Exploring a pocket for polycycloaliphatic groups in the CXCR3 receptor with the aid of a modular synthetic strategy

Article abstract of DOI:10.1016/j.bmcl.2009.02.093

A CXCR3 pocket capable of accommodating polycycloaliphatics was explored using a modular synthetic strategy. The systematic studies reveal that the tricyclic 2-adamantane and bicyclic (iso)bornyl group are efficiently recognized by CXCR3.

Full text of DOI:10.1016/j.bmcl.2009.02.093

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2252–2257
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Exploring a pocket for polycycloaliphatic groups in the CXCR3 receptor
with the aid of a modular synthetic strategy
Maikel Wijtmans, Dennis Verzijl, Cindy M. E. van Dam, Leontien Bosch, Martine J. Smit, Rob Leurs,
*
Iwan J. P. de Esch
Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
A CXCR3 pocket capable of accommodating polycycloaliphatics was explored using a modular synthetic
strategy. The systematic studies reveal that the tricyclic 2-adamantane and bicyclic (iso)bornyl group are
efficiently recognized by CXCR3.
Received 10 January 2009
Revised 22 February 2009
Accepted 24 February 2009
Available online 27 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
CXCR3
Reductive amination
GPCR
Polycycloaliphatic
CXCR3 is a G protein-coupled chemokine receptor involved in a
variety of inflammatory and infectious diseases and in certain
metastasis processes.1,2 Several series of small CXCR3 antagonists
have been developed to explore the associated physiological and
clinical roles of CXCR3.1–10 Of these, azaquinazolinone AMG487
(1, Fig. 1) is the most widely described in the public domain, while
some of the highest affinities reside with the broad class of piper-
azinyl-piperidines 2 (e.g., 2a/b: pIC50 = 9.5/9.7, respectively).2,3,10
The diversity amongst reported CXCR3 antagonists is high and it
key, paving the way for efficient identification and exploration of
the pocket. (2) The reported picomolar-affinity of 2 may allow
the removal of a substantial molecular portion without absolute
loss of affinity.
In the synthesis of virtually all products, two or three subse-
quent reductive aminations were used to install the benzyl, poly-
cycloaliphatic and methyl groups (Scheme 1). Routes A and B
both start from a mono-protected dibasic core and carbonyl build-
ing blocks but the peripheral groups are installed in different order.
Routes C and D are essentially the same as routes A and B but use
amine-building blocks for the polycycloaliphatic unit. Last, route E
adds an N–Me through an Eschweiler–Clark reductive amination.
Almost all reductive aminations proceeded smoothly with func-
tionalities such as double bonds, azides and pentafluorophenyl
groups left intact. Many non-commercial building blocks were pre-
pared by methods described in the literature (see Supplementary
data).
A few building blocks and final compounds required alterna-
tive approaches (Scheme 2). 1-Adamantyl substituted pyridine 4
was benzylated to salt 5 followed by a swift reduction to 22.
Benzylation of 4 by 4-ClBnBr was preferred instead of by 4-Cl,2-
F–BnBr. Sequential treatment of keto-ester 6 with 4-chloro-2-
fluorobenzaldehyde and then 2-adamantaneamine gave enamine
31. This enamine resisted NaBH(OAc)3, but NaCNBH3 in AcOH
provided a separable mixture of diastereomeric esters 32 and
33. The relative stereochemistry of these could not be unambigu-
ously determined. Aniline 57 was obtained from azide 56 by a Zn-
based reduction. Urea 37 was prepared by corresponding isocya-
nate-chemistry.
remains
a challenge to identify ‘CXCR3-priviliged’ molecular
motives.2
Our attention was drawn to a few bicycloaliphatic groups that
seem to be readily accommodated by CXCR3.8,9 Archetypical is
the unique (À)myrtenyl group, which was found in SAR studies
on 1-aryl-3-piperidin-4-yl-ureas (e.g., 3).8 In general, several
examples are known in which chemokine receptor antagonists
pick up considerable affinity by binding to hydrophobic domains
of the chemokine receptor.11,12 Therefore, with the goal of contrib-
uting to the understanding of CXCR3–ligand binding, we decided to
explore a hypothesized CXCR3 pocket for polycycloaliphatics
through a modular synthetic approach.
Our design strategy involved equipping the benzyl-aminopi-
peridine part of piperazinyl-piperidine 2 with the polycycloali-
phatic groups of choice (Fig. 2). The rationale for this strategy
was twofold: (1) We envisioned a highly modular synthetic proto-
col in which a reductive amination using simple building blocks is
* Corresponding author. Tel.: +31 20 5987600; fax: +31 20 5987610.
E-mail address: ideesch@few.vu.nl (I.J.P. de Esch).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.02.093

