Design, synthesis and structure activity relationships of spirocyclic compounds as potent CCR1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2013.04.047

A series of CCR1 antagonists based upon spirocyclic compounds 1b and 2b were synthesised in which substituted aniline moiety was replaced with substituted benzamides. In vitro data revealed that CCR1 potency could be retained in such compounds.

Full text of DOI:10.1016/j.bmcl.2013.04.047

Bioorganic & Medicinal Chemistry Letters 23 (2013) 3500–3504
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and structure activity relationships of spirocyclic
compounds as potent CCR1 antagonists
b,
Nafizal Hossain a, , Svetlana Ivanova , Jonas Bergare a, Marguérite Mensonides-Harsema b,
,
⇑
Martin E. Cooper a
a Department of Medicinal Chemistry, RIA Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden
b Department of Medicinal Chemistry, AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of CCR1 antagonists based upon spirocyclic compounds 1b and 2b were synthesised in which
substituted aniline moiety was replaced with substituted benzamides. In vitro data revealed that CCR1
potency could be retained in such compounds.
Received 14 March 2013
Revised 17 April 2013
Accepted 18 April 2013
Available online 28 April 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
CCR1
Antagonists
Chemokines
hERG
Spirocyclic
Inflammatory disorders are characterised by the excessive
recruitment of leukocytes to the site of inflammation. Leukocytes
trafficking in a controlled manner is an important feature of the
immune response to infections, while loss of such control results
in inflammatory diseases. Chemokines belong to a super family
of cytokines and play an important role in various inflammatory
diseases by mediating leukocyte recruitment.1–4 Various diseases
such as rheumatoid arthritis,5,6 multiple sclerosis7,8 and asthma
are characterised by deregulated leukocyte recruitment. Chemo-
kines bind to cell surface chemokine receptors and thus, transmit
intracellular signals to their target cells by activating G-proteins
coupled to the receptors. Chemokine receptors are attractive ther-
apeutic targets for drug developments due to their central role in
regulating leukocyte trafficking. The C–C (cystine–cystine) chemo-
in the literature.9–14 Here, we report the discovery of a novel class
of spirocyclic compounds as potent CCR1 antagonists.
Previously, we have reported a series of conformationally
constrained spirocyclic compounds as highly potent CCR1 antago-
nists15 (Fig. 1). However, this class of compound contains an
N-acetylated aniline moiety which may be prone to deacetyla-
tion16b by specific human enzymes to generate aniline derivative,
thus potentially leading to reactive metabolites formation, result-
ing in possible genotoxicity or other unwanted side effects. Thus,
when such a fragment is present in a drug candidate, a careful
analysis is required to make sure that the molecule as a whole
and the corresponding aniline fragments are free from genotoxi-
city16a before progression to clinical development. Therefore, it
may be desirable to identify possible alternatives to such an aniline
moiety in a series of candidate drug molecules. Thus, we focused
our attention towards finding a replacement for the N-acetyl group
in 1b and 2b (Fig. 1) without compromising CCR1 potency. Hence,
we investigated whether a benzamide derivative of the N-acetyl
aniline moiety would be feasible. Thus, we designed a series of
compounds with the N-acetyl moiety replaced by a CONRR group.
Synthesis of the carboxamide derivatives is outlined in Schemes
1–5. The starting material 5 was prepared from 4 according to a
kine receptor-1 (CCR1) and its’ major endogenous ligands MIP-1
a
(CCL3) and RANTES (CCL5) play an important role in chronic
inflammatory diseases such as rheumatoid arthritis and multiple
sclerosis and inhibition of CCR1 is expected to be beneficial for
patients who suffer from such inflammatory disorders. Thus, low
molecular weight synthetic CCR1 antagonists could be useful as
therapeutic agents. The search for specific and highly potent che-
mokine receptor antagonists has recently been a popular theme
published procedure.17 Reaction of
5 with (2S)-oxiran-2-yl-
methyl-3-nitrobenzene sulphonate in the presence of Cs2CO3 gave
epoxide 6 in high yield. Epoxide 6 was opened by spirocyclic amine
1 to yield 7 which was hydrolysed by aqueous NaOH to afford 8 in
quantitative yield. Standard amide coupling reaction of 8 with
⇑
Corresponding author. Tel.: +46 317761851; fax: +46 317763818.
