Oxazolidinones as novel human CCR8 antagonists

Article abstract of DOI:10.1016/j.bmcl.2006.12.076

High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series

Full text of DOI:10.1016/j.bmcl.2006.12.076

Bioorganic & Medicinal Chemistry Letters 17 (2007) 1722–1725
Oxazolidinones as novel human CCR8 antagonists
a,
a
a
b
b
*
Jian Jin, Yonghui Wang, Feng Wang, Jeffery K. Kerns, Victoria M. Vinader,
b
b
a
c
Ashley P. Hancock, Matthew J. Lindon, Graeme I. Stevenson, Dwight M. Morrow,
c
c
d
d
d
Parvathi Rao, Cuc Nguyen, Victoria J. Barrett, Chris Browning, Guido Hartmann,
d
d
d
c
David P. Andrew, Henry M. Sarau, James J. Foley, Anthony J. Jurewicz,
James A. Fornwald, Andy J. Harker, Michael L. Moore, Ralph A. Rivero,
e
f
a
a
d
d
Kristen E. Belmonte and Helen E. Connor
a
Discovery Medicinal Chemistry, Molecular Discovery Research,GlaxoSmithKline,
250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA
Medicinal Chemistry, Respiratory and Inflammation CEDD, GlaxoSmithKline,
250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA
Screening & Compound Profiling, Molecular Discovery Research, GlaxoSmithKline,
250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA
1
b
1
c
1
d
Biology, Respiratory and Inflammation CEDD, GlaxoSmithKline,
250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA
Gene Expression & Protein Biochemistry, Molecular Discovery Research, GlaxoSmithKline,
250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA
Drug Metabolism & Pharmacokinetics, Respiratory and Inflammation CEDD, GlaxoSmithKline,
250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA
1
e
1
f
1
Received 10 November 2006; revised 15 December 2006; accepted 18 December 2006
Available online 24 December 2006
Abstract—High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-
-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the
series that led to the identification of SB-649701 (1a), are described.
2006 Elsevier Ltd. All rights reserved.
5
ꢀ
2
Human CCR8, a 7TM receptor formerly known as
TER1, ChemR1, or CKR-L1, was first identified and
T lymphocytes. Analysis of bronchial biopsies and bron-
choalveolar lavage fluid before and following antigen
challenge of atopic asthmatic patients revealed that
TARC was highly upregulated in the airway epithelia
1
2
cloned in 1996. The CC chemokine I-309 functionally
activates the receptor with high potency and binding affin-
3
8
ity. Three other CC chemokines, TARC, MIP-1b, and
vMIP-I, were subsequently identified as the natural li-
after challenge. In addition, CCR8 and its ligands are
potentially implicated in viral infection and immune reg-
4
4b,c,9
gands of CCR8. Murine CCR8 and its functional ligand
5
ulation.
It was demonstrated that CCR8 served as a
TCA-3, the mouse ortholog of I-309, were also identified
6
co-receptor for diverse T-cell tropic, dual-tropic, and
macrophage-tropic HIV-1 strains and that I-309 was a
potent inhibitor of HIV-1 envelope-mediated cell-cell fu-
and cloned. Several lines of evidence suggest that CCR8
may represent a potential target for treatment of asthma
and other allergic diseases although CCR8 knock-out
9
sion and virus infection.
7
mouse data were inconclusive. CCR8 is preferentially ex-
6
pressed in Th2 lymphocytes, not Th1 lymphocytes. I-
3
Several small molecule CCR8 antagonists have recently
1
0
09, a specific ligand for CCR8, is secreted by activated
been reported in the literature. Herein we describe the
identification, synthesis, initial structure-activity relation-
ships (SAR), functional activity, and initial development
properties of a novel series of N-substituted-5-aryl-oxa-
zolidinones as potent human CCR8 antagonists.
Keywords: CCR8; Antagonists; N-substituted-5-aryl-oxazolidinones;
Asthma; HIV; Chemokine receptors.
