Discovery of BMS-641988, a Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer

Article abstract of DOI:10.1021/acsmedchemlett.5b00173

BMS-641988 (23) is a novel, nonsteroidal androgen receptor antagonist designed for the treatment of prostate cancer. The compound has high binding affinity for the AR and acts as a functional antagonist in vitro. BMS-641988 is efficacious in multiple human prostate cancer xenograft models, including CWR22-BMSLD1 where it displays superior efficacy relative to bicalutamide. Based on its promising preclinical profile, BMS-641988 was selected for clinical development.

Full text of DOI:10.1021/acsmedchemlett.5b00173

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Letter
The Discovery of BMS-641988, a Novel Androgen
Receptor Antagonist for the Treatment of Prostate Cancer
Aaron Balog, Richard Rampulla, Gregory Martin, Stanley Krystek, Ricardo Attar, Janet Dell-
John, John D DiMarco, David Fairfax, Jack Z Gougoutas, Christian Holst, Andrew Nation, Cheryl
Rizzo, Lana Rossiter, Liang Schweizer, Weifang Shan, Steven H. Spergel, Thomas Spires,
Georgia Cornelius, Marco Gottardis, George L Trainor, Gregory D. Vite, and Mark Salvati
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.5b00173 • Publication Date (Web): 19 Jun 2015
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ACS Medicinal Chemistry Letters
enzalutamide via AR mutations.4 Thus, there is a
The Discovery of BMS-641988, a Novel
Androgen Receptor Antagonist for the
Treatment of Prostate Cancer
1
2
3
need for novel antiandrogens with distinct
interactions in the AR ligand binding domain that
could be dosed together or sequentially in the clinic to
combat the potential pathways leading to CRPC
progression. Our laboratory has been focused on the
rational strucutral-based design of structurally novel,
non-steroidal small molecule AR antagonists for the
potential treatment of CRPC.
Aaron Balog§*, Richard Rampulla§, Gregory S.
Martin♯, Stanley R. Krystek§, Ricardo Attar§, Janet
Dell-John§, John D. DiMarco§, David Fairfax♯, Jack
Gougoutas§, Christian L. Holst♯, Andrew Nation§,
Cheryl Rizzo§, Lana M. Rossiter♯, Liang Schweizer§,
Weifang Shan§, Steven Spergel§, Thomas Spires§,
Georgia Cornelius§, Marco Gottardis§, George
Trainor§, Gregory D. Vite§ and Mark E. Salvati§
4
5
6
7
8
9
Figure 1. Known androgen receptor antagonists.
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§Bristol Myers-Squibb Research and Development, P. O. Box
4000, Princeton, NJ 08543
♯Albany Molecular Research Inc., 21 Corporate Circle,
Albany, NY 12203
RECEIVED DATE (will be automatically inserted after
manuscript is accepted).
Previously, we have reported a series of [2.2.1]
carbobicyclic7 and oxabicyclic8 succinimide based AR
antagonists (4 and 5, Figure 1). These compounds
demonstrated potent binding affinity (Ki) and
functional antagonist activity (IC50) against the wild-
type AR as found in the MDA-MB-453 cell-line (Table
1). These compounds compared favorably in terms of
potency to the clinically used antiandrogens
Abstract:
BMS-641988 (23) is a novel, non-steroidal
androgen receptor antagonist designed for the treatment of
prostate cancer. The compound has high binding affinity for
the AR and acts as a functional antagonist in vitro. BMS-
641988 is efficacious in multiple human prostate cancer
xenograft models, including CWR22-BMSLD1 where it
displays superior efficacy relative to bicalutamide. Based on
its promising preclinical profile, BMS-641988 was selected
for clinical development.
hydroxyflutamide (1) and bicalutamide (2).
designed a series of oxabicyclic-based AR antagonists,
such as 5, that demonstrated superior
We
Carcinoma of the prostate (CaP) is the most
common malignancy among men in the US and the 2nd
most common cause of cancer-related death worldwide
after lung cancer.1 The androgen receptor (AR) is a
member of the nuclear hormone superfamily of
ligand-induced transcription factors and is a key
signaling pathway leading to the emergence of CaP.