E-mail address: nafizal.hossain@astrazeneca.com (N. Hossain).
Former employee.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.04.047

N. Hossain et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3500–3504
3501
O
O
HN
O
HN
OH
O
O
O
O
N
N
X
X
OR
OH
1a
1b: X = Cl hCCR1 IC50 = 360 pM
2b: X = F hCCR1 IC50 = 520 pM
1: X = Cl
2: X = F
3: X = H
Figure 1. Previously reported CCR1 antagonists.
O
O
O
O
O
O
O
HO
HO
O
(a)
(b)
OPMB
OH
OPMB
4
5
6 (87%)
R1
R1
O
O
NH
O
OH
OH
O
O
(d)
O
O
N
N
Cl
Cl
R2
OPMB
9: R1 = CH2CH2OH R2 = OPMB (48%)
10: R1 = CH2CH2OH R2 = OH (60%)
7: R1 = Me (97%)
8: R1 = H (99%)
(e)
(c)
11: R1 = CH2CH2NHAc R2 = OPMB (72%)
12: R1 = CH2CH2NHAc R2 = OH (55%)
13: R1 = CH2CH2NH2 R2 = OPMB (44%)
14: R1 = CH2CH2NH2 R2 = OH (46%)
(e)
(e)
Scheme 1. Reagents and conditions: (a) (2S)-Oxiran-2-yl-methyl-3-nitrobenzene sulphonate, Cs2CO3, DMF, rt, 20 h (87%); (b) spirocycle 1, EtOH, reflux 20 h (97%); (c) aq
NaOH, EtOH, rt, 3 h (99%); (d) NH2CH2CH2OH or NH2CH2CH2NHAc or NH2CH2CH2NH2, CDI, DMF, rt, 20 h (44–72%); (e) TFA, CH2Cl2, rt, 1 h (46–60%).
R2
HN
R2
DMAP at room temperature in 43% yield. Compounds 5, and
15–18 were treated separately with cyclopropyl amine to give
19–22, and 24 in 31–84% isolated yield, whilst treatment of 5 with
methyl amine gave 23 in quantitative yield. Compounds 19–24,
were treated separately with (2S)-oxiran-2-yl-methyl-3-nitroben-
zene sulphonate in the presence of Cs2CO3 in DMF to give corre-
sponding epoxides 25–30 in good yields. Epoxides 25–30 were
opened by spirocyclic amines 1 or 2 in refluxing ethanol to give
31–34, 36 and 38 in moderate yields. Finally, the para-methoxy-
benzyl protecting group in 34, 36 and trityl group in 38 were
removed by TFA treatment to give 35, 37 and 38a in moderate
yield (Scheme 2, Table 1).
O
O
O
O
NH
O
HO
HO
O
(b)
(a)
R1
R1
15-18
R1
25-30
19-24
R2
NH
O
OH
O
(c)
O
N
The acid derivative 8 was converted to amide 39 and 41 in
quantitative yield as crude materials, by coupling with the respec-
tive amines under standard conditions. The para-methoxybenzyl
protecting group in 39 and 41 was removed by TFA treatment to
afford 40 and 42, respectively, in low yield (Scheme 3).
X
31-38a
R1
Scheme 2. Reagents and conditions: (a) Cyclopropyl amine, 70–100 °C, 20 h or rt,
20–170 h (31%-quant.); (b) (2S)-oxiran-2-yl-methyl-3-nitrobenzene sulphonate,
Cs2CO3, DMF, rt, 20 h (63–99%); (c) spirocycles 1, 2, EtOH, reflux 20 h (38–69%)
(Table 1).
