Reducing ion channel activity in a series of 4-heterocyclic arylamide FMS inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.05.013

During efforts to improve the bioavailability of FMS kinase inhibitors 1 and 2, a series of saturated and aromatic 4-heterocycles of reduced basicity were prepared and evaluated in an attempt to also improve the cardiovascular safety profile over lead ary

Full text of DOI:10.1016/j.bmcl.2010.05.013

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3925–3929
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Reducing ion channel activity in a series of 4-heterocyclic arylamide FMS
inhibitors
*
Kenneth J. Wilson , Carl R. Illig, Jinsheng Chen, Mark J. Wall, Shelley K. Ballentine, Renee L. DesJarlais,
Yanmin Chen, Carsten Schubert, Robert Donatelli, Ioanna Petrounia, Carl S. Crysler, Christopher J. Molloy,
Margery A. Chaikin, Carl L. Manthey, Mark R. Player, Bruce E. Tomczuk, Sanath K. Meegalla
Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, PA 19477, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
During efforts to improve the bioavailability of FMS kinase inhibitors 1 and 2, a series of saturated and
aromatic 4-heterocycles of reduced basicity were prepared and evaluated in an attempt to also improve
the cardiovascular safety profile over lead arylamide 1, which possessed ion channel activity. The resul-
tant compounds retained excellent potency and exhibited diminished ion channel activity.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 25 March 2010
Revised 4 May 2010
Accepted 7 May 2010
Available online 12 May 2010
Keywords:
FMS
CSF-1R
M-CSF
Colony stimulating factor-1
Macrophages
Anti-inflammatory activity
Colony stimulating factor-1 (CSF-1 or macrophage colony stim-
ulating factor-1, M-CSF) binds to the CSF-1 receptor (FMS) on the
cell surface of the monocyte/macrophage lineage, thus controlling
their growth and differentiation.1 Increased numbers of macro-
phages within a variety of human tissues portend a link to other
types of disease progressions such as cancer,2 rheumatoid arthri-
tis3 and immune nephritis.4 In addition, osteoclasts, whose forma-
tion requires the presence of receptor activator of nuclear factor
ligand jB (RANK) and CSF-1, mediate bone erosions leading to pain
and fracture in metastatic bone disease and osteoporosis as well as
deformity in rheumatoid arthritis.
Figure 1. Piperidinyl 4-arylamides
compound binding at 10 M.
1
and 2. aPercent inhibition of reference
l
The inhibition of CSF-1 for treating diseases such as rheumatoid
arthritis and metastatic cancer of the bone, where osteoclasts and
macrophages are pathogenic, is supported by biological studies
conducted with CSF-1-deficient mice.5 As a result, considerable ef-
fort continues to be invested in the discovery and optimization of a
variety of structural classes of FMS small molecule inhibitors.6,7
In contrast, it is noteworthy that recombinant CSF-1 (Lanimo-
stim/MacroTac™) is used clinically in bone marrow transplanta-
tion patients who suffer from fungal and bacterial infections due
to the lack of myeloid cells.8
were discovered6a,b using ThermofluorÒ screening technology and
whose potencies were optimized utilizing structure-based design.
6c,f As these compounds were further scrutinized it was found that
both 1 and 2 had poor bioavailability (F = 12% and 15%, respec-
tively) while 1 had a very high volume of distribution in mice
(32 L/kg). Furthermore, both 1 and 2 had activity in sodium and
calcium ion channel binding assays, which may foreshadow unde-
sired cardiovascular effects.9,10 It was found that both of these
compounds had poor cardiovascular safety profiles in the guinea
pig right atrium (GPRA) assay (Table 1).11 The compounds result
in a moderate (at the lowest concentration) to a very strong (at
the highest concentration) reduction in both the rate and force of
Previous Letters6 detailed the genesis of the potent CSF-1 inhib-
itors 1 and 2 (Fig. 1) in the arylamide series from initial leads that
* Corresponding author. Tel.: +1 215 628 7911; fax +1 215 540 4616.
E-mail address: kwilso10@its.jnj.com (K.J. Wilson).
contraction. For example, 1 at 10 lM resulted in a severe reduction
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.05.013