M. Wijtmans et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2252–2257
2253
R1
N
OEt
Cl
N
R2
O
N
N
2a: R1=4-Cl, R2=H
: R =4-Cl, R =2-F
N
H
N
1
2
N
b
N
O
H
N
H
N
N
N
CF3
O
N
O
OCF3
3
1 (AMG487)
F
Figure 1. Selected CXCR3 antagonists.
R1
R3
R1
N
N
Cl
N
R2
Polycycloaliphatic
group
N
R4
R2
N
H
N
N
benzyl-aminopiperidine
part
2
O
Figure 2. Design strategy.
A
HN
H
N
(c), a
a
b
N
H2N
N
NH
O
PA
PA
Ar
O
Ar
Boc
PA
PA
.xHCl
or
Ar
O
B
H2N
H
N
R
H
N
a
b
(c), a
N
NBoc
NH
O
Ar
PA
PA
O
.xHCl
N
R=H, Me
N
Ar
R
C
O
H
N
a
a
NH
.HCl
O
O
PA
PA
Ar
Ar
Ar
PA
NH2
Ar
H
N
H
D
O
a
b
(c), a
O
N
N
NH
NBoc
PA
PA
NH2
.xHCl
N
Ar
Me
N
H
E
d
N
N
PA
Ar
PA
Ar
Scheme 1. Modular synthetic routes A–E. Key: (a) NaBH(OAc)3, (AcOH), (Et3N), DCE, rt, 1–9 d. (b) HCl (2.0 M in dioxane), rt, 3–20 h. (c) 1 N aq NaOH, DCM, extraction.
(d) HCOOH, 37% aq H2CO, reflux, 2–4 h. PA = polycycloaliphatic group.
R-isobornylamine 7 was reductively alkylated on 20 g scale to
R-exo-piperidine 8. exo/endo Epimerization, that is, from an isobor-
nyl to a bornyl unit, may occur during reductive aminations on 7
through positional isomerisation of the intermediate imine,13 pos-
sibly compromising stereochemical integrity of final products. As
an exemplary case, we inspected two epimers 38 (exo) and 60
(endo) (vide infra), obtained after reductive aminations on epimeric
amines 7 and (commercial) 9 with ketone 10. Extensive NMR anal-
ysis (see Supplementary data) showed that both were distinguish-
able, epimerically pure and of the expected stereochemical
architecture.
All compounds were tested for their affinity for human CXCR3
(hCXCR3) by measuring the displacement of 125I-CXCL10 binding
to membranes of HEK293 cells expressing hCXCR3.14,15 Here, the