*
Corresponding author. Tel.: +1 610 917 6645; fax: +1 610 917
391; e-mail: jian.jin@gsk.com
7
0
960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.12.076

J. Jin et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1722–1725
1723
High-throughput screening (HTS) of our compound col-
lection using a radioligand binding assay (measuring
O
O
a
b
H
N
c
OH
N
Boc
N
1
25
H
Ar
Ar
inhibition of [ I] labeled human recombinant I-309
binding to human recombinant CCR8 stably expressed
Ar
5
3
4
1
1
on Chinese hamster ovary (CHO) cell membranes)
led to the identification of SB-633852 (2), a racemic mix-
O
O
d, e
1
2,13
O
O
ture, as a hit with a pIC50 of 5.8 (Fig. 1).
The com-
N
N
Boc
N
pound was subsequently tested in a fluorometric
imaging plate reader (FLIPR) assay (measuring inhibi-
tion of I-309-mediated [Ca ] -mobilization in rat baso-
R
Ar
Ar
7
6
2
+
i
Scheme 1. Reagents and conditions: (a) Me
CH CN, rt; (b) 4-amino-piperidine-1-carboxylic acid tert-butyl ester,
LiClO , CH CN, reflux; (c) 1,1-carbonyldiimidazole, 4-dimethylamino
pyridine, CH Cl , rt; (d) 30% trifluoroacetic acid in CH Cl , rt; (e)
2 2 4
S, Me SO , NaOMe,
philic leukemia (RBL) cells expressing human
1
4
3
recombinant CCR8) and found to be an antagonist
with a pIC50 of 5.8. The FLIPR assay has since been
used as the primary assay to support SAR work.
4
3
2
2
2
2
3 2 2
RCHO, Na(OAc) BH, CH Cl , rt.
In order to explore the SAR around the three key regions
of this chemical series, a general synthetic route outlined
Table 1. SAR of the central diamine moiety
1
5
in Scheme 1 was developed. Various aromatic aldehydes
were converted to the corresponding epoxides 4 using
OMe
O
3
O
1
6
standard yield chemistry. Ring opening of epoxides 4
with various mono-protected cyclic and acyclic diamines
such as 4-amino-piperidine-1-carboxylic acid tert-butyl
ester produced amino alcohols 5, which were cyclized to
afford oxazolidinones 6. Removal of the Boc group fol-
lowed by reductive amination of the corresponding
amines with various aldehydes produced the desired com-
pounds 7. Using this five-step synthetic route, multiple re-
gions of this chemical series were explored to improve
potency and demonstrate sustainable SAR.
N
R
N
H
N
N
R'
a
hCCR8 FLIPR (pIC50)
Compound
R
N
R'
2
5.8
N
H
We first explored the central diamine (DA) moiety via
preparing analogs containing a cyclic or acyclic linker.
As shown in Table 1, compound 8, a N–Me analog of
SB-633852 (2), showed antagonist activity with a slight
drop of potency, indicating that the NH of the propyl
diamine moiety is not crucial. We then explored analogs
containing a constrained (cyclic) diamine moiety and
were extremely pleased to find that compound 9, a 4-
amino piperidine containing analog, had about 100-fold
potency improvement comparing to SB-633852 (2).
Other constrained analogs such as 10 containing a
8
9
N
5.2
N
7.6
10
11
12
N
<4.3
<4.3
<4.3
<4.3
N
4
-aminomethyl piperidine moiety, 11 containing a 3-
N
aminomethyl piperidine moiety, 12 containing a 3-ami-
no pyrrolidine moiety, and 13 containing a 3-amino
azepine moiety showed no potency in the CCR8 FLIPR
assay—indicating that the configuration and the length
of the central diamine linker is extremely important.
N
1
3
a
Mean of at least 2 determinations with standard deviation of <±0.3.
Encouraged by this key finding, we then explored the
preferred stereochemistry at the 5-position of the oxazo-
lidinone. Compound 9, a racemic mixture, was separat-
ed via chiral HPLC to afford SB-649701 (1a) with 96.5%
1
7
ee and 1b with 95% ee. As shown in Figure 2, the R
enantiomer, 1a (96.5% ee), was greater than 100-fold
more potent than the S enantiomer, 1b (95% ee). The ob-
served FLIPR potency of lb could be due to the presence
of 2.5% of the R enantiomer in 1b as the enantiomeric
excess of 1b is 95%.
