The design and synthesis of novel, potent and orally bioavailable N-aryl piperazine-1-carboxamide CCR2 antagonists with very high hERG selectivity

Article abstract of DOI:10.1016/j.bmcl.2012.04.118

A novel N-aryl piperazine-1-carboxamide series of human CCR2 chemokine receptor antagonists was discovered. Early analogues were potent at CCR2 but also inhibited the hERG cardiac ion channel. Structural modifications which decreased lipophilicity and basicity resulted in the identification of a sub-series with an improved margin over hERG. The pharmacological and pharmacokinetic properties of the lead compound from this series, N-(3,4-dichlorophenyl)-4-[(2R)-4-isopropylpiperazine-2-carbonyl] piperazine-1-carboxamide, are described.

Full text of DOI:10.1016/j.bmcl.2012.04.118

Bioorganic & Medicinal Chemistry Letters 22 (2012) 3895–3899
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The design and synthesis of novel, potent and orally bioavailable N-aryl
piperazine-1-carboxamide CCR2 antagonists with very high hERG selectivity
John G. Cumming , Justin F. Bower , David Waterson à, Alan Faull, Philip J. Poyser, Paul Turner,
⇑
Benjamin McDermott, Andrew D. Campbell, Julian Hudson, Michael James, Jon Winter,
Christine Wood
Respiratory and Inflammation Research Area, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel N-aryl piperazine-1-carboxamide series of human CCR2 chemokine receptor antagonists was dis-
covered. Early analogues were potent at CCR2 but also inhibited the hERG cardiac ion channel. Structural
modifications which decreased lipophilicity and basicity resulted in the identification of a sub-series with
an improved margin over hERG. The pharmacological and pharmacokinetic properties of the lead com-
pound from this series, N-(3,4-dichlorophenyl)-4-[(2R)-4-isopropylpiperazine-2-carbonyl]piperazine-1-
carboxamide, are described.
Received 23 March 2012
Revised 25 April 2012
Accepted 27 April 2012
Available online 2 May 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
CCR2 antagonists
Chemokine receptor
hERG
CCL2, commonly known as MCP-1 (monocyte chemoattractant
protein-1), is a member of the CC chemokine family and plays a
key role in the recruitment of monocytes and other cell types in
various physiological and pathological processes.1 CCR2 is the only
known high affinity receptor for MCP-1 and is expressed on mono-
cytes, activated T-cells, dendritic cells, basophils, NK cells and
microglia cells.2 Early evidence of a key role for the MCP-1-CCR2
system in inflammatory diseases such as rheumatoid arthritis,
multiple sclerosis and atherosclerosis led to a widespread effort
to discover and develop small molecule CCR2 antagonists.3–5,6a
Ongoing studies using CCR2 and MCP-1 knockout mice and CCR2
antagonists have provided evidence of a role for this system in
metabolic disease,6 fibrosis, pain,7 COPD8 and even cancer,3a add-
ing further stimulus to the search for clinical candidates.
high degree of selectivity together with favourable physicochemi-
cal properties and scope for structural modification made this an
attractive starting point for drug discovery. Our exploration of
the SAR started with varying the terminal piperidine substituent.
Compounds9 were tested for their ability to inhibit binding of
MCP-1 to CCR2 expressed in THP-1 cell membranes using SPA
and to antagonise an MCP-1-induced calcium flux mediated by
CCR2 natively expressed in THP-1 cells using FLIPR technology.10
Since compound 1 was found to inhibit the hERG cardiac ion
channel this activity was also evaluated.11 The results are shown
in Table 1.
Cl
O
N
N
Cl
H
Our CCR2 antagonist programme began with the identification
of compound 1 during the screening of a large library designed
around a number of general GPCR ligand motifs. 1 was found to
displace 125I-labelled MCP-1 from HEK cell membranes expressing
N
1
N
human CCR2 with a Ki of 0.40
lM, and showed <50% binding at
10
lM to any of the other 45 GPCRs in the screening panel. This
Removal of the terminal piperidine methyl substituent reduced
CCR2 activity (racemic 2a) whereas increasing the size of the sub-
stituent to ethyl (rac-2b) gave a small increase in activity. Testing
of the two enantiomers of 2b revealed that the (R) absolute config-
uration is favoured (2b is 30-fold more active than ent-2b). Subse-
quent compounds were therefore prepared with the (R) absolute
configuration. Introduction of a phenyl ring onto the alkyl group
increased potency (2c, 2e, 2f) with the optimal ‘spacer’ being two
⇑
Corresponding author.