Compound 44 was prepared following a literature procedure.18
Reaction of 44 with para-methoxybenzyl chloride in the presence
of K2CO3 in acetone to give 45 in good yield. Compounds 43, 16,
and 45 were treated separately with (2S)-oxiran-2-yl-methyl-3-
nitrobenzene sulphonate and Cs2CO3 in DMF to give epoxides
46–48 in high yields. Epoxides 46–48 were opened by spirocyclic
amines 1–3 and the corresponding products were hydrolysed to
give 50, 52, 54, 56, 58 and 60 in high yields. Subsequently, these
free acids were converted to amides 61–66, 68, 70, 72, 74 and
76, in acceptable yields, by coupling with the respective amines
different amines in the presence of CDI afforded 9, 11 and 13 in
moderate yields. Finally, the para-methoxybenzyl (PMB) protect-
ing group in 9, 11 and 13 was removed by TFA treatment to afford
final compounds 10 (60%), 12 (55%) and 14 (46%) (Scheme 1).
Intermediate 18 was prepared from 4 by treatment with tri-
phenylmethyl (Tr) chloride in DMF in the presence of Et3N and

3502
N. Hossain et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3500–3504
R1
R1
N
O
O
O
OH
OH
O
O
(b)
O
O
N
N
Cl
Cl
R2
OPMB
39: R1 = OH R2 = OPMB (100%)
40: R1 = OH R2 = OH (17%)
7: R1 = Me
(c)
(c)
(a)
8: R1 = H (99%)
41: R1 = NMe2 R2 = OPMB (100%)
42: R1 = NMe2 R2 = OH (30%)
Scheme 3. Reagents and conditions: (a) aq NaOH, MeOH, rt, 3 h (99%); (b) (3R)-pyrrolidin-3-ol, CDI, DMF, rt, 20 h (100%) or (3R)-N,N-dimethylpyrrolidin-3-ol, PS-
carbodiimide, NMP, CH2Cl2, rt, 20 h (100%); (c) TFA, CH2Cl2, rt, 1 h (17–30%).
R2
O
O
O
O
O
O
OH
O
O
O
HO
O
N
(b), (c)
(a)
X
R3
R2
R2
R1
R1
43-45
R1
46-48
49-60
R3
N
O
OH
O
(d)
O
N
X
R2
R1
61-77
Scheme 4. Reagents and conditions: (a) (2S)-Oxiran-2-yl-methyl-3-nitrobenzene sulphonate, Cs2CO3, DMF, rt, 20 h (74–96%); (b) spirocycles 1, 2, 3, EtOH, reflux 20 h (42–
91%); (c) aq NaOH, EtOH, rt, 3 h (36–100%); (d) amine, CDI, DMF, rt, 20 h (28–100%) (Table 2).
X
N
O
O
O
OH
OH
O
O
(a)
O
O
N
N
Cl
Cl
R1
OPMB
78: X = CH2 R1 = OPMB (23%)
79: X = CH2 R1 = OH (54%)
(b)
8
80: X = CH2OH R1 = OPMB (47%)
81. X = CH2OH R1 = OH (55%)
(b)
(b)
82: X = O R1 = OPMB (55%)
83: X = O R1 = OH (54%)
Scheme 5. Reagents and conditions: (a) Amine, CDI, DMF, rt, 20 h (23–55%); (b) TFA, CH2Cl2, rt, 1 h (54–55%).
under standard conditions. The protecting groups from 66, 68, 70,
72, 74 and 76 were removed by TFA treatment to give 67, 69, 71,
73, 75 and 77 in moderate yields (Scheme 4, Table 2).