LHS aromatic
RHS
OMe
O
O
N
DA
N
H
We next turned our attention to exploring the left-hand
side (LHS) aromatic moiety. Changing the 6-methoxy
quinoline-4-yl group (9) to 2-methoxy-1,5-naphthyridin-
8-yl (14a) resulted in no or little potency loss (Table 2).
The des-methoxy compound, 14b, was about 30-fold less
potent. Further structural changes such as switching the
N
N
H
SB-633852 (2)
hCCR8 binding: pIC50 = 5
hCCR8 FLIPR: pIC50 = 5.8
Figure 1. Structure of HTS hit SB-633852 (2).

1724
J. Jin et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1722–1725
Table 3. SAR of the right-hand side (RHS) N-capping group
OMe
O
OMe
O
O
N
N
H
O
N
N
N
R
Chiral
separation
N
SB-649701 (1a), 96.5% ee
hCCR8 FLIPR: pIC50 = 7.7
N
9
Compound
R
hCCR8
a
FLIPR (pIC50)
OMe
O
O
N
9
1-H-Indol-2-ylmethyl
1-Methyl-indol-2-ylmethyl
1-H-indol-3-ylmethyl
Benzofuran-2-ylmethyl
Benzothiophen-2-ylmethyl
Quinolin-2-ylmethyl
Naphthalen-2-ylmethyl
Methyl
7.6
5.5
N
H
N
15a
15b
15c
15d
<4.3
5.9
N
1b, 95% ee
hCCR8 FLIPR: pIC50 = 5.5
6.1
5.5
Figure 2. Preferred stereochemistry.
15e
1
1
5f
5g
5.9
<4.3
6.3
Table 2. SAR of the left-hand side (LHS) aromatic moiety
15h
1-Hexyl
Cyclohexan-1-ylmethyl
Benzyl
1
1
1
1
5i
5j
5k
5l
5.1
4.9
Phen-1-ylpropyl
4-Chlorobenzyl
3-Chlorobenzyl
6.6
6.2
O
NH
O
15m
5.2
N
N
1
1
1
1
1
5n
5o
5p
5q
5r
2-Chlorobenzyl
<4.3
5.9
Ar
4-Methoxybenzyl
4-Cyanobenzyl
4-Bromobenzyl
4.9
7.3
a
Compound Ar
hCCR8 FLIPR
(
pIC50)
4-Phenylbenzyl
3,4-Dimethylbenzyl
3,4-Dichlorobenzyl
<4.3
7.4
9
6-Methoxyquinolin-4-yl
2-Methoxy-1,5-naphthyridin-8-yl
Quinolin-4-yl
7.6
7.5
6.0
15s
15t
15u
15v
1
1
1
1
1
1
4a
4b
4c
4d
4e
4f
6.9
5.2
3,4-Dichlorophen-1-ylcarbonyl
3,4-Dichlorophen-1-ylsulfonyl
1-Naphthyl
Quinolin-3-yl
<4.3
<4.3
<4.3
<4.3
<4.3
a
Mean of at least 2 determinations with standard deviation of <±0.3.
Quinolin-2-yl
Pyridin-4-yl
and 4-bromobenzyl (15q) was found to be optimal with
a pIC50 of 7.3. The 3,4-disubstituted benzyl analogs such
as 15s and 15t were also highly potent antagonists with a
pIC50 of 7.4 and 6.9, respectively. We also explored
amide and sulfonamide capping groups and found that
amide 15u and sulfonamide 15v were dramatically less
potent compared to amine 15t. In general, modifica-
tions in this region were well tolerated and several po-
tential sub-series with a different type of N-capping
group (e.g., fused bicyclic aromatic, mono- and di-
substituted benzyl, phenylpropyl) have been identified.
a
Mean of at least 2 determinations with standard deviation of <±0.3.
