging from full agonists such as progesterone (1)
and promegestone (R-5020, 2) to full antagonists such as
mifepristone (RU-486, 3) and Proellex (CDB-4124, 4). See
U
asymptomatic, in some women fibroids cause abnormal men-
strual bleeding, pelvic pain, and reproductive dysfunction.4 The
incidence of fibroids increases with age during the reproduc-
tive years and peaks between 35 and 40 years old.5 For those
women whose quality of life is negatively impacted, hyster-
ectomy is often necessary. As a result, fibroids are the primary
indication for over 200,000 hysterectomies in the U.S. per
year.6,7
An evaluation of hysterectomy cases revealed a similar
incidence (77%) in both post- and premenopausal women.8
The fertility of premenopausal women can be decreased by
the presence of submucosal myomas, which are fibroids
partially in the cavity and partially in the wall of the uterus.9
Since hysterectomy is unacceptable for a woman who de-
sires a future pregnancy, surgical procedures have been devel-
oped that preserve the uterus, such as myomectomy (fibroid
removal with uterine retention), laser ablation, or emboliza-
tion. Removal of fibroid growths can restore fertility.9 However,
these treatments are invasive, expensive, and associated with
a high rate of fibroid recurrence.10 Therefore, there is an unmet
medical need for a noninvasive, pharmaceutical treatment of
uterine fibroids in both post- and premenopausal women.
Currently the only pharmaceutical treatment for uterine
fibroids involves the use of gonadotropin-releasing hormone
(GnRH) agonists such as Lupron. These peptide hormones
act on the pituitary gland, resulting in a down-regulation of
the hypothalamic-pituitary-ovarian (HPO) axis, which de-
creases the release of gonadotropins (FSH and LH) and
Received Date: September 18, 2010
Accepted Date: November 27, 2010
Published on Web Date: December 09, 2010
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Chart 1. Structures of Progestins, Antiprogestins, and SPRMs
Chart 1. In between these two extremes are selective pro-
gesterone receptor modulators (SPRMs). Like their cousins,
the selective estrogen receptor modulators (SERMs), these
compounds elicit functional activities that depend on the cell
context in which ligand induced receptor conformations
recruit an ensemble of coactivators, resulting in promoter-
specific interactions and subsequent selective gene activa-
tions.21 Results from a recent phase III clinical study with the
steroidal SPRM asoprisnil (J-867, 5) suggest that PR modula-
tion can affect dysfunctional bleeding and reduce fibroid
size.22
We have recently described the development of SERMs
for the treatment of uterine fibroids in premenopausal
women.23-25 Since clinical experience with GnRH agonists
demonstrates that both estrogen and progesterone promote
fibroid growth, we have also pursued the development of
SPRMs for this indication. Here we describe for the first
time a novel series of 3-aryl indoles as nonsteroidal, highly
selective PR ligands.
Through screening efforts, we discovered that 3-[(4-meth-
oxyphenyl)phenylmethyl]indole binds weakly across the
steroidal nuclear hormone class of receptors (6, Figure 1).
We recently described a selective Mineralocorticoid Recep-
tor (MR, NR3C2) antagonist 7a based on this same non-
steroidal indole scaffold.26 We embarked on an extensive
SAR study around compound 7a, with the primary goal being
the removal of the tetrasubstituted, chiral carbon atom at
C3 on the indole ring. During the course of this work, we un-
expectedly discovered the highly selective PR ligands 8.
Figure 1 shows the previously described crystal structure
of 7a overlaid with a representative of the new, achiral PR
selective series (8c). The compounds are easily superimpo-
sable; however, in order to place the three common substit-
uents (alkyl, aryl, and methylsulfonamide) in the same
positions in chemical space, the indole rings must be rotated
significantly with respect to each other. The resulting com-
pounds showed reduced MR binding, increased PR binding,
Figure 1. MR selective 7a overlaid with PR selective 8c.
and even greater selectivity for PR over the androgen (AR,
NR3C4) and glucocorticoid (GR, NR3C1) receptors.
The syntheses of compounds 8a-h are outlined in
Scheme 1. In addition to being achiral, a significant advan-
tage of this platform was the ease with which a three point
SAR could be executed in rapid fashion. Therefore, several
flexible routes were developed.
