Scaffold-hopping with zwitterionic CCR3 antagonists: Identification and optimisation of a series with good potency and pharmacokinetics leading to the discovery of AZ12436092

Article abstract of DOI:10.1016/j.bmcl.2012.08.103

The discovery and optimisation of a series of zwitterionic CCR3 antagonists is described. Optimisation of the structure led to AZ12436092, a compound with excellent selectivity over activity at hERG and outstanding pharmacokinetics in preclinical species.

Full text of DOI:10.1016/j.bmcl.2012.08.103

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6694–6699
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Scaffold-hopping with zwitterionic CCR3 antagonists: Identification
and optimisation of a series with good potency and pharmacokinetics
leading to the discovery of AZ12436092
Ash Bahl b, Patrick Barton a, Keith Bowers b, Moya V. Caffrey a, Rebecca Denton c, Peter Gilmour b,
Shaun Hawley b, Tero Linannen a, Christopher A. Luckhurst a, Tobias Mochel a, Matthew W. D. Perry a,
Robert J. Riley c, Emma Roe c, Brian Springthorpe a, Linda Stein a, Peter Webborn c
⇑
,
a Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH, United Kingdom
b Department of Bioscience, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH, United Kingdom
c Department of Discovery DMPK, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 11 September 2012
The discovery and optimisation of a series of zwitterionic CCR3 antagonists is described. Optimisation of
the structure led to AZ12436092, a compound with excellent selectivity over activity at hERG and out-
standing pharmacokinetics in preclinical species.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Chemokine
Antagonist
Bioavailability
The CCR3 receptor is a seven transmembrane, G-protein-cou-
pled receptor, which belongs to the CC chemokine family.1 In
humans the receptor is expressed on eosinophils,2 basophils,3 air-
way epithelia,4 airway smooth muscle,5 dendritic cells,6 mucosal
mast cells7 and Th2 cells.8 These cell types are believed to play a
key role in the pathophysiology of asthma and rhinitis.2 Chemo-
kine activation of the CCR3 receptor leads to chemotaxis and acti-
vation of cells.9 The CCR3 receptor is activated by a range of
endogenous chemokines, which include eotaxin-1 (CCL11), eotax-
in-2 (CCL24), eotaxin-3 (CCL26), MCP-4 (CCL13) and RANTES
(CCL5). Levels of these chemokines are raised in allergic diseases
such as asthma (atopic and non atopic), allergic rhinitis and atopic
dermatitis. As such antagonists of CCR3 are an attractive target for
an oral treatment for asthma and other allergic diseases.10–12
We have described our earlier work on CCR3/H1 dual antago-
nists that lead to the discovery of AZ10565259 (1).13 Activity at
hERG was a major issue in this series that was overcome by the
addition of an acidic centre making the molecules zwitterionic.
The addition of the acidic centre to the molecule resulted in re-
duced bioavailability that was affected by poor solubility and
proved to be dependent on physical form. Whilst 1 progressed into
Early Development, work was started to identify an alternate series
of compounds, with particular focus on improving bioavailability
and pharmacokinetics.
The initial series of compounds were synthesised according to
Scheme 1. Thus reductive amination of phenoxypiperidine 2 and
an appropriate carbonyl compound gave, after deprotection, the
desired diamines 3–7 in good yield. Petasis boron-Mannich reac-
tion14 of the diamines gave racemic amino acids (8–12).
Once we had identified the advantages of the methylene linked
bispiperidine skeleton (7) we synthesised additional zwitterionic
compounds by reductive amination or nucleophilic aromatic
substitution (13–25) (Scheme 2). The nucleophilic aromatic substi-
tution reactions on unactivated halides required copper(I) cataly-
sis,15 even so yields were moderate to poor.
Initially 8–12 were synthesised as racemates. Once 12 had been
identified as an interesting starting point the enantiomers were
separated at the ester stage to give access to the optically pure
compounds 26 and 27. The synthesis of 26 and 27 as single enan-
tiomers required a different approach (Scheme 3). Acylation of
amine 2 with cyclopentene carboxylic acid gave amide 28. Dihydr-
oxylation gave a mixture of diols 29 that could be separated but
were normally progressed as a mixture. Reduction of the amide
with borane gave diols 30 that could be cleaved to the dialdehyde
31. The dialdehyde was not isolated but used immediately with an
amino acid ester and sodium triacetoxy borohydride to give the es-
ters 32. Hydrolysis gave acids 26, 27, 33–63; it is noteworthy that
as the steric bulk around the ester increased the conditions for the
⇑
Corresponding author. Address: AstraZeneca, Innovative Medicines, R&I
Chemistry, AstraZeneca R&D Mölndal, Peparedsleden, SE-431 83 Mölndal, Sweden.
E-mail address: matthew.perry@astrazeneca.com (M.W.D. Perry).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.08.103