E-mail address: john.cumming@astrazeneca.com (J.G. Cumming).
Present address: The Beatson Institute for Cancer Research, Switchback Road,
Bearsden, Glasgow G61 1BD, UK.
à
Present address: Medicines for Malaria Venture, 20, rte de Pré-Bois 1215, Geneva
15, Switzerland.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.04.118

3896
J. G. Cumming et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3895–3899
Table 1
CCR2 binding, Ca2+ flux and hERG binding data for selected compounds
Cl
Cl
O
N
N
H
N
N
2
R
CCR2 binding IC50 (nM)a
CCR2 Ca2+ flux IC50 (nM)
hERG binding IC50 (lM)
a
a
Compd
R
1
Me
H
Et
Et
170
780
123
37
1184
99
52
5
64
10
965
950
627
174
nt
244
161
42
1.6
1.6
4.3
2.1
rac-2a
rac-2b
2b
ent-2b
2c
2d
2e
2f
2g
Et
nt
CH2Ph
CH2c-Pr
CH2CH2Ph
(CH2)3Ph
c-Pr
0.56
0.93
<0.3
0.40
2.0
280
64
2h
i-Pr
16
58
1.3
a
IC50s were derived from triplicate measurements whose standard errors were normally <5% in a given assay. Assay to assay variability was within twofold based on the
results of a standard compound. nt = not tested.
Figure 2. Plot of hERG binding against calculated logP for 2 and 3.
Figure 1. Plot of CCR2 binding against calculated logP for 2 and 3.
methylenes (2e). Replacing this phenyl with cyclopropyl also gave
good activity (2d) but the N-cyclopropyl (2g) and N-isopropyl (2h)
analogues were almost as potent as the best phenyl containing
compound 2e. Both CCR2 and hERG binding activity increased with
increasing calculated logP (see Figs. 1 and 2). The two outliers in
Fig. 1 with the poorest ligand lipophilicity efficiency (LLE) are 2c
and 2f. The cyclopropyl analogue 2g had the highest CCR2 ligand
lipophilicity efficiency (LLE) and therefore gave the best separation
between hERG and CCR2b activity. The cyclopropyl substituent
was then fixed while the aryl substitution at the far end of the mol-
ecule was explored with a view to improving potency and/or LLE.
The results are shown in Table 2.
one with trifluoromethyl (3i, 3j) or bromo (3g) gave compounds
with reduced potency. Unsubstituted phenyl (3o) or polar substit-
uents such as methoxy (3h), cyano (3k, 3l) or methylsulfonyl (3n)
reduced or abolished activity. Ortho substitution appeared to be
deleterious since the 2-chloro analogue 3m was inactive. The addi-
tion of a methyl group on the urea NH also abolished activity (re-
sults not shown). Both CCR2 and hERG activity broadly correlated
with lipophilicity for 3 as well as 2 (Figs. 1 and 2). None of the com-
pounds achieved a tenfold increase in the separation between
CCR2 and hERG affinities relative to the original 3,4-dichlorophenyl
analogue 2g.
