Pyrrolidinyl phenylurea derivatives as novel CCR3 antagonists

Article abstract of DOI:10.1016/j.bmcl.2012.09.035

Optimization starting with our lead compound 1 (IC₅₀ = 4.9 nM) led to the identification of pyrrolidinyl phenylurea derivatives. Further modification toward improvement of the bioavailability provided (R)-1-(1-((6-fluoronaphthalen-2-yl)methyl)pyrrolidin-3-yl)-3-(2-(2- hydroxyethoxy)phenyl)urea 32 (IC₅₀ = 1.7 nM), a potent and orally active CCR3 antagonist.

Full text of DOI:10.1016/j.bmcl.2012.09.035

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6876–6881
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Pyrrolidinyl phenylurea derivatives as novel CCR3 antagonists
Aiko Nitta a, , Yosuke Iura a, Hideki Inoue a, Ippei Sato b, Koichiro Morihira b, Hirokazu Kubota b,
⇑
Tatsuaki Morokata b, Makoto Takeuchi b, Mitsuaki Ohta b, Shin-ichi Tsukamoto b, Takayuki Imaoka a,
Toshiya Takahashi a
a Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan
b Drug Discovery Research, Astellas Pharma. Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 May 2012
Revised 4 September 2012
Accepted 12 September 2012
Available online 20 September 2012
Optimization starting with our lead compound 1 (IC50 = 4.9 nM) led to the identification of pyrro-
lidinyl phenylurea derivatives. Further modification toward improvement of the bioavailability
provided (R)-1-(1-((6-fluoronaphthalen-2-yl)methyl)pyrrolidin-3-yl)-3-(2-(2-hydroxyethoxy)phenyl)urea
32 (IC50 = 1.7 nM), a potent and orally active CCR3 antagonist.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Allergic diseases
CCR3 antagonists
Pyrrolidinyl phenylurea derivatives
CC chemokine receptor 3 (CCR3) is an eotaxin receptor that ap-
pears predominantly on eosinophils. It is believed that antagonism
of CCR3 on eosinophils prevents the release of lipid mediators,
cytotoxic proteins, oxygen metabolites, and cytokines, all of which
have potential to produce the clinical manifestations of inflamma-
tory disease. A selective CCR3 antagonist that suppresses the infil-
tration of eosinophils into inflammatory sites may have clinical
potential for treatment of allergic diseases such as asthma.1–10
Previous reports from our joint research project detailed the
discovery of potent amide or urea series of CCR3 antagonists with
a 6-fluoronaphthalenyl methyl moiety.11–15 In these studies, the
urea-based series displayed different structure–activity relation-
ships from the amide. In our latest Letter,15 we described the po-
tent lead 1 (IC50 = 4.9 nM) as shown in Figure 1,16 a small
molecule CCR3 antagonist with a urea moiety. However, this com-
pound exhibited poor bioavailability in cynomolgus monkeys
(1.7%). This Letter will describe the results of our investigation into
improvement of the potency and bioavailability of 1.
antagonists, the linker part of the molecule, that is, the substruc-
ture exclusive of the key pharmacophores, should be changed.
It was considered what structural changes might be acceptable
to the linker of the CCR3 antagonist. Based on crystal X-ray analysis
of 2, our potent amide-based CCR3 antagonist,11 we selected vari-
ous linkers that might make the molecule take a U-shaped confor-
mation like that of 2 (Fig. 2). The stable conformations of structures
designed by chemists were estimated using the conformational
search functions of Molecular Operating Environment (MOE): Low-
ModeMD and MMFF94x.18 Several scaffolds that might take a U-
shaped conformation with energy not more than 0.5 kcal/mol
above the global minimum energy, were selected and synthesized.
The syntheses of 3–5 are displayed in Scheme 1. Alkylation of
alpha-position of ester 6, protecting its amine with a Boc group,
yielded 7. Substitution of chloride in 7 with an azide group and
subsequent cyclization with hydrogenation of the azide group
To improve bioavailability while maintaining CCR3 inhibitory
activity, it is important to identify which part of the molecule is
suitable for structural transformation. Our previous research re-
vealed key pharmacophores for CCR3 inhibitory activity, as shown
in Figure 1.13 One pharmacophore is a basic nitrogen atom in the
center of the molecule, and the other pharmacophores are two aryl
rings, a 6-fluoronaphthalene moiety and nitroaniline ring at the
other terminal. To improve the bioavailability of our CCR3
Key pharmacophore for CCR3 inhibitory activity
O
O
N
H
N
N
H
N
NO2
F
linker portion
1 (IC50 = 4.9 nM)
⇑
Corresponding author. Tel.: +81 467 32 9659; fax: +81 467 32 9891.
E-mail address: Aiko_Nitta@nts.toray.co.jp (A. Nitta).
Figure 1. Structure of compound 1.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.09.035