6
-methoxy quinoline-4-yl group to 1-naphthyl (14c),
quinolin-3-yl (14d), quinolin-2-yl (14e), and pyridin-4-yl
14f) resulted in complete potency loss. The SAR in this
region indicated a limited degree of tolerability for struc-
tural variation.
1
8
(
We then investigated the right-hand side (RHS) N-cap-
ping group. A number of analogs containing a variety of
capping groups were prepared and evaluated in the
CCR8 FLIPR assay (Table 3). Adding methyl to the in-
dole nitrogen resulted in about 100-fold potency loss (9
vs 15a). Changing the 1-H-indol-2-ylmethyl group to the
In addition to human CCR8 FLIPR assay, SB-649701
(1a) was also evaluated in two distinct chemotaxis as-
says. SB-649701 (1a) was a functional antagonist in a
HUT78 (a human T cell line) chemotaxis assay (measur-
ing the I-309 mediated migration of HUT78 through
3 lm ChemoTX filter systems) with a pIC50 of 6.3
(n = 3, SD = 0.28). In an activated Th2 chemotaxis assay
(measuring the I-309 mediated migration of activated
Th2 cells), SB-649701 (1a) was also a potent functional
antagonist with a pIC50 of 7.0 (n = 4, SD = 0.14). SB-
649701 (1a) was also tested in mouse, rat, and guinea
pig CCR8 FLIPR assays and found to have no activity.
The lack of rodent ortholog activity might be due to the
significant sequence differences between human and ro-
dent receptors (e.g., mouse CCR8 shows only 71%
1
-H-indol-3-ylmethyl (15b) abolished CCR8 antagonist
1
9
activity completely. Other fused bicyclic aromatic
groups such as benzofuran-2-ylmethyl (15c), benzothio-
phen-2-ylmethyl (15d), quinolin-2-ylmethyl (15e), and
naphthalen-2-ylmethyl (15f) were moderately potent in
the FLIPR assay. In addition to fused bicyclic aromatic
groups, a number of alkyl and benzyl groups were also
explored. While methyl (15g) was inactive, hexyl (15h)
was moderately potent and cyclohexylmethyl (15i) was
weakly active. Although benzyl (15j) showed only weak
potency, extending the chain length from 1 (15j) to 3
2
0
6
(
15k) resulted in 50-fold potency increase. The preferred
homology to human CCR8 ).
substitution pattern for the benzyl sub-series is: para >
meta > ortho (15l vs 15m vs 15n). Several 4-substituted
benzyl groups (15o–15r) were subsequently investigated
We also evaluated this series in selectivity, CYP450 inhi-
bition, hERG, and in vitro and in vivo PK studies.

J. Jin et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1722–1725
1725
SB-649701 (1a) showed at least 100-fold selectivity vs a
number of 7TM receptors including chemokine recep-
tors. SB-649701 (1a) and 15s did not significantly inhibit
all six major P450 isozymes (1a, pIC50 < 5.1; 15s,
pIC50 < 5.0). In hERG binding assay, SB-649701 (1a)
and 15s had a pIC50 of 5.8 and 5.2, respectively, which
provided a respective 79- and 158-fold hERG window
Zlotnik, A.; Barrat, F. J.; O’Garra, A.; Napolitano, M.;
Lira, S. A. J. Exp. Med. 2001, 193, 573; (b) Chung, C. D.;
Kuo, F.; Kumer, J.; Motani, A. S.; Lawrence, C. E.;
Henderson, W. R.; Venkataraman, C. J. Immunol. 2003,
1
70, 581; (c) Goya, I.; Villares, R.; Zaballos, A.; Gutierrez,
J.; Kremer, L.; Gonzalo, J.; Varona, R.; Carramolino, L.;
Serrano, A.; Pallares, P.; Criado, L. M.; Kolbeck, R.;
Torres, M.; Coyle, A. J.; Gutierrez-Ramos, J.; Martinez-
A, C.; Marquez, G. J. Immunol. 2003, 170, 2138.
over CCR8 IC . In in vitro human and rat liver micro-
5
0
some stability studies, SB-649701 (1a) showed moderate
intrinsic clearance (human: 7 mL/min/g liver; rat 7 mL/
min/g liver). SB-649701 (1a) also demonstrated moderate
clearance and low to moderate oral bioavailability
8. Panina-Bordignon, P.; Papi, A.; Mariani, M.; Di Lucia,
P.; Casoni, G.; Bellettato, C.; Buonsanti, C.; Miotto, D.;
Mapp, C.; Villa, A.; Arrigoni, G.; Fabbri, L. M.;
Sinigaglia, F. J. Clin. Invest. 2001, 107, 1357.