2g was profiled for ADME properties. It had good aqueous solu-
Changes such as one chloro to fluoro (3a), methyl (3d) or tri-
fluoromethyl (3b, 3c) retained most of the activity, while removing
one of the two chlorine atoms (3e, 3f) and replacing the remaining
bility (290
(5% free in human and rat), and moderate metabolic stability
in vitro (intrinsic clearance in rat hepatocytes: 11
L/min/106 cells,
lM in pH7.4 buffer), moderate plasma protein binding
l

J. G. Cumming et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3895–3899
3897
Table 2
CCR2 binding, Ca2+ flux and hERG binding data for selected compounds
O
Ar
N
H
N
N
N
3
CCR2 Ca2+ flux IC50 (nM)
hERG binding IC50
(lM)
a
a
a
Compd
Ar
CCR2 binding IC50 (nM)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3-Cl-4-F-Ph
3-Cl-4-CF3-Ph
3-CF3-4-Cl-Ph
3-Cl-4-Me-Ph
4-Cl-Ph
3-Cl-Ph
4-Br-Ph
4-OMe-Ph
3-CF3-Ph
4-CF3-Ph
3-CN-Ph
50
17
35
27
127
171
58
1458
98
75
31
14
0.89
6.3
7.1
14
28
7.1
nt
13
6.3
nt
nt
nt
421
184
220
202
162
nt
578
593
5870
4360
nt
68
1055
449
>10000
>10000
710
4-CN-Ph
2-Cl-Ph
3-SO2Me-Ph
Ph
nt
>3000
nt
nt
a
IC50s were derived from triplicate measurements whose standard errors were normally <5% in a given assay. Assay to assay variability was within twofold based on the
results of a standard compound. nt = not tested.
and in human microsomes: 5
l
L/min/mg protein). Rat pharmaco-
Unwanted activity at the hERG ion channel is a frequent prob-
lem in the optimization of chemokine receptor antagonists includ-
ing CCR2.3,5 The observed correlation of both CCR2 and hERG with
lipophilicity suggested that further changes in the substituents on
this scaffold would be unlikely to increase the separation of these
activities. Potential approaches to reduce hERG activity include
kinetic (PK) data was acceptable: iv clearance was 24 mL/min/kg,
with a half-life of 5 h and volume of distribution of 8 L/kg, and oral
bioavailability was 11%. Compound 2g inhibited CYPs 3A4 and 2D6
with IC50s of 1.6 and 3.1 lM, respectively, which did not meet our
desired profile of >10 lM.
Table 3
CCR2 binding, Ca2+ flux and hERG binding data for selected compounds
Cl
Cl
Cl
Cl
O
O
N
H
N
N
N
H
N
X
N
X
O
N
4: X = O
5: X = NH
6: X = CH2
7: X = O
N
R
R
8: X = NH
9: X = NMe
a
a
a
Compd
R
CCR2 binding IC50 (nM)
Ca2+ flux IC50 (nM)
hERG binding IC50 (lM)
4a
4b
4c
rac-5a
5b
6a
rac-7a
8a
Et
64
267
17
797
26
856
2570
21
277
262
42
Nt
32
588
>1000
55
7.9
16
c-Pr
i-Pr
Et
i-Pr
Et
6.3
8.9
5.6
5.0
5.0
10
Et
Et
8b
8c
8d
rac-9a
c-Pr
i-Pr
Me
Me
32
3.5
69
5500
38
19
17
20
13
5.8
362
Nt
a
IC50s were derived from triplicate measurements whose standard errors were normally <5% in a given assay. Assay to assay variability was within twofold based on the
results of a standard compound. nt = not tested.

3898
J. G. Cumming et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3895–3899
Table 4
In vitro and in vivo PK data for 8c
a
b
Species
Clint
(
l
L/min/106 cells)
Clb (mL/min/kg)
Vssb (L/kg)
t½ (h)
Fc
%
Rat
Dog
Human
<2
<2
<2
30
17
—
4.0
8.5
—
3.0
9.1
—
11
83
—
a
b
c
For experimental procedures see Ref. 14.
Compounds dosed 4 mol/kg iv.
l
Compounds dosed 11 (rat) and 4 (dog)
l
mol/kg po.
