Novel CCR1 antagonists with oral activity in the mouse collagen induced arthritis

Article abstract of DOI:10.1016/j.bmcl.2005.08.057

Cinnamides as novel CCR1 antagonist chemotypes are described with high affinity to human and rodent receptors. A1B1 and A4B7 showed oral activity in the mouse collagen induced arthritis.

Full text of DOI:10.1016/j.bmcl.2005.08.057

Bioorganic & Medicinal Chemistry Letters 15 (2005) 5160–5164
Novel CCR1 antagonists with oral activity in the mouse
collagen induced arthritis
Laszlo Revesz,* Birgit Bollbuck, Thomas Buhl, Joerg Eder, Ronald Esser, Roland Feifel,
Richard Heng, Peter Hiestand, Benedicte Jachez-Demange, Pius Loetscher,
Helmut Sparrer, Achim Schlapbach and Rudolf Waelchli
Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Autoimmunity and Transplantation,
CH-4002 Basel, Switzerland
Received 15 July 2005; revised 16 August 2005; accepted 22 August 2005
Available online 28 September 2005
Abstract—Cinnamides as novel CCR1 antagonist chemotypes are described with high affinity to human and rodent receptors. A1B1
and A4B7 showed oral activity in the mouse collagen induced arthritis.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The chemokine receptor CCR1 and its major ligands
CCL3 (MIP-1a) and CCL5 (RANTES) are believed to
play a role in the pathogenesis of several inflammatory
diseases including rheumatoid arthritis,1,2 multiple scle-
rosis3,4 and transplant rejection.5,6 Small molecules as
CCR1 antagonists are expected to be of great therapeu-
tic value in these indications. The first clinical proof-of-
concept with rheumatoid arthritis patients confirmed
that a small molecule CCR1 antagonist can have rele-
vant biological effects: reduction in the number of mac-
rophages and CCR1+ cells in the synovium and general
improvement after 14 days of treatment.7 Several chem-
otypes have been described as CCR1 antagonists:
hydroxyethylene peptide isosteres,8–11 4-hydroxypiperi-
dines,12,13 benzylpiperazines (e.g., BX-471 in clinical
trial for multiple sclerosis),14–17 arylpiperazines18 and
xanthene-9-carboxamides.19–21 Many CCR1 antagonists
reported above lack species cross-reactivity, in particu-
lar for rodent CCR1 which may limit their use, since
many disease models are run in mice and rats.
lead structure with its p-fluorobenzyl substituent kept
unchanged, while the aryloxy acetic acid moiety A and
the piperazine ring of B were the targets for bioisosteric
substitution by the fragments A1–A11 and B1–B8
(Scheme 1).
Compounds A1B1 through A1B8 in Table 1 were pre-
pared by coupling A1-OH17 with H-B1 through H-B8
using EDCI, HOBt as standard coupling conditions.
A3B1 and A3B7 were prepared similarly from A3-
OH.17 A2B1 and A4B7 were prepared from precursor
117 (Scheme 2).
A5B1 was prepared from A1B1 via NaBH4 reduction in
EtOH. Intramolecular Michael addition during ester
hydrolysis of the urea derivative of aniline 217 (Scheme
3) generated a cyclic urea intermediate, which was cou-
pled with H-B1 to render A7B1.
A6B1 was prepared from chloromethyl ketone 4,18
which was converted via phthalimide into the primary
amine 5 (Scheme 4). O-Bromo nitrobenzene 3 and 5
were heated to 130 ꢁC and delivered the piperazine ana-
logue 6 in modest yield. SnCl2-reduction of the nitro
group and acylation generated A6B1.
Here, we wish to report our work directed towards the
transformation of a modestly cross-reactive lead struc-
ture into novel CCR1 antagonists with equally high
potency for human (h), rat (r) and mouse (m) CCR1
and their oral activity in animal models of inflammation
and multiple sclerosis. BX-47114–16 was chosen as the
A8B1 and A9B1 were obtained by coupling A8-OH22
and A9-OH23 with H-B1 under standard conditions.
A10B1 and A11B1 were prepared as described previous-
ly.17 A11B7 was synthesized in analogy to the former
two compounds using H-B7. From the eight piperazine
*
Corresponding author. Tel.: +41 61 324 3231; fax: +41 61 324 327;
e-mail: Laszlo.revesz@novartis.com
0960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.08.057