Similarly, the acid derivative 8 was converted to the corre-
sponding amides 78, 80 and 82 via amide coupling reaction in
the presence of CDI in DMF and subsequently the protecting group
was removed by TFA treatment to give 79 (54%), 81 (55%) and 83
(54%) (Scheme 5).
As a first attempt NHAc in 1b and 2b (Fig. 1) was replaced with -
CONHMe and thus 35 and 37 (Scheme 2) were designed. Biological
evaluations15 revealed that CCR1 potency of these compounds was
dropped to some extend compared to N-acetyl analogues 1b and
2b but they were nevertheless very potent CCR1 antagonists (Table
3). In addition 35 was found to be stable in human hepatocytes but
less stable in rat hepatocytes. On the other hand 37 was less stable
both in rat and human hepatocytes. Both of these compounds had
good permeability in a caco-2 assay. Moreover, 35 and 37 were po-
tent rodent CCR1 antagonists. Next the tolerability with regard to
CCR1 potency of extended chain with polar groups instead of the
N-methyl group was explored and 10, 12 and 14 were designed.
However, these compounds were found to be 6- to 200-fold less
active compared to 35. In order to investigate whether this was
due to the lipophilic effect, a cyclopropyl group was introduced in-
stead of the hydrophilic groups such as hydroxyl, primary amine
and one model example 38a was synthesised. Indeed, 38a was
found to be a potent CCR1 antagonist. To explore further the meta
hydroxyl group of the substituted phenol was replaced by a hydro-
gen, O-methyl or fluorine and 31, 32, 33 were synthesised. Gratify-

N. Hossain et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3500–3504
3503
Table 1
Table 3
In vitro data, CCR1 antagonists19
Compound
R1
R2
X
Yield (%)
Compound hCCR1
IC50
hheps
rheps
(ll/
min/
Caco2
(cm/
hERG20 rCCR1
IC50 IC50
M) M)
(
l
l/min/
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
38a
H
F
(l
M)
106 cells)
s  106)
(l
(l
mg)
OMe
OTr
H
OMe
F
OPMB
OPMB
OTr
H
OMe
F
OPMB
OPMB
OTr
H
OMe
F
OPMB
OH
OPMB
OH
43
53
31
84
71
100
55
99
99
63
70
75
73
38
67
56
69
52
68
44
10
12
14
31
32
33
35
37
38a
40
42
61
62
63
64
65
67
69
71
73
75
77
79
81
83
0.012
0.071
0.4
n.a.
n.a.
n.a.
5.2
15
4.6
<4.6
26
10.6
n.a.
n.a.
10
n.a.
n.a.
n.a.
45
n.a.
20
33
22
28
n.a.
n.a.
n.a.
n.a.
<4
n.a.
n.a.
8.1
6.7
n.a.
n.a.
n.a.
23
1.4
n.a
n.a
24
12
16
14
8.1
12
0.1
0.4
5.3
6.5
14
n.a.
1.2
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Me
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Me
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Me
n.a.
n.a.
n.a.
0.038
n.a.
n.a.
0.3
n.a.
>17.5
n.a.
n.a.
0.7
0.0028
0.0025
0.0014
0.0018
0.0032
0.0014
0.0079
0.0013
0.0089
0.005
0.0025
0.13
0.012
0.00092 <3
0.0019
0.11
0.079
0.16
0.89
0.114
14
11
Cl
Cl
Cl
Cl
Cl
F
F
Cl
Cl
6.8
n.a.
n.a.
2.5
3
n.a.
n.a.
8.3
22.7
n.a.
n.a.
>10
n.a.
n.a.
1.6
8.1
0.6
0.8
n.a
3.9
0.2
13
18
0.2
2.6
0.88
14
Me
Me
Me
Cyclopropyl
Cyclopropyl
<3
n.a.
n.a.
n.a.
9.6
14
0.0079
0.089
0.0018
0.0071
0.0011
0.032
OTr
OH
52
n.a.
n.a.
n.a.
1.1
n.a.
n.a.
n.a.