A. Nitta et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6876–6881
6877
O
N
H
N
F
2
2 (IC50 = 20 nM)
3
4
5
Figure 2. Global minimum structure of compound 2, and conformations with energy not more than 0.5 kcl/mol above the global minimum energy of 3–5.
O
O
NBoc
CO2Et
N
a, b
c, d
NBoc
NH
e, f, g
Cl
N
HN
F
EtO2C
6
3
7
8
NBoc
BocHN
O
O
N
h
i, e, j
O
O
N
HN
F
9
4
10
O
N
NH2
k
N
HN
N
N
N
H
+
N
F
11
12
5
F
Scheme 1. Reagents and conditions: (a) Boc2O, Et3N, THF, H2O, 81%; (b) LDA, THF, ꢀ78 °C, then 1-bromo-2-chloroethane, rt, 67%; (c) NaN3, DMF, 90 °C; (d) H2, 10% Pd-C,
EtOH, 73% (2 steps); (e) TFA, CH2Cl2; (f) 2-(bromomethyl)-6-fluoronaphthalene, K2CO3, DMF, 36% (2 steps); (g) NaH, (2-bromoethyl)benzene, NaI, DMF, 6.0%; (h) tert-BuLi in
pentane, THF, ꢀ78 to ꢀ20 °C, then 1-boc-4-piperidone, ꢀ78 °C to rt, 45%; (i) NaH, DMF, then BnBr; (j) 2-(bromomethyl)-6-fluoronaphthalene, K2CO3, DMF, 43% (3 steps); (k)
ClCO2p–NO2Ph, NaHCO3, CH2Cl2, then 12, Et3N, 83%.
Table 1
derivative 10 was prepared from 9 using a previously reported
CCR3 inhibiting activity of compounds 3–5 possessing U-shaped conformation
method.19 Compound 10 was converted into 4 via benzylation,
Compds
Structure
IC50 (nM)
followed by deprotection of the amino group and alkylation.
Homopiperazine 5 was synthesized by urea coupling of 11 with
amine 12. The CCR3 inhibitory activity data for 3–5 are listed in
Table 1. Spiro derivative 3 (IC50 = 600 nM), spiro-benzoxazine
derivative 4 (IC50 = 2000 nM), and homopiperazine derivative 5
(IC50 = 380 nM), all had U-shaped linkers. Among these, 5 exhibited
promising CCR3 inhibitory activity and it was synthesized via a
simple method.
The synthetic methods of derivatives of 5 in the following opti-
mization are shown in Scheme 2. Sulfonamidation of amine 14
with sulfonyl chloride 13, followed by dechlorination by hydroge-
nation yielded deprotected product 15 and protected product 16 at
20% and 33%, ‘respectively’. Urea coupling of 15 with amines 12 or
18 afforded 17 or 19.14 Compound 21 was converted from 20 via
urea coupling with 18 and subsequent deprotection and mesyla-
tion of the amino group. Amine 22 and aniline 24 were used in
place of 20 as the starting materials for compounds 23 and 25,
‘respectively’.
O
N
3
600
N
F
N
O
O
F
4
5
20000
N
N
O
N
N
N
H
380
F
resulted in 8. Removal of the Boc group of 8, followed by alkylation
with 2-(bromomethyl)-6-fluoronaphthalene and then (2-bromo-
ethyl)benzene, yielded the spiro compound 3. Spiro-benzoxazine
First, the benzyl moiety of 5 was modified to improve inhibitory
activity (Table 2). Consequently, 17, bearing a hydroxyphenyl