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K. J. Wilson et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3925–3929
Table 1
Guinea pig right atrium assay results for 1 and 2
Compound
Rate of contraction (% of initial value)
Force of contraction (% of initial value)
1
l
M
3
l
M
10
l
M
1
l
M
3
lM
10 lM
1
2
84.9
92.1
95–103
54.6
86.3
93–106
23.2
37.6
94–110
76.4
79.4
80–95
40.0
65.3
68–91
21.0
42.1
61–90
95%PIa
a
The 95% prediction interval is the expected range of values for the control in the presence of solvent.
in the force of contraction to only 21% of the values measured in
the baseline period of the experiment.
Having reported on the X-ray crystallography and structure-
based design of this class of compounds6c,f it was evident that
the 4-position of the scaffold was a permissive region for substitu-
tion (Fig. 1). Thus, given the range of substituents allowable, a
series of saturated and unsaturated six-membered, nitrogen-
containing heterocycles were prepared to improve both the
pharmacokinetic properties and cardiovascular safety profile of
the arylamides.
Based on the cardiovascular properties of 1 and 2, less-basic and
non-basic non-piperidine-containing compounds were targeted on
the premise that this would lead to decreased sodium9 and cal-
cium10 ion channel activity and possibly reduced cardiovascular
safety liability. Recognizing that complete loss of basicity could
negatively impact the solubility of these analogues, compounds
of reduced basicity were prioritized.
First prepared were pyridines and non-basic aromatic groups,
such as pyridine N-oxides and substituted aryls, as surrogates for
the 4-piperidyl ring found in 1 and 2, the introduction of which
necessitated three strategically different approaches. It was found
that 5a was best prepared by introducing the pyridyl-N-oxide moi-
ety early in the synthesis (Scheme 1). All attempts to introduce this
regioisomer at a later stage in the synthesis (Scheme 2) resulted in
very poor yields. The other regioisomeric N-oxo-pyridines 5b and
5c were prepared using the methodology shown in Scheme 2, by
coupling the boronate 10 with 3-bromo- and 2-bromo-pyridine
N-oxides, respectively. The pyridines 6a–c were synthesized via
Fe reduction of their corresponding N-oxides. Amino and meth-
oxy-substituted pyridines 6d, e were prepared by the Suzuki cou-
pling reaction using the requisite chloro- or bromopyridine and
substrate 10. The aryl derivatives 11a–c were easily prepared by
Scheme 2. Reagents and conditions: (a) cyclohexen-1-yl boronic acid or 4,4-
dimethylcyclohexen-1-yl boronic acid, Pd(PPh3)4, toluene, EtOH, 2 M Na2CO3, 80 °C;
(b) potassium-4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-car-
boxylate, PyBrOP, DIEA, CH2Cl2; (c) for 11a: 4-(N,N-dimethylsulfonamido)-boronic
acid, Pd(PPh3)4, toluene/EtOH, 2 M Na2CO3, 80 °C; for 11b: 4-aminophenylboronic
acid, Pd(PPh3)4, toluene/EtOH, 2 M Na2CO3, 80 °C; for 11c: phenylboronic acid,
Pd(PPh3)4, toluene/EtOH, 2 M Na2CO3, 80 °C; (d) TFA, CH2Cl2; (e) for N-oxide
reduction of 5b, c to 6b, c: Fe, NH4Cl, EtOH–water; (f) bis(neopentylglycolato)-
diboron, Pd(dppf)Cl2, KOAc, dioxane, 80 °C; (g) for 5b, c: 3- or 2-bromopyridyl-N-
oxide respectively, Pd(PPh3)4, dioxane, 2 M Na2CO3, 80 °C; for 6d: 5-bromo-2-
aminopyridine, 2 M Na2CO3, dioxane 80 °C; for 6e: 5-bromo-2-methoxypyridine,
2 M Na2CO3, dioxane 80 °C.
Suzuki coupling using the requisite boronic ester and bromide 9,
followed by TFA-promoted SEM deprotection (Scheme 2).
With the pyridyl derivatives 5 and 6 and the aryl derivatives 11
in hand, their respective binding activities were evaluated in an
in vitro FMS kinase assay and a cell-based, bone marrow-derived
macrophage proliferation (BMDM) FMS activity assay (Table 2).6d
As X-ray structures had predicted, excellent in vitro activity in
the FMS kinase assay was retained by 5a and 6a. This is not sur-
prising, in that the placement of the nitrogen in the rings mimics
1 and 2. Indeed, all of the pyridyl derivatives (5a–c and 6a–c)
were well tolerated as the N-oxo-pyridyl compounds 5b, c and
pyridines 6b, c also had single digit activity in the FMS kinase
inhibitory assay.
The amino-substituted pyridine 6d also retained good FMS
inhibitory activity. Because the 4-methoxy analogue 6e had the
poorest FMS inhibitory activity of all the pyridyl compounds, fur-
ther testing was not warranted. Unsubstituted phenyl 11c lost
activity (>60 nM), while sulfonamide 11a and amine 11b were
modestly potent (20 and 23 nM, respectively). Despite most of
the aryl derivatives having good FMS IC50 values (except 11c), only
5a and 6a had good cellular activity. Unfortunately 6a (a potential
Scheme 1. Reagents and conditions: (a) 4-aminophenyl boronic acid, Pd(PPh3)4,
toluene/EtOH, 2 M Na2CO3, 80 °C; (b) NBS, CH2Cl2; (c) cyclohexen-1-yl-boronic acid,
Pd(PPh3)4, toluene/EtOH, 2 M Na2CO3, 80 °C; (d) potassium-4-cyano-1-(2-trimeth-
ylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate6c, PyBrOP, DIEA, CH2Cl2; (e)
TFA, CH2Cl2; (f) Fe, NH4Cl, EtOH, water.