The initial route began with 3-bromo-6-nitroindole (9),27
which was deprotonated with LiHMDS followedby alkylation
with alkyl halides to give 1-alkyl-3-bromo-6-nitroindoles 10.
Alternatively, the indole nitrogen could be alkylated with
alkyl alcohols using standard Mitsunobu conditions. Although
many aryl coupling methods were effective with the bromoin-
doles 10, Suzuki conditions using the air-stable trialkylpho-
sphonium tetrafluoroborate salt28,29 and tris(dibenzylidene-
acetone) dipalladium proved most versatile, allowing for a wide
variety of aryl substitutions at C3 on the indole ring. Thus,
1-alkyl-3-bromo-6-nitroindoles 10 were coupled to aryl boronic
acids to give 1-alkyl-3-aryl-6-nitroindoles 11. The nitro group
was then reduced using standard conditions [hydrogenation or
tin(II) chloride] followed by reaction with methanesulfonyl
chloride to give final compounds 8 for biological assays.
Alternatively, the indole nitrogen could be protected as the
phenyl sulfonamide 12 followed by Suzuki coupling and then
deprotection of the phenyl sulfonamide with TBAF to give
3-aryl-indoles 14. The indole nitrogen of 14 could then be
alkylated followed by reduction of the nitro group and
sulfonylation of the subsequent amine to give final com-
pounds 8.
In a third approach, 3-bromo-6-nitroindole was converted
to the pinacolboryl derivative 15. This allowed direct coupling
of more readily available aryl bromides without conversion to
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Scheme 1a
a Reagents and conditions: (a) LiHMDS, alkyl halide, DMF, 0 °C to RT; (b) alkyl alcohol, DIAD, PPh3, CH2Cl2, 0 °C to RT; (c) aryl boronic acid, Pd2(dba)3,
[(tBu)3PH]BF4, KF, THF, 40 °C; (d) H2, Pd/C or PtO2, THF or SnCl2 2H2O, DMF, 60 °C; (e) MsCl, pyr, CH2Cl2; (f) PhSO2Cl, DMAP, Et3N, CH2Cl2; (g) TBAF,
3
THF; (h) bis(pinacolato)diboron, PdCl2(dppf)2 CH2Cl2, KOAc, DMSO, 90 °C; (i) aryl bromide, Pd(PPh3)4, Na2CO3, LiOH, H2O, toluene, EtOH.
3
the corresponding boronic acids. Coupling of aryl bromides to
intermediate 15 worked well using standard, aqueous Suzuki
conditions [tetrakis(triphenylphosphine) palladium(0), bicar-
bonate, and lithium chloride]. This was followed by reduction
and sulfonylation to give final compounds 8.
cyano at the 40 position on the aromatic ring at carbon 3 of
the indole. For example, addition of a methyl group (8d)
improved binding affinity by 3-fold. However, addition of a
methoxy group at this position (8e) decreased binding affin-
ity, while addition of fluorine (8f) improved affinity for PR.
The same trend, although with somewhat muted differ-
ences, was also noted in the functional assays.
In our previous studies, we discovered a clear preference
of MR for the S-enantiomers of compounds 7. Compare, for
example, 7b, which has 5-fold better affinity than 7c. We
wondered if PR would have a similar preference for one
enantiomer over the other if chiral substituents were placed
at the N1 position of indoles 8. In practice, substituting chiral
groups at N1, such as the secondary butyl substituted indoles
8g and 8h, demonstrated a slight but consistent preference
of PR for the S-enantiomers.
Compound 8f was advanced to further testing in vivo. The
ovariectomized rat complement C3 assay was used to eval-
uate its ability to reverse the progestin (R5020) dependent
down-regulation of estrogen induced expression of comple-
ment C3 mRNA in the rat uterus (Figure 2).30 In this model,
when compound 8f was dosed orally, it demonstrated potent
antagonist activity, with an ED50 of 0.33 mg/kg, which is
comparable to that of asoprisnil (ED50 = 0.31 mg/kg).
The activity of 8f was also assessed in the McPhail model.
Progesterone treatment of immature estrogen-primed rab-
bits induces endometrial transformation, which is scored
using the McPhail Index (Figure 3).31 The animals were
dosed subcutaneously (sc) with or without progesterone to
evaluate the agonist or antagonist activity of the compound.