6878
A. Nitta et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6876–6881
OH
OH
O
O
OH
OH
Cl
SO2Cl
O
O
NH
S
a, b
c
S
N
O
+
N
BocHN
N
H
N
N
NH2
Cl
13
15
14
F
17
O
S
O
N
NHBoc
16
OH
OH
O
S
O
O
O
d
S
N
N
O
N
NH2
N
H
N
F
15
H
19
O
O
S
BocN
d, e, f
N
O
N
NH2
NH2
NH2
N
H
N
F
N
H
20
22
24
+
21
H2N
F
18
O
N
d
d
N
H
N
F
F
H
23
O
N
N
H
N
H
25
Scheme 2. Reagents and conditions: (a) iPr2NEt, CH2Cl2, quant.; (b) H2, 10% Pd-C, EtOH, 40 °C, 20% (15), 33% (16); (c) 12, ClCO2p–NO2Ph, NaHCO3, THF, CH3CN, then Et3N; (d)
18, ClCO2p–NO2Ph, NaHCO3, THF, CH3CN, then Et3N; (e) TFA, CH2Cl2, 77%; (f) MsCl, Et3N, CH2Cl2, 60%.
Table 2
19 was 150-fold more active than 5 (19: IC50 = 2.4 nM); however,
this antagonist exhibited very low oral bioavailability in cynomol-
CCR3 inhibiting activity of urea derivatives of 5
Compds Structure
IC50
(nM)
gus monkeys (data not shown).
It is generally known that decreasing the molecular weight (to
<500) and changing the group that supplies the hydrogen bond
are effective means of improving the bioavailability of compounds.
In order to confirm that the aryl group was a key pharmacophore
and the functional group was unnecessary, we designed 21, 23,
and 25 to reduce it. These derivatives exhibited relatively good
CCR3 inhibitory activity (21: IC50 = 14 nM; 23: IC50 = 41 nM; 25:
IC50 = 50 nM), and 21 and 23 unexpectedly showed this activity
without an aryl group on the left side. These results revealed that
no left-terminal aryl group was necessary for the activity of this
basic structure. Moreover, 25 exhibited moderate bioavailability
in cynomolgus monkeys (26%), as we expected.
To improve antagonist activity, we next investigated the effects
of various small substitutions around the phenyl moiety of 25. The
syntheses of 26–39, which were the most effective of the many
derivatives tested, are displayed in Scheme 3. Ureas 26, 29, and
36–39 were converted from amine 18 and appropriate anilines
via urea coupling. The aniline derivatives 42, 44, 47, and 50–52
were prepared by common routes. Alcohols 28, 30–32, and 35 were
synthesized from the nitrobenzene derivatives 54 and 56–59,
‘respectively’, by hydrogenation of the nitro group and protection
of the hydroxyl group, followed by urea coupling and deprotection.
Compounds 27, 33, and 34 were prepared by common synthetic
routes.
5
—
380
OH
O
O
S
S
N
O
O
17
25
N
H
N
N
N
F
F
OH
O
O
N
19
21
2.4
N
H
N
H
O
O
S
N
O
N
14
N
H
N
H
F
O
O
N
23
25
41
50
N
H
N
H
F
F
N
N
H
N
H
The CCR3 inhibitory activity data for 26–39 are listed in Table 3.
First, ureas with a methylene chain between the terminal group
supplying the hydrogen bond and the phenyl group were exam-
ined (26–29). Although the methoxymethyl group was not very
effective in improving antagonist activity (26: IC50 = 44 nM), the
sulfonyl group, was the most potent homopiperazine derivative
and was 15-fold more active than 5 (17: IC50 = 25 nM). When the
homopiperazine moiety was changed into (R)-aminopyrrolidine,