Androgen ablation, by surgical or chemical castration
in combination with an antiandrogen such as
hydroxyflutamide (1) or bicalutamide (2), has been the
standard of care for advanced CaP for many years.2
This therapy is initially effective in 80-90% of
patients, however >50% of the patients will ultimately
develop castration resistant prostate cancer (CRPC)
a
pharmacokinetic (PK) profile compared to the
carbocycles such as 4. Based on our understanding of
the need for sustained AR supression in an effective
AR antagonist, we expected that robust PK would be
essential for an efficacious AR antagonist.8
Accordingly, compound 5 was shown to be efficacious
in the CWR22-BMSLD1 human prostate cancer
xenograft model, where bicalutamide shows only
limited efficacy.8
We looked to incorporate PK
properties critical for an effective AR antagonist, such
as log T1/2, with a broader activity profile than is seen
with 1st generation agents such as bicalutamide.
Accordingly, we screened out agents against the
human CaP model CWR22, which has been shown to
after ~18 months.3
The treatment of CRPC is
challenging due to the sustained AR signaling, which
is the result of AR overexpression/activation and the
presence of activating AR mutations.4 Furthermore, it
has been reported that CRPC tumors express the
necessary cytochrome P450 enzymes for intratumoral
androgen production, thus by-passing the effects of
chemical castration which targets only gonadal
androgen production.5 These findings suggest that
CRPC remains AR dependent and effective therapies
must target AR signaling directly with improved next-
generation AR antagonists.
be
refractory
to
both
bicalutamide
and
hydroxyflutamide. Based on this result, we wanted to
expand the scope of this series by using a structure-
based approach to identify even more potent AR
antagonists.
Utilizing available X-ray co-crystal structures of the
AR generated at BMS, we developed a molecular
model of the WT AR LBD (Figure 2) to aid in the
indentification of new AR antagonists.9,10 In this
model, interactions of N-705 with both the C-5
hydroxyl and the bridging oxygen of compound 5 are
evident. Additional interactions between R752 and
Q711 and the aryl nitrile functionality of compound 5
MDV3100 (enzalutamide, 3) is a potent AR
antagonist that was recently approved by the US Food
and Drug Administration for the treatment of
metastatic CRPC patients that have progressed post
treatment with docetaxel.6 Although enzalutamide
has shown promise in treating these patients, nearly
all pateints go on to develop resistance to
are also present.
We postulated that endo-
substitution at C-5 or C-6 of the bicycle would result
in a direct interaction with helix-12 (H-12), possibly
creating a more classical AR antagonist conformation,
similar to that predicted for bicalutamide. The key
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Page 2 of 6
hydrogen bonding interaction with N-705 would be
ester of 2,5-dimethyl-3-furoic acid occurred at 120 °C
to give only the desired exo-isomer after
precipitation. Catalytic hydrogenation led to
1
2
3
4
5
6
7
8
maintained by the bridging oxygen as seen with
bicalutamide (2) which is shown in orange. Thus, we
set out to investigate the effect of various
substitutions on the endo-face of [2.2.1]-oxabicyclic
core of compound 5.
9
formation of the endo-ester by selective reduction
from the beta-face of the olefin. Normal-phase chiral
HPLC separation of the racemic endo-ester gave the
desired enantiomer 10 in 45% yield and >99% ee. The
optical isomer depicted by compound 10 was
determined to be optimal for potent AR antagonist
activity and the absolute and relative stereochemistry
was eventually confirmed by X-ray crystallographic
analysis of compound 23.12 Treatment of 10 with 3N
HCl gave the key intermediate acid 11 in good yield.
Compounds 12 and 13 were prepared by standard
ester and amide formation conditions.
The acid 11 was found to have poor potency in our
cellular in vitro assays (Table 1), but the ester 12 and
amide 13 had promising binding and functional
antagonist activity in the MDA-MB-453 cell-line.