L. Revesz et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5160–5164
5161
O
H2N
Cl
NH
O
F
O
N
N
A
B
O
O
O
R1
Cl
HN
O
O
NH
R2
NH
O
NH
O
X
Cl
Cl
A1 (R1=Me; R2=H)
A5 (X=CH2)
A6 (X=NH)
A7
A2 (R1=NH2; R2=H)
A3 (R1=Me; R2=OMe)
A4 (R1=Me2NCH2; R2=H)
O
O
R1
NH
O
NH
O
X
N
N
Cl
R
X
R2
B1 (R1=(R)-Me; R2=H)
B2 (R1=(R)-Me; R2=(S)-Me)
B3 (R1=(S)-Me; R2=(R)-Me)
B4 (R1, R2=H)
A8 (X=NH)
A9 (X=O)
A10 (X=CH)
A11 (X=N)
R: p-Fluorobenzyl
N
N
N
N
N
R
N
N
R
N
R
R
B8
B5
B7
B6
Scheme 1.
building blocks H-B1 to H-B8 (Scheme 1), H-B4 was
commercially available, while H-B1,24 H-B2,25 H-B3,25
H-B726 and H-B826 were prepared according to litera-
ture procedures. H-B6 was synthesized as described27
using 4-fluorobenzylchloride. H-B5 was obtained
(Scheme 5) by coupling 13 with BOC-D-Ala-OH. The
resulting product was deprotected under acidic condi-
tions followed by cyclisation to 14 at pH 9. Reduction
with BH3 yielded the desired homopiperazine H-B5.
piperazine A1B6 were considerably weaker with IC50s
of 1.6–1.7 lM. The unsubstituted piperazine derivative
A1B4 showed a 6-fold weaker potency than its methyl
substituted analogue A1B1. Both ethylene-bridged
piperazine fragments in A1B7 and A1B8 showed moder-
ate IC50s of 0.2–0.3 lM. However, in contrast to B1, B7
had the remarkable property to increase the affinity for
rodent receptors at least 10-fold, exemplified by the
compounds A3B7, A4B7 and A11B7. A3B7 proved to
be the most potent antagonist of rodent CCR1 within
this series with IC50s of 1 and 4 nM against mCCR1
and rCCR1. A3B1, on the other hand, had a slightly
higher affinity for hCCR1, but was 10- to 20-fold weaker
against rodent CCR1 compared to A3B7. It is notewor-
thy that the addition of a methoxy group in A3 in com-
parison to A1 resulted in a 10-fold higher affinity for
human and rodent CCR1, exemplified by the pairs of
compounds A1B1, A3B1 and A1B7, A3B7. The dihydro
analogue A5B1 showed a 10-fold drop in affinity. The
cyclic urea A7B1 was weak with an IC50 = 0.8 lM, dem-
onstrating either the wrong conformation of the urea
group or the need for a specific conformation of a rigid
side chain. Replacing the aryl ether in BX-471 by the
The ether functionality in BX-471 could favourably be
substituted by the bioisosteric double bond in A2B1,
which showed a 3- to 10-fold higher affinity for human,
mouse and rat CCR1 (Table 1). The urea functionality
of A2B1 was replaced without loss of affinity by the ace-
tyl group in A1B1 and was kept through the whole ser-
ies, assuming that the acetyl group was superior to the
urea functionality considering pharmacokinetic proper-
ties. Among the piperazines B1–B8 combined with A1,
A1B2 proved to be a potent hCCR1 antagonist with
IC50 = 9 nM, but only modest affinities for the rodent
receptors; its enantiomer A1B3 was 10- to 100-fold
weaker. Homopiperazine A1B5 and methylene-bridged