O
O
O
R1
N
Ar
Ar
HN
a, b
N
N
N
N
H
H
N
NH
N
X
N
Boc
10
d
e, f
HO
X
O
X
X
X = NCO2Bn
X = NH
N
N
c
g
Boc
R
N
N
2, 3: X = CH2
4: X = O
Boc
Boc
11: X = CH2, O or NCO2Bn
5: X = NH
Scheme 1. Reagents and conditions: (a) ArNCO, CHCl3, rt; (b) TFA, CH2Cl2, rt; (c) Dess–Martin periodinane; CH2Cl2, rt (quant.); (d) Na(OAc)3BH, CH2Cl2, rt (89% over three
steps); (e) TFA, CH2Cl2, rt or 4 M HCl, dioxane, rt; (f) RBr, K2CO3, acetone, reflux (48–77% over two steps); (g) 4 M HCl, dioxane; ZnBr2, 10% Pd/C, H2, NMP, rt (60%).
reducing lipophilicity by incorporating polar atoms and attenuat-
ing the pKa of the basic amine group.12 With this in mind we inves-
tigated replacing the piperidine with morpholine or piperazine and
changing the methylene linker to a carbonyl. The data for these
compounds is shown in Table 3.
piperidines 2. Surprisingly the isopropyl group which previously
had similar activity to the cyclopropyl and only twofold better than
the ethyl (2h vs 2g and 2b, Table 1) now gave significantly more
activity (4c vs 4a and 4b, 8c vs 8a and 8b). The most potent com-
pound 8c was selected for further profiling.
Replacing the piperidine in 2 with morpholine (4) or piperazine
(5) mostly retained the activity at CCR2 while reducing hERG activ-
ity somewhat. Not all changes were beneficial: replacement of the
methylene linker in 2 with carbonyl (6) led to a drop in activity
which was also seen going from methylene to carbonyl in the mor-
pholine sub-series (4 to 7). However, gratifyingly, the combination
of the carbonyl linker and the piperazine terminal ring (8) gave po-
tent compounds together with a 10-fold reduction in hERG activity
(8b, 8c). The proximal nitrogen of the piperazine compounds did
not tolerate substitution—racemic 9a was nearly 100-fold less po-
tent than 8d. Rationalising the effects of these changes on hERG
activity in terms of shifts in logD7.4 is not straightforward since
the structural changes affect ionization as well as lipophilicity.
For example, going from piperidine 2 to morpholine 4 reduces logP
by ꢀ0.6 units but increases logD7.4 by ꢀ0.8 units due to the reduc-
tion in basicity (pKa from ꢀ10 to ꢀ8) of the most basic terminal
nitrogen arising from the inductive effect of the oxygen.13 Simi-
larly, the change to a piperazine with a carbonyl linker (2 to 8)
which gave around a 10-fold improvement in hERG while slightly
improving the CCR2 activity is accompanied by a reduction in logP
but an increase in logD7.4 (e.g., matched pair 2h and 8c have mea-
sured logD7.4 values of 1.62 and 2.21, respectively and measured
basic pKa values of 10.0 and 7.8, respectively, giving logP values
of 4.2 and 2.7, respectively). The SAR of the terminal alkyl substitu-
ent did not recapitulate what had been seen in the original
Compound 8c had a clean CYP inhibition profile (IC50 >10
5 isoforms), excellent physical properties (aqueous solubility
>3100 M), high metabolic stability in hepatocytes across species,
acceptable in vivo PK in rat and excellent PK in dog (Table 4).