Unfortunately, neither the amide nor the ester had
potency that was superior to the exo-hydroxy analog
5, so we investigated additional functionalities on the
oxabicycle in an effort to find highly potent AR
antagonists. The endo-amine 14 could be prepared
Figure 2. Compound 5 docked into a model of the wild-type
AR ligand binding domain.
9
10
11
12
13
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from
the
acid
11
by
sequential
Curtius
rearrangement13 and subsequent TFA-promoted
cleavage of the resulting Teoc-carbamate in 77% yield.
Compound 14 had only modest affinity to the AR, but
Our efforts started with the synthesis of compounds
11-13 by the synthetic route shown in Scheme 1.
Maleimide 8 was prepared from the aniline 6 and
maleic anhydride (7) under standard conditions.11
Diels-Alder cycloaddition between 8 and the MEM
offered
a
good handle with which to further
functionalize the oxa-bicyclic core.
Scheme 1. Synthetic route to endo-substituted bicycles
H3C
O
NH2
H3C
O
CF3
CN
O
O
CF3
CN
H
H
H
b
a
c,d
O
N
O
N
CN
CF3
O
N
MEMO2C
F3C
MEMO2C
H
CH3
O
O
O
CN
O
CH3
10
6
7
8
9
>99% ee
e
H3C
H3C
O
O
CF3
CN
CF3
CN
H
H
H
f or g
O
O
N
N
R
HO2C
H
O
O
O
CH3
12, R = Oi-Pr
CH3
11
13
, R = NCH3Ph
15
COEt
H3C
H3C
h,i
O
H
CF3
CN
16 SO2NHCH3
17 CONHi-Pr
O
CF3
CN
H
H
conditions
O
N
18 CO2(N-CH3-Piperdine)
O
N
R
19 SO2Me
H2N
N
H
H
CH3
O
20
SO2Ph
O
CH3
21 SO2(2-F-Ph)
22 SO2-3-pyridine
23 SO2Et
14
a) HOAc, 110 °C, 88%; b) MEM 2,5-dimethyl-3-furoate, 120 °C, 33%, exo-isomer only; c) H2, Pd/C, EtOAc, 1 atm, 50%; d)
Chiral HPLC separation, 45%, >99% ee; e) 3 N HCl, THF, 22 °C, 98%; f) (COCl)2, DCM then i-PrOH, TEA, 97%; g) EDC,
HOBt, DIEA, N-methylaniline, DMF, 88%; h) 2-trimethylsilylethanol, DPPA, TEA, 4Å MS, 1,4-dioxane, 75 °C, 78%; i) TFA,
CH2Cl2, 22 °C, 99%;
A series of amides, sulfamides, carbamates, ureas
and sulfonamides was prepared from the amine 14 in
library format. Standard coupling techniques were
utilized to prepare analogs 15-23 (see Supporting
Information); the corresponding in vitro biological
data is shown in Table 1. In general, these analogs
were potent binders to, and functional antagonists of,
the wild-type AR present in the MDA-MB-453 cell
line. The amide 15 and the carbamate 18 had
excellent potency in vitro, while the sulfamide 16 and
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urea 17 were weakly active. The sulfonamides 19-23 is very weak (>40 µM) and there is very low potential
1
2
3
4
5
6
7
8
had the best overall in vitro profile, with robust
affinity and potent antagonist activity, superior to
that for bicalutamide (2).