Table 2
Data represent the average values of at least two experiments.
n.a.: Not available.
hheps: Human hepatocytes.
rheps: Rat hepatocytes.
Compound
R1
R2
R3
X
Yield (%)
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
Me
OH
OPMB
Me
F
OPMB
Me
Me
Me
Me
F
H
Caco: Human colonic adenocarcinoma.
hERG: Human ether-a-go-go-related-gene.
Cl
Cl
H
H
Cl
Me
H
Me
H
Me
H
Me
H
Me
H
Me
H
H
H
H
H
H
Cl
Cl
H
H
H
H
H
H
H
60
75
96
74
91
79
77
36
64
84
77
72
42
70
67
quant.
73
56
28
40
40
37
59
52
62
100
32
34
80
59
27
37
72
membered ring was explored, thus 40 and the corresponding iso-
mer 69 were designed. In vitro data revealed that constrained com-
pounds 40 was equipotent to 10 whilst 69 was sixfold more potent
than the analogue with flexible chain 10. However, they were less
permeable as well. The hydroxyl group in the pyrrolidine ring in 40
and 69 was replaced with a NMe2 moiety. Thus, 42 and 71 were de-
signed. Compound 42 was equipotent to 69 whilst 71 was almost
100-fold less potent than 69. Next, 69 was modified either by
replacing the meta hydroxyl group of the substituted phenol with
methyl or fluorine or by replacing the hydroxyl group on the pyr-
rolidine ring with methoxy, N-acetyl or hydrogen. Thus, 62, 63, 73,
75 and 77 were designed and synthesised. These compounds were
all found to be potent CCR1 antagonists with good permeability ex-
cept 75 whilst 63 was also found to be metabolically stable both in
human and rat hepatocytes. However, 63 was active in hERG chan-
nel (Table 3). To investigate the substitution effect on the phenyl
ring of the spirocycle, 63 was compared with 64 and 65. Compound
65 was found to be fivefold less potent CCR1 antagonist than 63
whereas 64 was more than 60-fold less potent compared to 63.
The drop of potency observed with 64 and 65 was presumed to
be due to reduced lipophilicity. Similarly comparison of 69 with
67, showed that introduction of chlorine in the para position of
the substituted phenol improved CCR1 potency, albeit to a small
extent, whilst good stability in human and rat hepatocytes was re-
tained. However, the permeability of 67 was not improved, relative
to 69, despite increased lipophilicity. The reason for low perme-
ability of 69 is at present unclear. In addition, this compound
was less active in hERG channel. Finally, expansion of the five
membered ring to a six membered ring was explored, thus 79,
81 and 83 were designed. Evaluation of these compounds revealed
81 to be potent CCR1 antagonist whilst 79 and 83 were less potent.
H
H
H
H
H
H
H
H
H
H
Cl
Cl
OH
OH
OH
OH
OH
OH
OH
OH
OH
NMe2
NMe2
OMe
OMe
NHAc
NHAc
H
Cl
Cl
F
F
Cl
Cl
F
F
F
F
F
F
H
H
Cl
Cl
F
Cl
Cl
H
F
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
OPMB
OPMB
Me
Me
F
F
F
OPMB
OH
OPMB
OH
OPMB
OH
OPMB
OH
OPMB
OH
OPMB
OH
H
H
H
H
ingly, these compounds were found to be potent CCR1 antagonists
with good permeability. They were also found to be stable in hu-
man hepatocytes except 32. In addition, 32 was found to be very
potent rat CCR1 antagonist (Table 3). Next, the possibility of replac-
ing the flexible chain such as in 10 with more constrained five

3504
N. Hossain et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3500–3504
9. Liang, M.; Hallari, C.; Rosser, M.; Ng, H. P.; May, K.; Monahan, S.; Baumann, J. G.;
Islam, I.; Ghannam, A.; Buckman, B.; Shaw, K.; Wei, G. P.; Zu, W.; Zhao, Z.; Ho,
E.; Shen, J.; Oanh, H.; Subramanyam, B.; Vergona, R.; Taub, D.; Dunning, L.;
Harvey, S.; Snider, R. M.; Hesselgeser, J.; Morrissey, M. M.; Perez, H. D.; Horuk,