K. J. Wilson et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3925–3929
3927
Table 2
Biological activities of 4-aryl/pyridyl imidazoyl amides
Compound
R1
R2
FMS
(nM)
BMDM IC50
(nM)
Ca+2/Na+a
(%)
5a
6a
H
H
1.5
4.5
6.6
n.d.b
9.2
12/25
5b
H
1.4
26.7
15/18
6b
5c
6c
6d
H
H
H
H
2.3
7.1
11
15.5
131
>100
65
13/27
n.d.
12/25
n.d.
4.5
6e
Me 41
n.d.
23
n.d.
n.d.
11a
H
20
11b
11c
H
H
23
66
n.d.
n.d.
>60
n.d.
a
Percent inhibition of reference compound binding at 10
Not determined.
lM.
b
metabolite of 5a) also displayed strong cytochrome P450 inhibition
(2C9 IC50 = 3 nM, 3A4 IC50 = 87 nM)—a potential liability for both
compounds.
Nevertheless, the pyridines 6a–c and the N-oxide 5b were eval-
uated for ion channel activity. All four compounds had significantly
lower Ca channel binding compared to lead compounds 1 and 2,
and equal or lower Na channel binding, thereby supporting the
hypothesis that by lowering the basicity of the arylamides, their
ion channel liability could be reduced.
Attention was then focused on the preparation of saturated
nitrogen-containing heterocycles which retain more of the lipo-
philic character of the piperidine rings in 1 and 2. The series of het-
erocycles 19 were made according to the synthesis outlined in
Scheme 3. A variety of heterocycles could be prepared from the
commercially available scaffolds 12 and 13. These included glutari-
mides 19a–c (from 12), cyclic ureas 19d–g (from 13), and cyclic
sulfonyl ureas 19h, i (from 18).12 The cyclohexenyl rings (R2 = H
or Me) in the compound series 15, 17, and 18 were introduced
using Suzuki coupling. Unlike series 17, which could be prepared
using standard aqueous Suzuki conditions, substrates 15 and 18
were synthesized using Buchwald’s non-aqueous Suzuki condi-
tions after ortho bromination of their respective precursor
amines.13 The hydrolytic propensity of the aforementioned glutari-
mide and sulfonyl ureas compounds also mandated different
deprotection conditions to remove the SEM group. Instead of using
Scheme 3. Synthesis of saturated heterocyclic arylamides. Reagents and condi-
tions: (a) HNO3/H2SO4 (for 16 use 13, for 14 use 12; (b) Ac2O, heat; (c) R-NH2; (d)
Pd–C/H2, MeOH; (e) NBS, CH2Cl2; (f) cyclohexen-1-yl boronic acid pinacol ester,
Pd(OAc)2, K3PO4, dicyclohexyl-biphenylphosphine, toluene/dioxane; (g) potassium-
4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate,
PyB-
rOP, DIEA, CH2Cl2; (h) TFA, CH2Cl2; (i) BOC2O; (j) MsCl, NEt3, then NaN3; Pd–C/H2,
one step; (k) (1) bis-4-nitrophenylcarbonate, DCE, reflux; (2) for 17 (R1 = methyl):
K2CO3, MeI, DMF, heat or K2CO3, NBu4Br, Me2SO4, DCE; (l) cyclohexen-1-yl boronic
acid pinacol ester or 4,4-dimethyl-cyclohexen-1-yl boronic acid pinacol ester or, for
19g, cyclohepten-1-yl boronic acid, Pd(PPh3)4, toluene, EtOH; (m) (1) sulfamide,
pyridine, reflux; (2) For 18 (R1 = methyl): K2CO3, NBu4Br, Me2SO4, DCE; (n) TBAF,
DMF, 60 °C.
our standard SEM deprotection conditions (TFA, CH2Cl2), 19a–c
and 19h, i were deprotected using TBAF in DMF with mild heating.
Both deprotection methods generally gave >80% yields from their
respective substrates.
To complete the set of targeted heterocycles, the cyclic cyano-
guanidines 21a–c were prepared using the diol 13 (Scheme 4).
Alkylation was performed after amide formation for the N-alkyl-
ated derivative 21b, in contrast to the saturated heterocycles
19e–g, i which were alkylated prior to amide coupling (see 17
and 18).