A. Nitta et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6876–6881
6879
b
a
NO2
g
i, f
NO2
NO2
NH2
NH2
HO
HO
MeO
MeO
TBSO
40
41
42
MeO
NH2
O
43
44
n
o, f
NO2
NO2
Me
O
O
O
O
45
N
Me
MsO
46
47
p
f
q, f
O
NO2
NH2
NO2
NH2
NO2
Me
O
Me
O
N
O
O
OH
48
N
HO
MeO
Me
49
Me
45
51
50
O
r, f
c
N
aniline derivatives
42, 47, 50, 51, 52
O
NH2
N
H
N
H
NO2
F
O
R
OH
48
H2N
52
26, 36, 37, 38, 39
O
c, h
N
NH2
N
H
N
H
F
TBSO
R
44
29
j
m
e
HO
NO2
NO2
NO2
O
NO2
NO2
NO2
HO
O
n
HO
F
O
F
55
HO
55
O 53
59
54
56 (n=3)
57 (n=4)
58 (n=2)
O
f, g
c, h
N
nitrobenzene derivatives
54, 56, 57, 58, 59
NH2
N
H
N
H
F
TBSO
HO
linker
linker
28, 30, 31, 32, 35
60
O
N
b
d
c, e
NO2
NH2
NO2
N
H
N
F
O
O
H
O
O
62
HO
N
HO
O
O
O
27
40
61
k, f
O
c, l
HO
MeO
HO
NH2
O
N
H
N
H
O
NO2
F
O
63 (meta)
64 (para)
65 (meta)
33 (meta)
34 (para)
66 (para)
Scheme 3. Reagents and conditions: (a) NaH, MeI, THF, 53%; (b) Fe, NH4Cl, THF/MeOH/water (1:2:2), 80 °C, 68%; (c) 18, ClCO2p–NO2Ph, NaHCO3, CHCl3, then Et3N; (d) tert-
butyl 2-bromoacetate, NaOH, toluene, TBAB; (e) LiAlH4, MeOH; (f) H2, 10% Pd-C, EtOH; (g) TBSCl, imidazole, THF; (h) TBAF, THF; (i) DIBAL, CH2Cl2; (j) HO(CH2)nOH, NaH, THF;
(k) methyl 2-bromoacetate, K2CO3, DMF; (l) NaBH4, MeOH; (m) 2,20-oxydiethanol, NaH, THF; (n) MsCl, Et3N, CH2Cl2, 92%; (o) dimethylamine HCl, K2CO3, DMF; (p) 2-chloro-
N,N-dimethylacetamide, K2CO3, CH3CN, 83%; (q) MeI, NaH, THF; (r) 2-bromoacetamide, K2CO3, DMF
hydroxyethoxymethyl group showed five fold greater potency than
25 (27: IC50 = 9.9 nM). Compound 28, possessing a hydroxyethyl
group, and 29, possessing a hydroxypropyl group, had similar
antagonist activity that was half that of 27 (28: IC50 = 12 nM; 29:
IC50 = 24 nM). Next, derivatives with an ether bond between the
terminal group supplying the hydrogen bond and the phenyl group
were examined (30–39). Introduction of hydroxypropoxyl or
hydroxybutoxyl substitution to the phenyl group of 25 resulted
in alcohol 30 or 31. Compound 30 had twice the potency as 25
and 31 had potency that was similar to 25 (30: IC50 = 23 nM; 31:
IC50 = 51 nM); however, compound 32, which had a hydroxyeth-
oxyl group, had the most potent activity of the tested antagonists

6880
A. Nitta et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6876–6881
Table 3
CCR3 inhibiting activity of pyrrolidinyl phenylurea derivatives
O
N
R
N
H
N
H
F
Compds
R
IC50 (nM)
Compds
R
IC50 (nM)
Compds
R
IC50 (nM)
110
25
50
30
31
32
23
35
HO
O
O
O
26
27
44
51
36
37
50
HO
HO
HO
O
HO
9.9
1.7
190
O
O
HO
HO
HO
HO
O
28
29
12
24
33
34
28
71
38
39
110
44
O
O
O
N
O
O
O
O
O
N
H2N
O
(32: IC50 = 1.7 nM). Comparisons between 30, 31, and 32 revealed
that shorter substituent have better activity than longer ones.
Introduction of a hydroxyethoxyl substitution to the phenyl group
of 25 showed that the most suitable substitution position for CCR3
inhibitory activity is the 2-position, as in 32 (33: IC50 = 28 nM; 34:
IC50 = 71 nM). The hydroxyethoxyethoxyl group on 35 was not
effective (35: IC50 = 110 nM). Finally, in addition to the hydroxyalk-
oxyl groups, various hydrophilic substituents were examined
(36–39), but compounds with a dimethylaminoethoxyl group
(36), N,N-dimethylacetamide (37), methoxyethoxyl group (38), or
acetamide (39) did not show any improvement in activity over that
of 32 (36: IC50 = 50 nM; 37: IC50 = 190 nM; 38: IC50 = 44 nM; 39:
IC50 = 110 nM).
The most potent compound, 32, exhibited passable oral bio-
availability in cynomolgus monkeys (22%). Compound 32 did not
inhibit CCR1, CCR2, or CCR5 at a dose of 10 lM. Furthermore, the
effect of 32 on CC chemokine ligand 11 (CCL11/eotaxin)-induced
eosinophil degranulation was investigated as a functional assay.20
CCR3 antagonist 32 inhibited eosinophil-derived neurotoxin (EDN)
release from CCL11-induced human peripheral eosinophils in a
dose-dependent manner and had an IC50 value of 0.87 nM.
In conclusion, to improve CCR3 inhibitory activity and the
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200
lL of 2.5% BSA diluted in
l
L of eosinophils RPMI 1640 medium containing 0.5% BSA (5 ꢁ 105 cells)
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