Novel small molecule guanidine Sigma1 inhibitors for advanced prostate cancer

Article abstract of DOI:10.1016/j.bmcl.2017.03.030

Prostate cancer is the most frequently diagnosed malignancy and the leading cause of cancer related death in men. First line therapy for disseminated disease relies on androgen deprivation, leveraging the addiction of these tumors on androgens for both growth and survival. Treatment typically involves antagonizing the androgen receptor (AR) or blocking the synthesis of androgens. Recurrence is common and within 2–3?years patients develop castration resistant tumors that become unresponsive to AR-axis targeted therapies. In order to provide a more effective treatment, we are utilizing an approach that targets a key scaffolding protein, Sigma1 (also known as sigma-1 receptor), a unique 26-kilodalton integral membrane protein that is critical in stabilizing the AR. Herein we report on a new series of Sigma1 compounds for lead optimization derived from a hybrid pharmacophore approach.

Full text of DOI:10.1016/j.bmcl.2017.03.030

Accepted Manuscript
Novel Small Molecule Guanidine Sigma1 Inhibitors For Advanced Prostate
Cancer
Joseph M. Salvino, Yellamelli V.V. Srikanth, Rongliang Lou, Halley M. Oyer,
Nan Chen, Felix J. Kim
PII:
S0960-894X(17)30267-6
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.03.030
BMCL 24782
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 January 2017
15 March 2017
15 March 2017
Please cite this article as: Salvino, J.M., Srikanth, Y.V.V., Lou, R., Oyer, H.M., Chen, N., Kim, F.J., Novel Small
Molecule Guanidine Sigma1 Inhibitors For Advanced Prostate Cancer, Bioorganic & Medicinal Chemistry
Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.2017.03.030
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Novel Small Molecule Guanidine Sigma1 Inhibitors For Advanced Prostate Cancer
Joseph M. Salvino,a * Yellamelli V.V. Srikanth,a Rongliang Lou,b Halley M. Oyer, a Nan Chen, a
Felix J. Kim,a
a Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N 15th Street
Philadelphia, PA 19102-1101, USA
b AstaTech, Inc., Keystone Business Park, 2525 Pearl Buck Road, Bristol PA, 19007, USA
Keywords: Sigma1; sigma-1 receptor; sigma-1 chaperone; prostate cancer; guanidine; small molecule
inhibitor
Prostate cancer is the most frequently diagnosed malignancy and the leading cause of cancer related death
in men.1It is estimated that 217,000 men in the US will be diagnosed with prostate cancer and up to
32,000 men will die of advanced disease. Early detection of the primary tumor and treatment of localized
disease by radical prostatectomy and/or radiation therapy generally leads to favorable prognostic
outcomes.2 However once the disease disseminates it becomes much more difficult to treat and unlike
other solid tumors, prostatic adenocarcinoma responds poorly to standard chemotherapeutic intervention.3
Thus first line therapy for disseminated disease relies on androgen deprivation, leveraging the addiction
of these tumors on androgens for both growth and survival.3 Treatment typically includes the androgen
receptor (AR) antagonist enzalutamide (Xtandi®)4,5 that directly antagonizes the AR or abiraterone
acetate (Zytiga®), a molecule that blocks the synthesis of androgens.6,7 Despite this chemical castration
approach, recurrence is common and within 2-3 years patients develop castration resistant tumors that
become unresponsive to AR-axis targeted therapies such as enzalutamide and abiraterone.3 At this stage
of the disease, advanced castration resistant prostate cancer (CRPC), the AR in these tumors has adapted
to the stress of treatment resulting in alternative splicing, AR mutation, or over expression of the AR to
overcome treatment regimes.3 In order to provide a more effective treatment for CRPC patients we are
utilizing an approach that targets a key scaffolding protein that is critical in stabilizing the AR.
We are targeting Sigma1 (also known as sigma-1 receptor), a unique 26-kilodalton integral membrane
protein8,9 primarily located in the ER in cancer cells. Sigma1 acts as a chaperone or scaffolding protein
that coordinates the maturation and transport of client proteins critical to the AR axis. Sigma1 is highly
expressed in prostate cancer cells and RNAi-mediated knockdown of Sigma1 results in tumor growth
inhibition.11 Upon profiling known Sigma1 inhibitors for their ability to affect Sigma1 mediated
translational repression10 and ER homeostasis pathways,11 we identified IPAG (1-adamantan-1-yl)-3-(4-
iodophenyl)guanidine) and the anti-psychotic drug, haloperidol, as potent inhibitors of Sigma1-mediated
AR signaling, protein homostasis, as well as inhibitors of cancer cell proliferation and growth.10,11 In an
effort to create new composition of matter for intellectual property protection, and to provide a new series
of Sigma1 compounds for lead optimization, we utilized a hybrid pharmacophore approach to identify
novel Sigma1 compounds.
IPAG12 is a high affinity Sigma1 ligand (Ki = 2.7 nM; [3H]-(+)-pentazocine) based on the 1,3-di-o-
tolylguanidine (DTG) template13,14 and is a valuable probe for studying Sigma1 function. IPAG shows
antiproliferative activity in AR-positive prostate cancer cell lines and cellular activity in the androgen
reporter assay15,16,17 (EC50 AR = 9.7 µM) in a comparable range to the indirect androgen synthesis blocker,
abiraterone (EC50 AR = 17.1 µM), and about 20 fold less potent than the direct androgen receptor
antagonist, enzalutamide (EC50 AR = 0.42 µM).17 However, it is unstable when in solution, and particularly
unstable when exposed to normal fluorescent light due to the aryl iodide functionality. It is also slightly
more lipophilic than desired for optimal drug-like qualities (CLogP = 4.46). Haloperidol, an antipsychotic
neuroleptic drug widely used in the treatment of schizophrenia. It shows high affinity to Sigma1 (Ki =