2254
M. Wijtmans et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2252–2257
N
N
N
Br
a
b
N
H
4
N
H
Cl
Cl
N
H
Cl
Cl
5
22
COOEt
COOEt
H
N
COOEt
H
N
O
c,d
e
N
N
.HCl
NH
6
31
Major diastereomer:
Minor diastereomer:
32
33
F
F
H
N
56
: R=4-N3-Bn
f
Cl
H
N
H
g
N
N
NR
OCN
NH
57: R=4-NH2-Bn
O
F
F
Cl
37
H
N
h, i
N
NH2
.HCl
.xHCl
O
F
Cl
NH2
8
9
7
10
Scheme 2. Synthesis of specific building blocks and final compounds. Key: (a) 4-ClPhCH2Br, toluene, reflux, 4 h (84%). (b) NaBH4, MeOH, rt to 80 °C, 3 h (37%). (c) 4-Cl,2-F–
PhCHO, NaBH(OAc)3, DCE, rt, 18 h (61%). (d) NaBH(OAc)3, DIPEA, 2-adamantane-amine.HCl, AcOH, DCE, rt, 72 h (67%). (e) NaBH3CN, AcOH, rt, 18 h (20% of 32, 10% of 33). (f)
NH4Cl, Zn(s), EtOH/H2O, rt, 20 h (31%). (g) 4-(2-adamantylamino)-piperidine, DCM, rt, 18 h (36%). (h) 1-Boc-4-piperidinone, NaBH(OAc)3, AcOH, DCE, rt, 1 d (66%). (i) HCl
(2.0 M in dioxane), rt, 2 h (62%).
reference piperazinyl-piperidine 2a gave pKi = 8.5. Our initial SAR
attempts left intact the 4-amino-piperidine core and mostly
utilized the 2-F,4-Cl-benzyl group, as in 2b (Fig. 2 and Table 1).
Neither attachment of a diphenylpropyl- (11) or a tetrahydro-
isoquinolinyl-group (12), nor of monocyclic units such as
pyrrolidinyl-, cyclooctenylmethyl-, cyclohexyl- and cyclohexyl-
methyl-groups (13–16) provided appreciable affinity. The same
was true for the bicyclic (À)-myrtenyl group (17), which is in sharp
contrast to the 1-aryl-3-piperidin-4-yl-urea series (3).8 A tropine
moiety had a detrimental effect on affinity (18). Gratifyingly, a
tricyclic 2-adamantane group lifted the affinity to pKi = 6.8 (19).
Compound 19 was found to be an antagonist (pKb = 6.1 0.1,
n = 3) as measured by its inhibitory effect on [3H]-inositolphos-
phates levels after stimulation with 50 nM CXCL10 in HEK293T-
hCXCR3/Gaqi5 cells.14
A small SAR exploration with other benzyl groups revealed that
4-Cl-substitution (20) is slightly less efficient than 4-Cl,2-F substi-
tution yet still beneficial (20 vs 21) and that 2-adamantane substi-
tution is superior over 1-substitution (20 vs 22). Reverting back to
the 4-Cl,2-F-benzyl pattern, it was found that elongation of the
N-adamantane distance decreased affinity (23, 24). N-Methylation
of 19 and 23 to 25 and 26, respectively, consistently lowered
affinity. Dimethyladamantane 27 was tolerated but to a lesser
extent as 19. Last, azaadamantane 28 had little affinity.
The 4-aminopiperidine-benzyl spacer was also varied (Table 2).
Substitution on the benzylic CH2 (29), methylene insertion adja-
cent to the piperidine (30) or introduction of an (un)saturated ester
(31– 33) led to more than a log unit drop in affinity. An inverse 4-
amino-piperidine (34), 3-amino-piperidine (35), azepane (36) and
urea (37) were also tested but none matched 19. Therefore, we
decided to retain the 4-amino-piperidine-benzyl unit throughout
the remainder of our work.
To further define the pocket, we sought to investigate in-depth
an additional polycycloaliphatic group. This also provided an
opportunity to overcome the high crystallinity and suboptimal
solubility kinetics of many symmetrical adamantane-compounds.
We selected the bicyclic isobornyl group, derived from camphor.
When compared to 19, R-isobornyl analogue 38 displayed some-
what lower affinity (pKi = 6.4) and functional activity
(pKb = 5.7 0.1, n = 3), but had satisfactorily reduced crystallinity.
Interestingly, camphor itself is a key unit of an unrelated series
of CXCR3 antagonists that was disclosed in a patent shortly after
our switch to an isobornyl unit,16 suggesting a more general appli-
cability of camphor-like groups as CXCR3–ligand motives.17
We tested twenty-one R-isobornyl-compounds with chemically
diverse benzyl groups (Table 3). Plain benzyl or heterocyclic groups
(39–42) were ineffective. Of some fluorinated benzyl groups (43–
46), the pentafluorobenzyl group (46) gave good affinity
(pKi = 6.3). Analogous to the 2-adamantane series, the 4-Cl contrib-
utes much more to the affinity of 38 than the 2-F (47 vs 48). Like-
wise, omission of 2-F from
a 4-MeO,2-F derivative has no
significant effect (49 vs 50). A MeO-scan (50–52) revealed the
para-position as the preferred anchor for substitution and we thus
introduced additional substituents on this position (53–58). Of
these, the 4-CF3O– (53) and 4-N3 substituents (56) units gave
sub-lM affinity.
In contrast to the achiral 2-adamantane system, the isobornyl
group has multiple stereomers providing a subtle way to probe
the ‘polycycloaliphatic-pocket’. However, little effect of stereo-
chemistry was observed between stereomers 38, 60 and 62 (Table
4). Last, both N-methylation (59, 61) and methylene insertion (63)
led to a drop in affinity (Table 4), reinforcing the SAR similarity be-
tween the tricyclic 2-adamantane and bicyclic (iso)bornyl series.
Summarizing, with the aid of a highly modular synthetic ap-
proach we probed a hCXCR3 pocket able to efficiently accommo-
date specific bi- and tri-cycloaliphatics. A comparison of the best
compounds to several monocyclic counterparts clearly puts for-
ward the interaction of a polycycloaliphatic moiety with a comple-
mentary CXCR3 pocket as a straightforward yet very significant
ligand binding element. Thereby, our results confirm that hydro-
phobic domains of chemokine receptors may provide efficient an-
chor points for small molecules. Our findings will be translated to
future series from our lab and can generally be useful in the design
of CXCR3 antagonists.