In the antagonist mode, mifepristone, asoprisnil, and 8f
antagonize the effects of progesterone dosed at 1 mg/kg.
Biological data for compounds 8a-h are shown in Table 1.
The binding affinity data were generated using appropriate
tritium labeled standards and recombinant, full-length hu-
man receptors in competitive binding assays. The functional
activity was measured using a transcription assay with full-
length human PR cotransfected into a HEK293 cell line.
In general, the more rigid achiral series displayed much
higher selectivities than the chiral series with its flexible
linker between the aryl group and the indole ring. The
screening hit, indole 6, possesses a binding affinity for PR
of 478 nM but is 6- to 10-fold more potent at the other steroid
receptors. It is nearly a full antagonist of PR but with a re-
latively weak IC50 of about 4 μM. The previously reported
chiral indole 7a possesses a binding affinity for MR of 0.64 nM
with 710-fold selectivity over PR while the new achiral indole
8c possesses a binding affinity for PR of 0.795 nM with 1900-
fold selectivity over MR. In the functional antagonist assays,
the chiral indole 7a is about 12-fold selective for MR while the
achiral indole 8c is greater than 1500-fold selective for PR.
Indole 8c displays similarly high selectivity for PR over AR and
GR in both the binding and functional assays.
The alkyl substituent at N1 played a very important role in
binding potency. Changing this substituent from methyl (8a)
to ethyl (8b) and then from ethyl to isopropyl (8c) improved
the binding affinity 7- and 5-fold, respectively. The functional
activities follow this same trend. We also noted a preference
for substitution of select small functional groups ortho to the
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Table 1. PR Binding and Functional Activities of 6, 7a-c, and 8a-ha
binding
functional
MR
PR
MR
Ki (nM)
AR
GR
PR
cmpd R1 R2 isomer
Ki (nM)
Ki (nM)
Ki (nM)
IC50(nM)
% Inhib
IC50 (nM)
% Inhib
6
478 ( 287
454 ( 188
464 ( 158
1230 ( 260
28.0 ( 10.7
4.23 ( 1.95
86.8 ( 49.6
68.9 ( 16.8 50.2 ( 19.4 3720 ( 563 86.5 ( 2.26 >10000
40.8 ( 3.39
91.7 ( 4.59 64.1 ( 25.8 76.3 ( 12.8
89.7 ( 9.38 27.2 ( 13.7 62.9 ( 11.5
7a
7b
7c
8a
8b
8c
8d
8e
8f
H
F
0.640 ( 0.864 220 ( 97.7 6.39 ( 3.43 765 ( 171
0.319 ( 0.156 211 ( 99.4 5.93 ( 4.18 715 ( 61.9
S
F
R
1.51 ( 0.856 676 ( 306 54.4 ( 8.33 2020 ( 155 94.5 ( 0.141 306 ( 53.3 87.0 ( 2.12
Me
Et
H
H
H
>4170
>4020
2590
>4290
927 ( 93.8 12.6 ( 2.47 97.0 ( 3.28 >10000
1530 ( 156 6.81 ( 1.11 96.2 ( 1.34 >10000
485 ( 214
87.8 ( 3.70 >10000
-2.2
1770 ( 640
23.8 ( 7.23
36.6 ( 9.12
56.0 ( 7.37
35.8 ( 2.31
50.2 ( 11.9
43.4 ( 9.22
39.2 ( 6.79
iPr
0.795 ( 0.286 1490 ( 123
0.298 ( 0.150 126 ( 12.1
>3900
iPr Me
403 ( 212 157 ( 15.2 3.38 ( 0.698 95.8 ( 4.03 >10000
490 ( 172 977 ( 65.7 7.28 ( 1.06 97.4 ( 0.726 2420
iPr OMe
1.45 ( 0.760
1390 ( 403
iPr
F
0.214 ( 0.0924 849 ( 223
0.320 ( 0.227 1000 ( 155
0.834 ( 0.339 1440 ( 223
648
523 ( 148 2.29 ( 0.860 94.9 ( 4.74 8150
8g
8h
sBu
sBu
S
1740 ( 795 1860 ( 552 3.89 ( 1.04 96.8 ( 1.03 9800
2550 ( 666 780 ( 147 9.92 ( 1.88 96.2 ( 0.635 >10000
R
a Experimental values represent the average of at least duplicate determinations. Standard deviations are indicated by ( of the geometric mean.