5162
L. Revesz et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5160–5164
Table 1. CCR1 antagonists AB
arylamine in A6B1 gave rise to a nearly equipotent com-
pound, with slightly weaker activity on rodent receptors.
Incorporation of the aniline nitrogen of A7 into the
indole ring in A8B1 did not improve potency. Benzofu-
ran A9B1—representing a rigidified A fragment of BX-
471—led to a 3-fold loss in activity against h/m/rCCR1.
The naphthyl- and quinolinyl building blocks in A10B1
and A11B1 showed properties similar to those of their
benzene analogue A1B1. However, the quinoline ana-
logue A11B7 revealed—in agreement with all B7-deriva-
tives—a more pronounced rCCR1 inhibitory profile,
with an IC50 = 6 nM being 25-fold more potent against
rCCR1 than against hCCR1. All compounds discussed
were functional antagonists of hCCR1, demonstrated
by their ability to inhibit the MIP-1a induced Ca2+
mobilization28 in THP-1 cells (Table 1).
Compound
hCCR1a
mCCR1a
rCCR1a
Ca2+b
BX-471
A1B1
A1B2
A1B3
A1B4
A1B5
A1B6
A1B7
A1B8
A2B1
A3B1
A3B7
A4B7
A5B1
A6B1
A7B1
A8B1
A9B1
A10B1
A11B1
A11B7
0.040
0.030
0.009
0.100
0.190
1.60
1.5
0.58
0.6
0.55
0.32
1.35
10.5
0.15
n.t.
0.0004
0.001
0.0001
0.001
0.058
n.t.
23.0
0.448
n.t.
1.70
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
0.200
0.300
0.016
0.004
0.007
0.030
0.360
0.050
0.800
0.560
0.120
0.080
0.03
n.t.
n.t.
n.t.
0.3
0.04
0.02
0.001
0.01
n.t.
0.0009
0.0015
0.0000
0.009
n.t.
0.05
0.004
0.04
n.t.
3.0
1.7
0.0024
n.t.
n.t.
n.t.
3.0
4.8
1.0
1.0
0.0096
0.028
0.013
0.020
n.t.
Pharmacokinetic data (Table 2) for BX-471 and A2B1
revealed that the double bond in A2 was superior to
the aryl ether functionality in BX-471, leading to
remarkably higher AUC-, Cmax- and half life values.
The acetyl group in A1—compared with the urea in
A2—led to a further increase in AUC and half life,
two important requirements for in vivo activity in ro-
dent models. The methoxy group in A3B1 demonstrated
0.5
1.5
0.3
1.00
0.05
0.15
0.006
n.t., not tested.
a IC50 (lM).29
b IC50 (lM) of Ca2+ mobilization in MIP-1a stimulated THP-1 cells.28
O
O
H2N
Cl
NH
F
a) c)
N
N
O
A2B1
NH
O
O
OH
O
N
Cl
NH
O
b) d)
F
N
1
N
Cl
A4B7
Scheme 2. Reagents and conditions: (a) H-B1, HOBt, EDCI.HCl, CH2Cl2, rt, 12 h, 63%; (b) H-B7, HOBt, EDCI.HCl, CH2Cl2, rt, 12 h, 66%;
(c) NaOCN, HOAc, water, rt, 30 min, 65%; (d) i—Chloroacetyl chloride, THF, rt, 1 h, 85%, ii—HNMe2, THF, 10 min rt, 95%.
O
O
NH2
O
HN
O
NH
H
a) b) c)
F
O
N
N
Cl
Cl
O
A7B1
2
Scheme 3. Reagents and conditions: (a) NaOCN, HOAc, water, rt, 30 min, 68%; (b) 2 N NaOH, EtOH, reflux, 10 min, 75%; (c) H-B1, HOBt,
EDCI.HCl, CH2Cl2, rt, 12 h, 65%.
N+
O
O
O
R
O
H
F
N
F
X
Br
c)
N
N
+
N
N
Cl
Cl
4 (X=Cl)
5 (X=NH2)
6 (R=NO2)
A6B1 (R=AcNH)
3
a) b)
d) e)
Scheme 4. Reagents and conditions: (a) Phthalimide-K, DMF, 120 ꢁC, 30 min, 90%; (b) H2NNH2, MeOH, reflux 1.5 h, 96%; (c) neat, 130 ꢁC,
45 min, 30%; (d) excess SnCl2, EtOH/HClconcd/water 3/1/1 reflux 15 min, 93%; (e) Ac2O, NEt3, THF, rt 12 h, 27%.