M. Wijtmans et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2252–2257
2255
Table 1 (continued)
Table 1
Exploration of polycycloaliphatic group
a
#
R1
R2
H
R3
Route
pKi SEMb
R3
N
24
Af
6.3 0.0
R1
N
F
F
F
F
F
Cl
Cl
Cl
Cl
Cl
R2
a
#
R1
—
R2
—
R3
—
Route
n.a.c
pKi SEMb
25
26
27
28
Me
Me
H
E
E
A
A
5.9 0.0
5.6 0.1
6.3 0.1
5.1 0.1
2a
8.5 0.2
Ph
11
12
13
14
15
16
17
H
—
—
H
H
H
H
C
C
C
A
C
C
A
<4
Ph
F
F
F
F
F
F
F
Cl
Cl
Cl
Cl
Cl
Cl
Cl
5.3 0.0
<5
H
N
5.6 0.1
5.3 0.1
5.4 0.0
5.4 0.2
a
Codes refer to Scheme 1.
n = 2–5.
See Ref. 10.
b
c
d
e
f
Obtained as a ꢀ6/1 mixture of diastereomers.
See Scheme 2.
Used as maleate salt.
Table 2
Exploration of spacer
Cl
SPACER
F
18
19
H
H
Ad
<5
#
Spacer
Routea
pKi SEMb
N
F
F
Cl
Cl
N
N
19
A/C
6.8 0.2
N
H
A/C
6.8 0.2
29
30
B
5.3 0.0
5.4 0.0
N
H
20
H
B
6.4 0.1
Cl
N
Bc
H
N
21
22
23
H
H
H
B
5.4 0.1
6.0 0.0
6.0 0.1
EtOOC
N
31
32
n.a.d
5.3 0.2
n.a.e
N
H
Cl
EtOOC
N
n.a.e
5.3 0.1
A
N
H
F
Cl
(continued on next page)

2256
M. Wijtmans et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2252–2257
Table 2 (continued)
Table 4
Exploration of (iso)bornyl substituent
#
Spacer
Routea
n.a.f
pKi SEMb
EtOOC
N
N
R1
33
5.4 0.1
N
F
Cl
N
H
R2
H
N
#
R1
Stereochemistry
R2
H
Routea
pKi SEMb
34
35
Ag
5.4 0.0
5.7 0.1
N
38
C/D
6.4 0.1
R-exo
Dh
N
N
H
59
60
61
62
Me
H
E
C
E
C
5.8 0.1
6.4 0.2
5.9 0.1
6.2 0.2
N
36
37
Ag
5.8 0.1
N
R-endo
O
Me
H
n.a.d
<5
N
N
H
S-exo
N
H
a
Codes refer to Scheme 1.
n = 2–5.
Carried out with tert-butyl 4-(aminomethyl)piperidine-1-carboxylate instead of
b
c
63
2 Epimersc
H
A
5.7 0.1
with tert-butyl 4-aminopiperidine-1-carboxylate.
d
See Scheme 2.
Major diastereomer, see Scheme 2.
Minor diastereomer, see Scheme 2.
Carried out with tert-butyl 4-aminopiperidine-1-carboxylate (for 34) or with
e
a
f
Codes refer to Scheme 1.
b
c
g
n = 2–5.
Mixture of epimers (ꢀ2/1).
10 equiv of homopiperazine (for 36, omitting HCl treatment) instead of tert-butyl
piperidin-4-ylcarbamate (see Scheme 1).
h
Carried out with N–Boc-3-piperidinone instead of N–Boc-4-piperidinone.
Acknowledgments
Table 3
Luc Smeets, Rogier Smits, Benjamin Faasse and Milagros Chong
are acknowledged for providing four compounds. This work was
financially supported by the Dutch Top Institute Pharma (project
number D1.105: the GPCR Forum).
Exploration of aromatic group in isobornyl series
H
N
N
R
Supplementary data
#
R
Routea
pKi SEMb
Syntheses of building blocks, activity curves, NMR spectra and
optical rotations of selected compounds. Supplementary data asso-
ciated with this article can be found, in the online version, at
doi:10.1016/j.bmcl.2009.02.093.
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
4-Chloro-2-fluorobenzyl
Benzyl
2-Pyridylmethyl
3-Pyridylmethyl
2-Furylmethyl
4-Fluoro-3-trifluoromethylbenzyl
3-Fluoro-5-trifluoromethylbenzyl
2,4-Difluorobenzyl
2,3,4,5,6-Pentafluorobenzyl
4-Chlorobenzyl
2-Fluorobenzyl
2-Fluoro-4-methoxybenzyl
4-Methoxybenzyl
3-Methoxybenzyl
2-Methoxybenzyl
4-Trifluoromethoxybenzyl
4-(Methoxycarbonyl)benzyl
4-Acetamidobenzyl
4-Azidobenzyl
C/D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
6.4 0.1
5.6 0.1
5.1 0.2
<5
5.2 0.1
5.6 0.1
5.4 0.1
5.7 0.1
6.3 0.2
6.3 0.1
5.2 0.1
5.8 0.1
5.7 0.1
5.1 0.1
5.0 0.1
6.1 0.1
5.5 0.1
<5
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D
6.1 0.0
5.2 0.2
5.4 0.2
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4-(Dimethylamino)benzyl
n.a.c
D
a
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