0.21 nM; [3H]-(+)-pentazocine).18 Cellular activity in the androgen reporter assay was about 2 fold greater
than abiraterone. It has potent affinity for D2 dopamine receptors, as well as affinity at several other
receptors. However, CYP3A4 oxidation of the 4-hydroxyphenyl piperidine moiety of haloperidol results
in the formation of pyridinium metabolites, such as, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-
oxobutyl]pyridinium (HPP+), that have been shown to bind irreversibly to Sigma1 protein,19 and display
neurotoxic properties resembling those of their structural analog MPP+ thus making this functionality
undesirable in a compound moving forward due to its potential toxic liability. For these reasons, and the
desire for novelty we envisioned a hybrid approach to combine the best features of the two potent Sigma1
ligands and create a new series (Fig. 1).
Figure 1. Conceptually, combining the aryl guanidine of IPAG and the side chain of haloperidol provides
a novel series of hybrid analogs with potential to improve on drug-like properties, potency, and
selectivity.
Weber et al20, 21, 22 have identified symmetrically substituted guanidines (i.e. DTG), and further developed
the SAR13 to demonstrate the importance of the aryl guanidine in DTG analogs for Sigma1 activity. We
envisioned elaborating the right hand side chain of a symmetrical di-substituted aryl guanidine by
replacing it with side chains of various Sigma1 ligands, and then using this mix and match approach we
sought to identify new Sigma1 ligands suitable for lead optimization. We also noted that the molecular
volume of the aryl piperidine motif in haloperidol is approximately the same size as the aryl guanidine
motif in IPAG suggesting a hybrid. To synthesize these hybrid analogs we started with the same
chemistry used to expand the aryl guanidine SAR study by Scherz, et al.13 This method (Scheme 1)
provided the desired product, 1, but also a significant amount of the symmetric di-substituted guanidine,
2, that required reverse phase HPLC purification due to the polar nature of the molecules. We used the
equivalent and more metabolically stable aryl ether bioisosteric side chain22 instead of the aryl ketone side
chain in haloperidol for ease of synthesis. Using a similar approach we also made the symmetric di-
substituted guanidine, 2, to confirm the structure and to provide enough material to test both analogs side-
by-side (Scheme 1). In order to improve the yield and ease of synthesis, we attempted the synthesis via
the side chain amino nitrile, unfortunately this only lead to poor yields of the side chain dimer, 3, which
we purified by reverse phase chromatography and tested as an additional compound for potency (Scheme
2).
H
N
H
N
O
NH
F
I
a
H
N
b or c
1
I
NH2
I
N
H
N
H
N
NH
I
I
2
Scheme 1. Reagents and conditions: (a) Cyanogen bromide, THF, DIEA, rt, 48h, 20% (b) 3-(4-
fluorophenoxy)propan-1-amine, chlorobenzene, TsOH, 200 oC (microwave), 40 min., 32% (c) 4-
iodoaniline, chlorobenzene, TsOH, 200 oC (microwave), 40 min., 30%.