9
. Horuk, R.; Hesselgesser, J.; Zhou, Y.; Faulds, D.; Halks-
Miller, M.; Harvey, S.; Taub, D.; Samson, M.; Parmen-
tier, M.; Rucker, J.; Doranz, B. J.; Doms, R. W. J. Biol.
Chem. 1998, 273, 386.
(
Clb = 38 mL/min/kg, F = 18%, T1/2 = 1 h, Vdss = 2.4 L/
kg) in in vivo mouse PK studies (1 mg/kg iv, 2 mg/kg
po). Overall, SB-649701 (1a) possessed good selectivity
and initial development properties.
1
1
0. (a) Ghosh, S.; Elder, A.; Guo, J.; Mani, U.; Patane, M.;
Carson, K.; Ye, Q.; Bennett, R.; Chi, S.; Jenkins, T.;
Guan, B.; Kolbeck, R.; Smith, S.; Zhang, C.; LaRosa, G.;
Jaffee, B.; Yang, H.; Eddy, P.; Lu, C.; Uttamsingh, V.;
Horlick, R.; Harriman, G.; Flynn, D. J. Med. Chem. 2006,
49, 2669; (b) For published patents, see Ref. 10a.
In summary, SAR exploration of a novel oxazolidinone
series identified via HTS led to the discovery of potent
human CCR8 antagonists such as SB-649701 (1a) with
good chemotaxis activity, selectivity, DMPK, and
hERG properties. The further optimization of this series
will be the subject of future publications.
1. Binding assay method: assays were performed in a 384-
well microtiter plate format. Each reaction well contained:
1
25
0
.35 nM [ I]-I309, 3.0 lg/mL of human CCR8 CHO
membranes prebound to 60 lg of LEADseeker WGA-PS
SPA (Wheatgerm–agglutinin coupled polystyrene scintil-
lation proximity imaging) beads in 25 mM bis-trispropane
Acknowledgments
2
buffer, 2 mM MnCl , 1 mM EDTA, 100 mM NaCl, 7.5%
glycerol, 0.05% CHAPS at pH 7.5, and appropriate
concentration of a test compound.
We thank Bing Wang, Chad Quinn, Qian Jin, and Carl
Bennett for NMR, analytical LC/MS, and preparative
HPLC support, and Arun Kaura for chiral HPLC
separation.
12. The chiral centers in the structures shown in the paper are
racemic unless the chirality is explicitly illustrated.
1
3. (a) The biological assay results in the paper are a mean of
at least 2 determinations with standard deviation of <±0.3
unless otherwise noted; (b) pIC50 = ÀlogIC50 (M).
References and notes
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Wang, Y. WO Patent 2004032856-A2, 2004; Jin, J.; Kerns,
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15. For experimental details, see Ref. 14.
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G.; Nista, A.; Storlazzi, C. T.; Rocchi, M.; Santoni, A.
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2
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‘‘A’’: 70% eluent ‘‘B’’ gave two components at R = 17.7
T
and
33 min.
‘‘A’’ = EtOH:MeOH:isopropylamine =
3
. (a) Roos, R. S.; Loetscher, M.; Leglar, D. F.; Clark-Lewis,
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1
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4
18. Amide 15u and sulfonamide 15v were prepared via
reaction of the piperidine intermediate with the corre-
sponding acid and sulfonyl chloride, respectively.
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. (a) Chensue, S. W.; Lukacs, N. W.; Yang, T.; Shang, X.;
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5
6
7