Substituted dipiperidine alcohols as potent CCR2 antagonists

Article abstract of DOI:10.1016/j.bmcl.2008.05.010

The synthesis and biological evaluation of a series of substituted dipiperidine alcohols are described. Structure-activity relationship studies led to the discovery of potent CCR2 antagonists displaying IC₅₀ values in the nanomolar or subnanomolar range. The cinnamoyl compounds had higher binding affinities than the corresponding urea analogs.

Full text of DOI:10.1016/j.bmcl.2008.05.010

Bioorganic & Medicinal Chemistry Letters 18 (2008) 3562–3564
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Substituted dipiperidine alcohols as potent CCR2 antagonists
*
Mingde Xia , Cuifen Hou, Duane DeMong, Scott Pollack, Meng Pan, James Brackley, Monica Singer,
Michele Matheis, Druie Cavender, Michael Wachter
Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 8 Clarke Drive, Cranbury, NJ 08512, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and biological evaluation of a series of substituted dipiperidine alcohols are described.
Structure–activity relationship studies led to the discovery of potent CCR2 antagonists displaying IC50
values in the nanomolar or subnanomolar range. The cinnamoyl compounds had higher binding affinities
than the corresponding urea analogs.
Received 9 April 2008
Revised 30 April 2008
Accepted 1 May 2008
Available online 4 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Chemokines
MCP-1
CCR2 antagonist
Chemokines (chemotactic cytokines) are small molecular
weight proteins that play an important role in leukocyte migration
and activation.1 Chemokine receptors are mediators of inflamma-
tory and immunoregulatory disorders and diseases including rheu-
matoid arthritis, asthma, and allergic diseases. Monocyte
chemoattractant protein-1 (MCP-1) is a major chemoattractant
for monocytes and memory T cells through binding to its specific
cell-surface receptor, CC-chemokine receptor-2 (CCR2). CCR2 be-
longs to the G-protein-coupled seven-transmembrane receptor
superfamily. MCP-1 and CCR2 knockout (KO) mice have demon-
strated a phenotype of significantly decreased monocyte infiltra-
tion into inflammatory lesions.2,3 In addition, such knockout mice
are resistant to the development of experimental allergic enceph-
alomyelitis, cockroach allergen-induced asthma, atherosclerosis,
and uveitis. Many studies have implicated the importance of
MCP-1 and CCR2 in a variety of inflammatory diseases. Rheuma-
toid arthritis and Crohn’s disease patients have demonstrated a
reduction in symptoms during the treatment with TNF-a antago-
nists at dose levels that correlate with decreases in MCP-1 expres-
sion and the number of infiltrating macrophages.4 The therapeutic
potential of CCR2 antagonists in preventing, treating, or ameliorat-
ing a CCR2-mediated inflammatory syndrome or disease has at-
tracted considerable interest.5–19
vealed that alcohol 1i had much higher affinity for the human CCR2
receptor than the amine, ester, amide, and unsubstituted analogs
(Table 1). We now report the identification of additional substi-
tuted dipiperidine alcohols as potent CCR2 antagonists and present
details of our structure–activity relationship (SAR) studies.
The synthesis of compound 1i and its analogs 6a–w is outlined
in Scheme 1.
Boc-protected piperidin-4-yl-acetic acid ethyl ester 2 was con-
verted to a-bromoester 3 through bromination (LHMDS/TMSCl,
Table 1
Functional group effect on CCR2 binding affinity
R
O
N
N
F
N
H
F
F
Compound
R
CCR2 IC50 (nM)
In earlier reports,20,21 we described both the phenyl piperidinyl
derivatives as CCR2 antagonists with submicromolar binding affin-
ity and the more potent carboxylic acid analogs with IC50 in the
nanomolar range. The systematic structure–activity relationship
studies on the CH2 linker between the two piperidine moieties re-
1a
1b
1c
1d
1e
1f
1g
1h
1i
CH2NMe2
CO2Me
CH2NHCONHEt
CONH2
4800
3300
2400
1800
470
80
H
CH2NHCOMe
CH2OCOMe
CO2H
20
5
4
2
2
CH2OH
* Corresponding author. Tel.: +1 609 409 3485; fax: +1 609 655 6930.
E-mail addresses: mxia@prdus.jnj.com, mingde_xia@hotmail.com (M. Xia).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.05.010