H
N
H
N
H
N
O
NH2
O
a
O
N
O
NH
F
F
F
F
3
Scheme 2. Reagents and conditions: (a) Cyanogen bromide, DCM, H2O, NaHCO3, 0 oC to rt, 1h., 10%.
We also utilized the activated thiourea synthesis of guanidines to make the first batch of the 1-(4-
chlorophenyl)-3-(3-(4-fluorophenoxy)propyl)guanidine analog, 4. This route provided product in good
yield, however purification by chromatography was still challenging due to the polar nature of the
guanidine product. Seeking a general method and an improved synthetic route for the unsymmetrical
guanidines we evaluated the "pyrazole guanidine" reagent reported by Bernatowicz24 that was developed
for the synthesis of mono-substituted guanidines or arginine containing peptides. Important advantages of
this method were that the intermediates are N-Boc protected and relatively non-polar so that they can be
more readily purified by normal phase flash chromatography. Using the commercially available bis-boc-
pyrazolocarboxamidine (AstaTech, Inc.; CAS No.: 862686-58-6) we synthesized the alcohol side chain, 23
and then installed it via a Mitsunobu reaction27 to provide the di-N-boc pyrazole guanidine reagent
(Scheme 4; R=H) as a suitable advanced intermediate envisioned for the synthesis of numerous analogs
derived from anilines.
H
N
H
N
H
N
H
N
O
NH2
S
a
b
NH
S
NH
F
Cl
Cl
Cl
4
Scheme 3. Reagents and conditions: (a) Methyl iodide, acetone, reflux, 1h., 83% (b) 3-(4-
fluorophenoxy)propan-1-amine, ethanol, reflux, 12h., 78%.
This methodology also provided a facile means to incorporate various alcohol side chains in high yield.
Although this worked satisfactorily on a small scale, scale up to multigram level was still difficult
because of the poor nucleophilicity of the anilines used to generate the aryl guanidine analogs. In
addition, when heating was used in order to drive the reactions to completion typically one of the N-Boc
protecting groups was lost, making purification difficult. Thus a further improvement of the synthesis was
found using the more electrophilic variant,25,26 4-nitro-1H-pyrazole-1-N,N'-bis(tert-
butoxycarbonyl)carboxamidine (Scheme 4; R=NO2). This more reactive guanidylating reagent provided a
facile method for analog synthesis. Importantly the reactions proceeded to completion at ambient
temperature without loss of the N-Boc protection. This method was then successfully utilized to
synthesize key analogs for SAR purposes and for multigram scale synthesis for further profiling and in
vivo efficacy studies.
H
N
H
N
O
R
N
N
Boc
N
NH
X
R
b, c
a
O
F
N
N
N
1
X = I;
X = Cl; 4
N
F
Boc
HN
X = MeO; 5
X =CF3; 6
Boc Boc
R = H or NO2
Scheme 4. Reagents and conditions: (a) DIAD, Ph3P, THF, 3-(4-fluorophenoxy)propan-1-ol, 0 oC to rt,
18h, 61%. (b) The corresponding aniline, anhyd. MeOH, Et3N, 24-36 h., 86%. (c) DCM, 4N HCl in
dioxane, 0 oC to rt, 18-24 h., 92 %.

In vitro radio-ligand binding assays using membranes from MDA-MB-468 cancer cells, which express
Sigma111, 28, 29 provided confirmation of Sigma1 binding affinity for our new hybrid analogs compared to
IPAG and haloperidol (Table 1). The hybrids 1, 4, 5, 6 all demonstrated reasonable affinity to Sigma1
with about a 5-10 fold decrease in binding affinity compared to IPAG. Notably the dimer 3 had no
affinity for Sigma1. The di-aryl dimer 2 maintained binding affinity similar to IPAG.
Table1. Sigma1 affinity, AR report assay activity, andcalculated LogP of haloperidol , IPAG, and new
hybrid sigma ligands
EC50AR (µM)c
Structure
ID
Ki(nM)a
CLog P
27.05
Haloperidol
0.21
3.85
9.75
IPAG
2.76
4.46
NAd
NAd
1
2
46.08
3.0b
4.50
4.25
> 1000b
38.00
4.55
4.09
NAd
3
4
H
H
N
N
O
12.68
NH
Cl
F
28.13
NAd
5
6
13.36
43.32
3.30
4.26
a Ki values represent duplicate or triplicate determinationsagainst [3H]-(+)-pentazocine . b Ki determined against [125I]-IPAG. c AR
reporter assay EC50 values represent the average of duplicate or triplicate independent determinations. d Not available
We also noted that the aryl iodides 1 and 2 showed a photo-stability issue similar to IPAG. Evaluation of
IPAG, 1, 4, and 5 in a cell viability assay (Cell Titer Glo; MDA-MB-468 cells) demonstrated that the new
analogs were not acutely cytotoxic, and showed antiproliferative activity with potencies in the 3-20 µM
range. We further profiled analogs 1, 4, and 5, for plasma protein binding, plasma stability, liver
microsome stability, and water solubility (Table 2).
In vitro ADME properties of new hybrid analogs
Table 2.
% Plasma protein
Liver microsome
stability (min)
ID
binding
Plasma Stability
Water solubility
PBS buffer
pH 7.4 (mg/mL)
mouse
human
mouse
human
mouse
human
1
4
97.9
88.8
96.6
93.4
> 6 h
> 6 h
> 6 h
> 6 h
24.6
24.8
>90
>90
5.37
4.58