L. Revesz et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5160–5164
5163
F
F
X
HN
H
a) b) c) d)
O
N
N
X
O
13
14 (X=O)
H-B5 (X=H,H)
Scheme 5. Reagents and conditions: (a) EDCI, HOBt, BOC-D-Ala-OH, THF, rt 5 h, 90%; (b) 4 N HCl dioxane, rt, 16 h, 39%; (c) pH 9, water, rt;
(d) BH3 THF, 60 ꢁC, 97%.
related chemokine receptors, muscarinic, adrenergic
and opioid receptors and proved to be highly selective.32
Since most GPCRs tested for selectivity were of human
origin, animal in vivo data have to be interpreted with
caution. More work is needed—e.g., chemotaxis experi-
ments with rat and mouse cells—to relate in vivo activity
with inhibition of the CCR1 receptor.
Table 2. Pharmacokinetics in rats and chemotaxis
a
Compound F (%) Cmax
T1/2 (h) AUCb CCL3
c
chemotaxis
BX-471
A1B1
A2B1
A3B1
A3B7
A4B7
100
95
0.400
0.85
1.9
16.5
11.0
4.1
139
784
2.36
9.97
90
0.934
0.396
0.080
0.407
487
750
45.00
69.7
7.50
100
83
5.1
2.92
158
1071
In summary, our pilot set aiming at the discovery of
novel CCR1 antagonists with cross-reactivity for human
and rodent receptors yielded a number of potent antag-
onists. Two compounds—A1B1 and A4B7—demon-
strated oral efficacy in a model of rheumatoid arthritis
in the mouse.
77
41.00
F, bioavailability; T1/2, half life; AUC, area under the curve.
a lM/L; dose normalized.
b ng h/mL.
c IC50 (nM) of MIP-1a (CCL3) induced transwell chemotaxis.30
a 2- to 4-fold drop of Cmax and half lives, while replace-
ment of B1 by B7 reduced all parameters, except the half
life in A3B7. However, combining B7 and A4 led to the
highest AUC value of the series in A4B7.
Acknowledgment
The authors wish to thank the Analytical Department of
Novartis Pharma AG for NMR, MS, and IR spectra
including their interpretation.
Based on their promising pharmacokinetic properties in
rats and potency to inhibit CCL3- induced chemotax-
is,30 A1B1, A4B7 and A3B7 were tested in the LPS-ac-
celerated collagen-induced arthritis model in mice.31
Due to their shorter half lives, A3B7 and A4B7 were
dosed 2 · 30 mg/kg p.o. per day, while A1B1 with a
longer half life was dosed once per day 60 mg/kg p.o.
A4B7 reduced the clinical severity score by 58%, A1B1
by 48%, while A3B7 was inactive. The lack of activity
of A3B7 can be explained by its lower exposure
(AUC = 158; Table 1) in comparison to A1B1
(AUC = 784) and A4B7 (AUC = 1071). At a dose of
100 mg/kg p.o. A1B1 (plasma levels after 4 h: 8.15 lM;
after 18 h: 1.4 lM) significantly reduced histological
scores of inflammation, pannus formation, cartilage
degradation and bone resorption. As a representative
of the novel cinnamide chemotype CCR1 antagonists,
A1B1 underwent a GPCR selectivity screen including
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CCR5 (mouse): >10. CCR6: >100. Serotonin 5HT1A: >1.
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D4.4: >1. Adrenergic A1: >1. A2A: >1. A2C: >1. A2B: >1.
B1: >1. B2: >1. Opiate mu: >1. kappa: >1. delta: >1.
EFFECT OF A1B1 ON THE CLINICAL
SEVERITY OF COLLAGEN-INDUCED ARTHRITIS
10
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4
2
Arthritis Control
A4B7
A3B7
0
16
20
24
28
32
36
26. Blumberg, L. C.; Brown, M. F.; Glaude, R. P.; Poss, C. S.
WO 2002032901. Chem. Abstr. 2002, 136, 340711.
27. Smith, David William; Yocca, Frank D.; Yevich, Joseph
Paul; Mattson, Ronald John. EP 345808 Chem. Abstr.
1991, 113, 172049.
Day After Collagen Immunization
A4B7 and A3B7 were administered at a dose of 2 · 30 mg/
kg in 5% aerosil in water. Treatment was initiated prior to
LPS challenge and continued until study termination on day
34.