for CYP induction based on the human PXR
transactivation assay. Plasma protein-binding of 23
was measured by equilibrium dialysis and very low
levels of plasma protein binding were observed in all
species (>10% free). Compound 23 demonstrated
excellent metabolic stability in hepatocyte incubations
and the predicted clearance in all species is low,
especially for human. Finally, the PK properties of
compound 23 were assessed in mouse, rat and dog
following both oral and IV doses. Consistent with the
We
pharmacodynamic effects of these novel AR
antagonists in vivo. Compounds 13-23 were
next
wanted
to
investigate
the
progressed into the immature rat prostate weight
(IRPW) PK/PD model, where the compound effect on
AR dependent growth of the prostate and seminal
vesicles was measured (Table 2).14 In this model,
compounds were dosed orally once a day at 1 or 10
mg/kg for 4 days with plasma concentrations of drug
measured 2 hours post-dose on day 4. Agents that
effectively block the proliferative effect of the AR in
these tissues would result in a decrease in the total
weight of organs relative to a control group. As
expected, the amide 13 had poor pharmacodynamic
effect in this model, most likely due to modest
functional antagonist potency. The amide 15 and the
urea 17 gave only modest PD effects even with very
high exposure after 1 and 10 mg/kg doses. This result
correlated with the very high serum protein binding
measured for these two compounds (>99% in mouse
serum). The sulfonamide 16 and the carbamate 18
also had only modest PD effects, but this was most
likely due to poor exposure relative to compound 2.
The sulfonamide series stood out in the IRPW model
by having excellent PD with modest exposure,
suggesting superior in vivo potency compared to the
9
10
11
12
13
14
15
16
17
18
19
20
21
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23
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predicted
hepatic
clearance,
compound
23
demonstrated moderate to long half-lives and very low
clearance across species.
Table 2. Immature rat prostate weight assay results
IRPW
10
mg/kg
SV/FBa
Exposure 1
mg/kg
Exposure
10 mg/kg
(µM)b
IRPW
1 mg/kg
SV/FBa
#
(µM)b
2
69 24
41
4
2.3 0.4
9.5 1.4
13
14
15
16
17
88 19
89 22
87 39
89 5.9
115 3.9
43 8.0
89 8.1
34 6.0
36 4.2
56 8.9
1.8 0.68
0.08 0.02
24 1.7
0.01 0.001
8.3 0.4
12.0 0.82
0.48 0.32
190 73
0.23 0.08
60 6.1
0.012
0.004
0.076
18
105 24
87 16
0.017
19
20
21
22
23
64 13
63 14
56 6.5
44 8.6
58 13
26 4.2
31 5.2
24 1.8
23 11
26 3.0
0.29 0.07
0.23 0.03
0.16 0.02
0.05 0.01
0.79 0.17
4.0 1.2
2.4 0.52
1.9 0.06
0.52 0.09
4.0 0.42
ureas,
amides,
carbamates
and
sulfamides.
aSV/FB is the percentage of weight of the seminal vesicles over
the full body weight of the rat (n=3) where testosterone treated
control = 100% and sham = 10%.
Compounds 19-23 all demonstrated robust PD at a 10
mg/kg dose with exposures significantly less than
observed for bicalutamide.
Of these promising
bPlasma exposure measured 2 hours post-dose on day 4.
analogs, the ethyl sulfonamide 23 was chosen for
further studies due to robust potency in vivo and a
promising PK profile in rats.
Figure 3. In vivo efficacy of compound 23 in the CWR22-
BMSLD1 prostate cancer xenograft model.
Table 1. In vitro biological activity
2000
MDA-MB-
MDA-MB-453 Ki
453 IC50
(nM)b
173
#
2
(nM)a
1500
64
Vehicle
Therapy Switched to
5
8
10
Bicalutamide, 150 mg/kg
BMS-641988
BMS-641988, 90 mg/kg
1000
11
12
13
14
15
16
17
18
19
20
21
22
23
1600
23
50
>5000
22
34
Bicalutamide, 150 mg/kg
BMS-641988, 90 mg/kg
500
0
31
60
3.0
50
31
7.0
12
10
1.0
2.0
1.7
23
34
60
6
15
25
35
45
55
65
75
20
Days post Implant
1.0
10
7.0
16
Compound 23 was then tested in the human
prostate cancer xenograft model CWR22-BMSLD1
(Figure 3).15 Treatment with bicalutamide (2) (150
mg/kg, po, qd x 35 days) resulted in good tumor
growth inhibition for the initial 10 days, followed by
regrowth of the tumor at a rate that was similar to
control. When compound 23 was dosed (90 mg/kg, po,
qd x 45 days) excellent tumor growth inhibition was
observed over the entire dosing period, demonstrating
superior efficacy to bicalutamide (2). Additionally, we
investigated the possibility of treating bicalutamide
aBinding (Ki) determined through direct displacement with
[3H]-DHT in the MDA-MB-453 cell-line
bFunctional antagonist activity (IC50) in the MDA-MB-453
cell-line determined through a transiently transfected reporter
system utilizing the secreted alkaline phosphatase reporter gene
driven by the AR-dependent PSA promoter.