M. Xia et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3562–3564
3563
Table 3
COOEt
COOEt
(i)
(ii)
CCR2 binding affinities of the different enantiomers
N
Boc
N
Boc
Br
R2
R1
N
O
3
2
F
N
CO2Et
R1
(iii)
(iv)
N
Boc
N
F
N
H
N
F
H
4
Compound
R1
R2
CCR2 IC50 (nM)
CH2OH
R1
7a
7b
H
CH2OH
H
2.4 2.0
10
N
Boc
N
N
CH2OH
N
H
5
O
X
CH2OH
sition of the cinnamoyl phenyl ring was preferred (less active 2-po-
sition substituted analogs were not listed). Substitution on the 5, 6,
or 7-position of the indole ring was tolerated. Compounds with a 5-
methoxy (6o) or a 7-methoxy group (6n) had higher affinity than
the analog with a 6-methoxy group (6k). The urea analogs (6t,
6u) had much lower affinity (67- and 45-fold, respectively) than
the corresponding cinnamoyl compounds (6e, 6f). Compounds
6e, 6f, and 6j had subnanomolar binding affinities.
Compounds 1i and 6a–w had one chiral center. The enantio-
mers were prepared from the known chiral intermediate through
the same synthetic route outlined in Scheme 1. The biological
data indicated that (S)-enantiomer was more potent than (R)-
enantiomer. For example, compound 7a had higher binding affin-
ity than compound 7b (Table 3). In a chemotaxis assay using the
THP-1 cell line, compound 7a effectively antagonized the MCP-1-
induced effect with an IC50 of 3.5 nM. The IC50 was 0.38 nM when
the MCP-1-induced flux of Ca2+ ions was measured instead of
chemotaxis.
In summary, substituted dipiperidine alcohols have been syn-
thesized and identified as potent CCR2 antagonists with IC50 values
in the nanomolar or subnanomolar range. Alcohol 1i had much
higher affinity for the human CCR2 receptor than the amine 1a, es-
ter 1b, amide 1d, and unsubstituted analog 1e. The cinnamoyl
compounds had higher binding affinity than corresponding urea
analogs and three analogs (6e, 6f, and 6j) had IC50 values below
1 nM. Further pharmacology studies on this series will be reported
in due course.
R2
R1
N
N
H
1i, 6a-w
Scheme 1. Synthesis of alcohol analogs. Reagents and conditions: (i) LiHMDS,
TMSCl, À78 °C, then Br2 82%; (ii) substituted 4-(indol-3-yl)piperidine, CH3CN, N(i-
Pr)2Et, reflux, 49–80%; (iii) LAH, 0 °C 80–90%; (iv) (a) TFA; (b) ArCH@CHCOCl or
ArNCO, 21–82%.
Br2). Then compound 3 was refluxed with the desired substituted
4-(indol-3-yl)piperidine in acetonitrile to give ester 4, which was
reduced to alcohol 5 with LAH. Alcohol 5 was converted to the tar-
get compounds 1i and 6a–w through deprotection of the Boc group
with TFA, and acylation with appropriate acid chloride or
isocyanate.
Table 2 lists the CCR2 binding affinities for the alcohol analogs
6a–w. Halogen or trifluoromethyl substitution on the 3, 4, or 5-po-
Table 2
CCR2 binding affinities of alcohol analogs
HOH2C
R1
O
N
R2
N
X
N
H
Acknowledgments
Compound
R1
Xa
R2
CCR2 IC50 (nM)
10
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
H
H
H
H
H
H
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
NH
3-CF3
3-Br
3,4-diF
3-Br-4-F
3,5-diF
We thank Dr. William Murray for support and Dr. Mark Macie-
lag, Dr. Peter Connolly, and Dr. Zhihua Sui for helpful discussions.
9
6
2
2
2
1
References and notes
0.6 0.3
0.2 0.2
30
3,4-diCl
3,4-diCl
3,4-diCl
3,4-diCl
3,4-diCl
3,4,5-triF
3,4,5-triF
3,4,5-triF
3,4,5-triF
3,4,5-triF
3,4,5-triF
3,4,5-triF
3,4,5-triF
3,4,5-triF
3,5-diF
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