In the hERG ion current electrophysiology assay 8c had a mean
IC50 of 60 lM (std. dev. 19 lM, N = 6), giving a 10,000-fold selectiv-
lM vs
l
ity for CCR2 over hERG. 8c inhibited MCP-1-induced chemotaxis in
CCR2-expressing THP-1 cells with a mean IC50 of 5.1 nM and inhib-
ited MCP-1-induced
L-selectin shedding in human peripheral
whole blood with a pA2 of 8.46. In common with other CCR2 antag-
onists3a,5g 8c displayed a drop-off in activity in non-human
species: IC50 values in mouse, rat and dog versions of the calcium
flux FLIPR assay were 1.2, 0.2 and 1.6
in human). In a secondary pharmacology panel consisting of 72
receptor and enzyme assays 8c showed <33% inhibition at 3
lM, respectively (cf. 5.8 nM
l
M
in all tests. Compound 8c had no activity at other human chemo-
kine receptors (CCR1, CCR8, CXCR4, CXCR5) with the exception of
CCR5 (FLIPR IC50 = 22 nM). Low selectivity over CCR5 is also
commonly observed for CCR2 antagonists.3a
A general route to the synthesis of compounds 2, 3, 4 and 5 is
shown in Scheme 1. The left hand side aryl urea was installed by
reaction of mono-protected piperazine with the appropriately
substituted phenyl isocyanate to give intermediate 10. The right
hand side methyl piperidine, morpholine or piperazine moiety
was commercially available as
a
homochiral Boc-protected
O
HN
Ar
HO
Boc
O
N
HO
Boc
O
N
N
a
b
c, d
N
N
O
N
H
N
O
N
N
Boc
NH
HN
R
R
N
R
12
8
Scheme 2. Reagents and conditions: (a) RI, Na2CO3, EtOH, reflux (63%); (b) DMTMM, N-methyl morpholine, piperazine, CH2Cl2, rt (50%); (c) ArNCO, CHCl3, rt or ArHNCO2Ph,
NEt3, THF, 60 °C; (d) TFA, CH2Cl2, rt (56–89% over two steps).

J. G. Cumming et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3895–3899
3899
primary alcohol 11. Dess–Martin oxidation of 11 gave an aldehyde
References and notes
which was coupled with 10 in a reductive amination. Removal of
the Boc group with trifluoroacetic acid paved the way for alkyl-
ation of the terminal nitrogen to give compounds 2, 3 and 4. For
compounds 5 having piperazine as the terminal ring, the nitrogen
proximal to the methylene was first protected as the benzyl carba-
mate (Cbz) (X = NCO2Bn in 11). Removal of the Boc in step (e) re-
quired a change from TFA to HCl to avoid unwanted cleavage of
the Cbz. The Cbz was removed in the final step using palladium
catalysed hydrogenation of the hydrochloride salt of the starting
material in the presence of zinc bromide which avoided hydrogen-
olysis of the aryl halogen atoms on the left hand side Ar group.15
The sequence of steps could also be reversed so that the final step
was the reaction of a phenyl isocyanate with an advanced interme-
diate which already contained the N-alkyl substituent on the ter-
minal piperidine, morpholine or piperazine ring.9
1. For a recent review of MCP-1 see: Deshmane, S. L.; Kremlev, S.; Amini, S.;
Sawaya, B. E. J. Inteferon Cytokine Res. 2009, 29, 313.
2. Charo, I. F.; Myers, S. J.; Herman, A.; Franci, C.; Connolly, A. J.; Coughlin, S. R.
Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 2752.
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2009, 19, 295.
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The synthesis of compounds 6–9 containing the carbonyl linker
followed a similar strategy and is illustrated for compounds 8 in
Scheme 2. Starting from the mono-Boc-protected homochiral
piperazine carboxylic acid 12, N-alkylation was followed by amide
coupling to piperazine using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-
4-methyl-morpholinium chloride (DMTMM)16 and N-methyl mor-
pholine avoiding unwanted cleavage of the Boc protecting group.
The aryl urea was installed by reaction with either a phenyl isocy-
anate or an N-aryl phenyl carbamate. Finally, removal of the Boc
group resulted in compounds 8.
In summary, testing of a ‘GPCR ligand motif’ library resulted in
screening hit 1. Exploration of SAR led to the identification of a no-
vel, potent and selective series of N-aryl piperazine-1-carboxamide
CCR2 antagonists with good DMPK properties but unacceptable
hERG margin. Changes to the series scaffold increased ligand lipo-
philicity efficiency and serendipitously led to a compound, 8c,
which had low nanomolar activity at CCR2 and a 10,000-fold mar-
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Acknowledgements
The authors would like to thank our colleagues John Shaw, Lucy
Ashman, Susan Mellor and Lorraine Newboult for developing and
carrying out the biological assays, and Martin Wild, Kerry Frost,
Warren Keene and Victoria Starkey for providing the DMPK data.
We also thank Mirek Tomaszewski and Jin Hu (AstraZeneca,
Montréal) for the design and synthesis of the GPCR library which
contained the initial screening hit 1.
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