Compound 23 was further profiled to determine in
vitro safety and ADME properties (Table 3).
Inhibition of human cytochrome P450 (CYP) isoforms
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Table 3. Summary of androgen receptor biological data
and ADME properties for compound 23
resistant tumors in this model by allowing the
bicalutamide-treated tumors to triple in size followed
by a switch to treatment with compound 23. As
shown in Figure 3, tumor growth continued for ~10
days after switching to compound 23, followed by
nearly complete tumor growth inhibition for the
remainder of dosing period. We were encouraged by
this result as it gave strong evidence that compound
23 has the potential to treat forms of prostate cancer
resistant to bicalutamide (2).
1
2
3
4
5
6
7
8
Assay
Results
WT AR binding (Ki)
MDA 453 (IC )
1.7 0.56 nM
16 3 nM
153 77 nM
LNCaP (IC50)50
human CYP 1A2, 2B6, 2C8,
2C9, 2D6, 3A4) IC50
PXR-TA EC50
> 40 µM
> 50 μM
0 %
hERG inhibition @ 30 µM
Protein binding (% free):
mouse, rat, dog, human
Rate of metabolism in
hepatocytes: mouse, rat, dog,
monkey, human
9
14.8, 10.6, 16.5, 10.4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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46
47
48
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50
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57
58
59
60
Figure 4. Compound 23 docked into a model of the WT AR
ligand binding domain.
0, 26, 3.0, 1.0, 2.0
(pmol/min/106 cells)
Predicted clearance: mouse,
rat, dog, monkey, human
(mL/min/kg)
0, 16, 1.8, 0.6, 0.8
IV / PO PK: T1/2 (h), CL
(mL/min/kg), AUC0-∞ (µM*h),
%F
Mouse (5 / 10 mg/kg):
Rat (5 / 10 mg/kg):
2.4, 4.5, 39.1/74.1, 94.7
3.7, 6.5, 31.7/40.5, 63.9
21.8, 0.35,
Dog (1 / 2 mg/kg):
102.1/160.2,79
a IC50 values are an average of three experiments.
ACKNOWLEDGMENT
The authors thank Linda
Fleming and the Department of Discovery Synthesis at
Bristol-Myers Squibb for preparation of key intermediates.
We also acknowledge the Departments of Lead Discovery &
Optimization and Discovery Analytical Sciences for ADME
and compound characterization support.
Docking compound 23 into the wild-type AR ligand
binding domain (Figure 4)10 revealed the H-bond from
N-705 to the bridging oxygen is likely intact as
observed for compound 5. To accommodate the endo-
sulfonamide at C-5, F876 must reorient resulting in a
positional shift of Helix-11. This significant shift of
Supporting Information Available: Synthetic procedures
and characterization data for compounds 9-23 and biological
methods. This material is available free of charge via the
Internet at http://pubs.acs.org.
Helix-11 results in
a
change in the overall
architecture of the LBD, potentially giving compound
23 the promising antagonist profile presented here.
Further profiling of compound 23 demonstrated an
acceptable preclinical safety profile both in vitro and
in vivo. This compound was selected for clinical
development and advanced into phase I clinical
trials.15,16
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In summary, we have utilized structure-based
design to identify a new series of amino [2.2.1]-
oxabicyclosuccinimide AR antagonists.