R. J. Biol. Chem. 2000, 275, 19000.
10. Naya, A.; Sagara, Y.; Ohwaki, K.; Saeki, T.; Ichikawa, D.; Iwasawa, Y.; Noguchi,
K.; Ohtake, N. J. Med. Chem. 2001, 44, 1429.
11. Ng, P. H.; May, K.; Baumann, J. G.; Ghannam, A.; Islam, I.; Liang, M.; Horuk, R.;
Hesselgesser, J.; Snider, R. M.; Perez, H. D.; Morrissey, M. J. Med. Chem. 1999, 42,
4680.
However, whilst 79 was found to have good permeability, this was
not the case for 81 and 83.
In conclusion, we have shown that the N-acetyl group (a frag-
ment of pro aniline), of the potent CCR1 antagonists 1b and 2b,
could be replaced by -CONRR (substituted benzamide) moiety with
retention of CCR1 potency and good in vitro pharmacokinetics
properties. Often, species cross-over is a challenge in the evalua-
tion of chemokine receptor modulators, making it difficult to eval-
uate the pharmacodynamic properties of the compounds and the
potential clinical relevance of the mechanism. However, this inves-
tigation showed that, although compounds in this series are gener-
ally much less potent against rat than human CCR1 receptors, some
of these compounds may in fact be expected to show moderate
efficacy in rodent models of inflammatory diseases. However, it
was also observed that these compounds are prone to inhibit hERG
channel and this activity could only be minimized at the expense of
permeability. Thus, further studies will be required to optimize
such parameters before progression of any of these compounds
to clinical evaluation.
12. Kath, J. C.; Brissette, W. H.; Brown, M. F.; Conklyn, M.; DiRico, A. P.; Dorff, P.;
Gladue, R. P.; Lillie, B. M.; Lira, P. D.; Mairs, E. N.; Martin, W. H.; McElroy, E. B.;
McGlynn, M. A.; Paradis, T. J.; Poss, C. S.; Stock, I. A.; Tylaska, L. A.; Zheng, D.
Bioorg. Med. Chem. Lett. 2004, 14, 2169.
13. Brown, M. F.; Avery, M.; Brissette, W. H.; Chang, J. H.; Colizza, K.; Conklyn, M.;
DiRico, A. P.; Glaude, R. P.; Kath, J. C.; Krueger, S. S.; Lira, P. D.; Lillie, B. M.;
Lundquist, G. D.; Mairs, E. N.; MaElroy, E. B.; McGlynn, M. A.; Paradis, T. J.; Poss,
C. S.; Rossulek, M. I.; Shepard, R. M.; Sims, J.; Strelevitz, T. J.; Trusdell, S.;
Tylaska, L. A.; Yoon, K.; Zheng, D. Bioorg. Med. Chem. Lett. 2004, 14, 2175.
14. (a) Revesz, L.; Bollbuck, B.; Buhl, T.; Eder, J.; Esser, R.; Feifel, R.; Heng, R.;
Hiestand, P.; Jachez-Demange, B.; Loeetscher, P.; Sparrer, H.; Schlapbach, A.;
Waelchli, R. Bioorg. Med. Chem. Lett. 2005, 15, 5160; (b) Xie, Y. F.; Lake, K.;
Ligsay, K.; Komanda, M.; Sircar, I.; Nagarajan, G.; Li, J.; Xu, K.; Parise, J.;
Schneider, L.; Huang, D.; Liu, J.; Dines, K.; Sakurai, N.; Barbose, M.; Jack, R.