Figure 2. Dose response (mg/kg, po) of asoprisnil and 8f in the
ovariectomized rat complement C3 assay. E2 is estrogen. R5020 is
promegestone. By comparison, the fold over asoprisnil (5 mg/kg) for
vehicle control was 0.018 ( 0.011, while E2 (0.05 mg/kg) alone was
0.73 (0.05, and E2 (0.05 mg/kg) þ R5020 (0.1 mg/kg) was 0.12 (0.03.
Mifepristone reached full antagonism at 1 mg/kg, whereas
asoprisnil and 8f demonstrated only partial antagonism with
a McPhail score of 3.1 for asoprisnil at 10 mg/kg and 2.0 for
8f at 3 mg/kg. At 30 mg/kg, 8f resulted in a McPhail score of
2.5 in the antagonist mode. In the agonist mode, mifepristone
had no effect, but asoprisnil and 8f increased the McPhail
Index to 3.1 and 1.5, respectively, at 30 mg/kg.
The oral bioavailability of 8f (dosed as a suspension) in rats
was 31.4 ( 7.3% with a tmax of 4 h and an elimination half-
life (t1/2) of 19.8 ( 5.0 h. The volume of distribution (Vd) was
2.3 ( 0.7 L/kg, while its clearance was 2.5 ( 0.6 mL/min/kg.
Figure 3. Dose responses (mg/kg, sc) of asoprisnil, mifepristone,
and 8f in the immature, estrogen-stimulated rabbit McPhail assay:
(a) antagonist mode with 1 mg/kg progesterone (P4) þ test compound
at various doses; (b) agonist mode with progesterone (P4) alone at
1 mg/kg compared to test compound alone at 1, 10, and 30 mg/kg.
The indole 8f is a potent, selective antagonist of PR in vitro.
It is orally efficacious in an in vivo rat uterine model of PR
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antagonist activity. In the McPhail model, in the antagonist
mode, it demonstrated activity less efficacious than the full
antagonists mifepristone but more efficacious than the par-
tial antagonist asoprisnil.
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SUPPORTING INFORMATION AVAILABLE Synthesis pro-
cedures and characterization data for compounds 8a-h, and a
description of the biological assays. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author: *Phone: 317-433-2372. E-mail:
t_richardson@lilly.com.
Author Contributions: T.I.R. designed and interpreted experi-
ments, synthesized compounds, wrote the manuscript, and con-
tributed to the Supporting Information; C.A.C. designed experi-
ments, synthesized compounds, wrote the Supporting Information,
and contributed to the manuscript; Y.K.Y., T.J.B., J.E.L., S.A.J.,
N.E.H., B.S.M., and C.W.L. designed experiments, synthesized com-
pounds, and contributed to the Supporting Information; K.-L.Y. led
the chemistry team, designed and interpreted experiments, synthe-
sized compounds, and contributed to the Supporting Information;
A.G.G., T.L.M. and P.K.S. designed, performed, and interpreted
in vivo experiments; R.W.Z., J.J.O., and C.M.-R. designed, per-
formed, and interpreted in vitro experiments and contributed to
the Supporting Information; N.P. designed and interpreted animal
exposure experiments, R.J.S.G. led the biology team, designed and
interpreted experiments, and contributed to the manuscript and
the Supporting Information; J.A.D. led the discovery team, designed
and interpreted experiments, and contributed to the manuscript.
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(19)
Clinical trials of Proellex were suspended after Repros
Therapeutics Inc. recieved verbal notice from the FDA that
the INDs had been placed on clinical hold for safety reasons
due to increased liver enzymes in a number of patients.
http://www.reprosrx.com/.
ACKNOWLEDGMENT We thank Xuhao Yang, Ellen R. Rowley,
Harlan Cole, Leah L. Porras, and Lynnie Irwin for technical assis-
tance with the in vivo models.
(20) Aupperlee, M. D.; Smith, K. T.; Kariagina, A.; Haslam, S. Z.
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