Lead
molecules demonstrated potent antagonist activity in
cellular binding and transactivation assays in vitro
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Compound 23 was shown to be superior to
bicalutamide in the CWR22-BMSLD1 human CaP
tumor xenograft model, and has the potential to
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escalation study of the novel antiandrogen BMSꢀ641988 in patients with
castrationꢀresistant prostate cancer. Clinc. Cancer Res. 2010, 17(4), 880ꢀ887.
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(10) Molecular modeling was performed using ICM software (Molsoft LLC,
San Diego, CA). The docking of the ligands into WT AR LBD was carried out
using the ICM docking procedure which is a two step process. Initial docking
of ligands were carried out using grid potential representation of the receptor
and flexible ligand. Five grid potentials describe the shape, hydrophobicity,
electrostatics, and hydrogen bonding potential of the receptor. The
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conformations from the grid were then optimized with
a full atom
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representation of the receptor and flexible ligand, by an ICM stochastic global
optimization algorithm as implemented in version 2.7 of the Molsoft ICM
program (Refs. a and b). (a) Molsoft (1998) ICM 2.7 Program Manual
(Molsoft, San Diego, CA). (b) M. Totrov and R. Abagyan, Proteins Suppl. 1
(1997), p. 215.
(11) Salvati, M.E.; Balog, A.; Pickering, D.A.; Giese, S.; Fura, A.; Li, W.;
Patel, R.; Hanson, R.L.; Mitt, T.; Roberge, J.; Corte, J.R.; Spergel, S.H.;
Rampulla, R.A.; Misra, r.; Xiao, H.ꢀY. Preparation of fused succinimides as
modulators of nuclear hormone function. WO 20040077605.
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(12) The absolute and relative stereochemistry of compound 23 was confirmed
by singleꢀcrystal xꢀray crystallography. The coordinates have been deposited
in the Cambridge Crystallographic Data Center, #779603.
(13) Smith, P. A. S. Curtius reaction. Org. React. 1946, 3, 337.
(14) Hershberger, L.G.; Shipley, E.G.; Meyer, R.K. Myotrophic activity of 19ꢀ
nortestosterone and other steroids determined by modified levator ani muscle
method. Proc. Soc. Exp. Biol. Med. 1953, 83, 175.
(15) Attar, R. M. ; Kunkel, M. J.; Balog, A.; Cvijic, M. E.; DellꢀJohn, J.;
Rizzo, C. A.; Schweizer, L.; Spires, T. E.; Platero, J. S.; Obermeier, M.; Shan,
W.; Salvati, M. E.; Foster, W. R.; Dinchuk, J.; Chen, S.ꢀJ.; Vite, G.; Kramer,
R.; Gottardis, M. Discovery of BMSꢀ641988, a novel and potent inhibitor of
androgen receptor signaling for the treatment of prostate cancer. Cancer Res.
2009, 69, 6522ꢀ 6529.
(16) Rathkopf, D.; Liu, G.; Carducci, M. A.; Eisenberger, M. A.; Anand, A.;
Morris, M. J.; Slovin, S. F.; Sasaki, Y.; Takahashi, S.; Ozono, S.; Fung, N. K.
E.; Cheng, S.; Gan, J.; Gottardis, M.; Obermeier, M. T.; Reddy, J.; Zhang, S.;
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The Discovery of BMS-641988, a Novel Androgen Receptor Antagonist for the Treatment of Prostate
Cancer
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Aaron Balog§*, Richard Rampulla§, Gregory S. Martin♯, Stanley R. Krystek§, Ricardo Attar§, Janet Dell-
John§, John D. DiMarco§, David Fairfax♯, Jack Gougoutas§, Christian L. Holst♯, Andrew Nation§,
Cheryl Rizzo§, Lana M. Rossiter♯, Liang Schweizer§, Weifang Shan§, Steven Spergel§, Thomas Spires§,
Georgia Cornelius§, Marco Gottardis§, George Trainor§, Gregory D. Vite§ and Mark E. Salvati§
Table of Contents Graphic
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