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K. J. Wilson et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3925–3929
Table 3
Biological activities of nitrogen-containing saturated heterocycles
Compound
R1
R2
FMS
IC50
BMDM Ca+2
IC50
/
Metabolicb
stability
Na+a
(nM)
(nM)
(%)
HLM/RLM
19a
19b
H
1.0
ꢀ5.9
0/11
87/67
65/46
Scheme 4. Synthesis of 4-substituted cyclic ureas. Reagents and conditions: (a)
HNO3/H2SO4; (b) AcO2, pyridine; (c) Pd–C, H2; (d) (i) NBS; (ii) CH2Cl2, cyclohexen-1-
yl boronic acid pinacol ester, Pd(PPh3)4, toluene, EtOH, 2 M Na2CO3; (e) 2 M NaOH,
iPrOH; (f) MsCl, NEt3, then NaN3; Zn, NH4Cl; (g) potassium-4-cyano-1-(2-trimeth-
ylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate, PyBrOP, DIEA, CH2Cl2; (h) (i)
dimethyl-N-cyanodithioiminocarbonate, CH2Cl2, reflux; (ii) K2CO3, (n-Bu)4NBr,
methyl iodide, DCE; (i) N-(bis-methylsulfanyl-methylene)-methanesulfonamide,
DCE, reflux; (j) TFA, CH2Cl2.
c
Me 0.8
7
n.d.
<10/
<10
19c
19d
H
H
0.5
2.3
3.6
75
18/49
87/78
n.d.
Remarkably, 19a–i and 21a–c all possessed FMS inhibitory IC50
values of less than 3 nM, with many in the set having picomolar
activities (Table 3). It is noteworthy that the three compounds
19b, 19f, and 21b where R2 = Me are especially potent. This is con-
sistent with prior observations gleaned through X-ray crystallogra-
phy that this space is well-suited to fit 1–2 Me groups at this
position.6c A cycloheptenyl group is also well tolerated (19g).
Excellent activities were also observed in the cellular assay,
with eight of the thirteen compounds having single digit nanomo-
lar activity. Upon examination of the BMDM assay results of com-
pound sets 19 and 21, it is clear that the compounds having two
exchangeable hydrogens (19d, 19h, 21a, 21c) have poor cellular
activity. Replacing these hydrogens with methyl groups (19d to
19e and 19h to 19i) restored single digit nanomolar potency,
although this trend did not extend to the cyano-guanidines 21a
and 21b.
Five compounds (19a, c, e, f, i) were then selected for the cal-
cium and sodium channel binding assay. Consistent with the
hypothesis regarding the effects of basicity or the presence of a
piperidine ring in this region on ion channel binding, low values
of binding inhibition were observed with the exception of 19e
(60% Na channel binding). With five candidates to choose from,
19c, e, f were eliminated from further consideration due to meta-
bolic instability. Finally, 19a, despite its apparent in vitro metabolic
stability, was eliminated due to chemical instability during
formulation.
21/
60
19e
19f
H
0.5
2.2
2.6
4/40
20/
30
Me ꢀ0.3
19/27
19g
19h
19i
Hd
H
0.9
2.9
1.7
4.3
47
n.d.
n.d.
0/38
2/27
92/85
58/80
H
3.6
21a
21b
H
2.5
42
40
n.d.
n.d.
88/100
n.d.
Me 0.4
The pharmacokinetic behavior of compound 19i was then as-
sessed in rat.14 Plasma concentrations reached a mean Cmax of
839 ng/ml. The compound showed a low volume of distribution
of 564 ml/kg (compared to rat total body water volume of
668 ml/kg), and low clearance (4 ml/min/kg, compared to the
rat liver blood flow rate of 55 ml/min/kg). This compound had a
measured half-life of 113 min after iv administration. Unfortu-
nately, the mean bioavailability (F = 15%) was unimproved over
1 and 2.
21c
H
1.9
100
n.d.
93/98
a
b
c
Percent inhibition of reference compound binding at 10
Microsomal stability percent remaining at 10 min.
Not determined.
lM.
d
19g possesses a cyclohepten-1-yl group instead of a cyclohexen-1-yl group.
Thus, utilizing our previous knowledge of the FMS binding site,
we were able to replace the piperidine ring in 1 and 2 with a series
of less-basic and nonbasic heterocycles which maintain a low po-
tential for undesired cardiovascular effects as a result of their re-
duced ion channel binding inhibition. Although improvements in
the bioavailability of these compounds were not attained, they
were consistently very potent in both kinase and cell assays. Com-
pound 19b modeled into the FMS binding pocket clearly demon-
strates the spatial allowance of groups that can be substituted
for the piperidine ring in 1 and 2 (Fig. 2). Further exploration of
the SAR in this region will be reported in due course.

K. J. Wilson et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3925–3929
3929
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Figure 2. Compound 19b bound to FMS binding site.
Acknowledgments
The author would like to thank Bruce Damiano, An Herman
(GPRA assay), and Michael Kolpak (analytical).
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