5
82.1
75.1
> 6 h
> 6 h
7.0
23.2
8.45
In vitro profiling suggests that the new hybrid series has good drug-like properties with regards to in vitro
ADME. The compounds show modest plasma protein binding with compound 4 and 5 below 95%. The
compounds are stable in mouse and human plasma. Mouse liver microsome stability for compounds 1 and
4 is acceptable in the mouse and very good in human. Compound 5, the 4-methoxy aryl analog, is most
likely being degraded due to dealkylation of the methoxy group, or oxidative metabolism of the electron
rich aromatic ring. Water solubility for these analogs is very good. We further evaluated compound 4 for
plasma and brain exposure in the mouse, as well as oral bioavailability at two different oral doses for an
initial evaluation of escalating dose linearity (Table 3).
Table 3. Mouse pharmacokinetic exposure of compound 4
A. Levels of compound 4 in Male Swiss Mice
10 mg/kg, 5 mL/kg, IP
Cmax, ng/mL
Plasma (ng/ mL)
Brain (ng/g)
141 (438.18 nM)
691 (2,147.4 nM)
Tmax,
h
0.25
161
166
1.1
0.25
829
856
1.1
AUC0-t, ng*h/mL
AUC0-¥, ng*h/mL
t1/2, h
Mean, n=3 per time point
B. Plasma levels of compound 4 in Male Swiss Mice
2 mg/kg IV 2 mg/kg IV
10 mg/kg Oral
30 mg/kg Oral
t1/2, h
Cmax, ng/mL
Tmax,
1.4
67
1.8
53
98 (304.5 nM)
217 (674.3 nM)
AUC0-t, ng*h/mL
AUC0-¥, ng*h/mL
h
0.25
119
141
>3
1.00
414
480
>3
AUC0-t, ng*h/mL
AUC0-¥, ng*h/mL
t1/2, h
71
57
57.6
469
91.0
586
V, L/kg
CL, mL/min/kg
Mean, n=3 per time
point
Data set 2
Data set 1
Bioavailability, % 40
56
The mouse PK study shows that compound 4 has good plasma exposure in the 400 nM range by the IP
route of administration at this 10 mg/kg dose and has a brain: plasma ratio of about 5 showing this
compound has good brain exposure of about 2 µM at this dose (Table 3A). The dose escalation by the
oral route of administration (Table 3B) from a 10 mg/kg dose to the 30 mg/kg dose is showing less than a
3-fold escalation. This could be due to the relatively high volume of distribution, suggestive of tissue
accumulation. The five-fold increase in brain levels versus plasma levels (Table 3A) also suggests this
tendency for high tissue distribution. Compound 4 is also showing a high clearance from plasma, that
could be due to the compound's tendency to accumulate in tissue rather than poor stability, because of the
relatively good mouse liver microsome stability. The compound is showing good oral bioavailability, and
thus overall, this appears like a reasonable pre-clinical lead for further optimization.
Finally we evaluated compound 4 in the CEREP safety screen 44 panel.30 This panel is a good cost
effective compilation of targets for off-target profiling to identify undesirable off-target activities that
may hinder or halt development of a compound. In summary we observed only six off target activities out

of the 44 that were greater than 50% at a 1 µM concentration, suggestive of a highly selective series. We
then evaluated IPAG and compounds 1, 4,and 5 for hERG binding (performed at Reaction Biology
Corporation, Malvern, PA) and hERG functional Patch clamp inhibition (QPatch; performed at Eurofins
Panlabs, Inc., St. Charles, MO).
Table 4. hERG binding and QPatch functional inhibition
ID
hERG Inhibition (IC50 nM)
Binding
QPatch
491.4
109.1
216.0
416.80
2600
NAa
IPAG
1
4
430.0
NAa
5
a
Not Available
We found modest hERG binding, and modest inhibition of hERG functional activity, which will be
addressed in lead optimization. In conclusion, compound 4 provides an interesting new chemotype for
lead optimization based on its modest off-target activity, affinity at Sigma1, high plasma exposure in the
mouse. Due to its relatively clean off target profile and good in vivo exposure, compound 4 is a useful
tool compound for use in future studies to validate sigma for in vivo efficacy in mouse models of CRPC.
We are actively improving this compound series to improve potency, off-target selectivity, and
pharmacokinetic exposure and will report on these activities in the future.
Acknowledgments
This work was funded by an American Cancer Society Institutional Research Grant, Drexel University
Clinical and Translational Research Institute Grant, Drexel University College of Medicine Professional
Enrichment Grant, Sidney Kimmel Cancer Center Consortium Pilot Study Award to FJK, and a Coulter-
Drexel Translational Research Partnership Program Award (FJK/JMS). JMS would like to thank Mr.
Martin Lehr and Professor James E. Barrett for resources and helpful discussions.
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