Bioorg. Med. Chem. Lett. 2007, 17, 3367; (c) Xie, Y. F.; Sircar, I.; Lake, K.;
Komandla, M.; Ligsay, K.; Li, J.; Xu, K.; Parise, J.; Schneider, L.; Huang, D.; Liu, J.;
Sakurai, N.; Barbose, M.; Jack, R. Bioorg. Med. Chem. Lett. 2008, 18, 2215; (d)
Pernell, A. M. K.; Aggen, J. B.; Sen, S.; Chen, W.; Xu, Y.; Sullivan, E.; Li, L.;
Greenman, K.; Charvat, T.; Hansen, D.; Dairaghi, D. J.; Wright, J. J. K.; Zhang, P.
Bioorg. Med. Chem. Lett. 2013, 23, 1228; (e) Bhaley, G.; Albrecht, B.; Akhlaq, M.;
Baettig, U.; Beer, D.; Brown, Z.; Charlton, S.; Dunstan, A.; Bradley, M.; Gedeck,
P.; Glen, A.; Howe, T.; Keller, T.; Davies, J. L.; Li, A.; McCarthy, C.; Mocquet, C.;
Owen, C.; Nicklin, P.; Rosethorne, E. Bioorg. Med. Chem. Lett. 2011, 21, 6249.
15. Hossain, N.; Ivanova, S.; Bergare, J.; Eriksson, T. Bioorg. Med. Chem. Lett. 2013,
23, 1883.
16. (a) Hillebrecht, A.; Muster, W.; Brigo, A.; Kansy, F.; Weiser, T.; Singer, T. Chem.
Res. Toxicol. 2011, 24, 843; (b) Taxac, N.; Prasad, K. C.; Bharatam, P. V. Comput.
Theor. Chem. 2013, 1007, 48.
17. Tangdenpaisal, K.; Sualek, S.; Ruchirawat, S.; Ploypradith, P. Tetrahedron 2009,
65, 4316.
18. Anderson, W. K.; Boehm, T. L.; Makara, G. M.; Swann, R. T. J. Med. Chem. 1996,
39, 46.
19. For biological assay see Ref. 15.
20. hERG IC50 was determined in human embryonic kidney cells via ion flux
electrophysiology according to the following reference: Furber, M.; Alcaraz, L.;
Luckhurst, C.; Bahl, A.; Beaton, H.; Bowers, K.; Collington, J.; Denton, R.; Donald,
D.; Kinchin, E.; Macdonald, C.; Rigby, A.; Riley, R.; Soars, M.; Springthorpe, B.;
Webborn, P. Bioorg. Med. Chem. Lett. 2012, 22, 7707.
Acknowledgments
We thank to our colleagues at the Departments of Biosciences
and DMPK for generating data, Drs. Soren Andersen and Hans
Lönn for reading the manuscript. We also thank Dr. Peter Sjö,
Director of the Department of Medicinal Chemistry, for his sugges-
tion in writing this manuscript.
References and notes
1. Strieter, R. M.; Standiford, T. J.; Huffnagle, G. B.; Colletti, L. M.; Lukacs, N. W.;
Kunkle, S. L. J. Immunol. 1996, 156, 3583.
2. Luster, A. D. N. Eng. J. Med. 1998, 338, 436.
3. Gerard, C.; Rollins, B. J. Nat. Immunol. 2001, 2, 108.
4. Proudfoot, A. E. I. Nat. Rev. Immunol. 2002, 2, 106.
5. Godessart, N.; Kunkel, S. L. Curr. Opin. Immunol. 2001, 13, 670.
6. Loetscher, P.; Moser, B. Arthritis Res. 2002, 4, 233.
7. Karpus, W. J.; Kennedy, K. J. J. Leukoc. Biol. 1997, 62, 691.
8. Godiska, R.; Chantry, D.; Dietsch, G. N.; Gray, P. N. J. Neuroimmunol. 1995, 58,
167.