A. Bahl et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6694–6699
6695
O
Cl
O
Cl
Cl
iii
N
N
Cl
N
NH
3
8
9
HO
O
O
O
Cl
Cl
Cl
Cl
iii
iii
iii
O
O
Cl
Cl
Cl
Cl
N
N
N
NH
N
N
4
5
O
O
HO
N
O
2
Cl
Cl
O
O
i, ii
O
O
NH
NH
HO
10
11
O
O
Cl
Cl
O
O
Cl
Cl
N
N
N
NH
NH
N
N
6
O
OH
HO
O
Cl
Cl
Cl
Cl
iii
N
7
12
Scheme 1. Syntheses of compounds 8–12. (i) RCHO or RCOR, NaBH(OAc)3, AcOH, CH2Cl2, rt, 18 h; (ii) TFA, CH2Cl2, rt, 16 h; (iii) PhB(OH)2, OHCCOOH, EtOH, 100 °C
lwave.
OH
O
O
Cl
Cl
O
Cl
Cl
NH
N
X
i, iv
N
N
13 X = CH
25 X = N
7
ii, iv
iii,
iv
O
O
OH
Y
OH
O
Cl
Cl
O
Cl
Cl
N
N
N
N
22-24
14,15 Y = bond
16-18 Y = CH2
19-21 Y = OCH2
Scheme 2. Syntheses of compounds 13–25. (i) ArF, K2CO3, DMF, 90 °C; (ii) ArI, CuI, K2CO3, L-proline, DMSO, 85 °C; (iii) ArCHO, NaBH(OAc)3, AcOH, CH2Cl2, rt, 18 h; (iv) LiOH–
MeOH–THF, H2O, rt, 16 h.
OH
OH
OH
OH
O
O
Cl
Cl
Cl
Cl
O
Cl
Cl
O
Cl
Cl
i
ii
iii
NH
N
N
N
O
O
2
29
mixture of isomers
30
mixture of isomers
28
O
N
O
O
N
OH
1R2
R3
O
O
Cl
Cl
O
Cl
Cl
iv
v
vi
O
Cl
Cl
1R2
R
R
N
N
N
O
32
26, 27, 33-63
31
Scheme 3. Chiral synthesis of 26, 27, 33–63. (i) Cyclopentene carbonyl chloride, Et3N, CH2Cl2, 0 °C to rt 2 h; (ii) K2OsO4Á2H2O, NMO, acetone–water, rt, 18 h; (iii) BH3.THF,
THF, reflux, 2 h; (iv) NaIO4, AcOH, H2O, rt, 1 h; (v) amino acid ester, NaBH(OAc)3, AcOH, CH2Cl2 or THF, rt, 18 h (vi) R1 = H, R3 = Me LiOH, MeOH–THF–H2O, rt, 18 h or 6 M aq
HCl, i-PrOH, 80 °C, 24 h; R1 = Me, R3 = Me 48% aq HBr, reflux, 48 h; R1 = Me, R3 = t-Bu HCl, dioxan-THF, rt, 16 h.

6696
A. Bahl et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6694–6699
hydrolysis of methyl esters changed from mild to forcing; fortu-
nately the most hindered cases with an -methyl were not suscep-
tible to racemisation. Ultimately we switched to using t-butyl
esters to simplify this step. The synthetic sequence was high-yield-
ing and required few chromatographic steps and was thus an ideal
method to explore these systems.
chemistry further with the hope of discovering alternate structures
where good CCR3 potency and acceptable bioavailability were
combined. Unlike 1 solubility did not seem to be a limiting factor
for bioavailability (data not shown).
a
Cl
Cl
O
Many amino acids are available commercially and there are
many methods for their synthesis, thus this route enabled a wide
N
H
N
O
S
N
range of substitution to be investigated.
a-Methyl amino acids
were purchased or synthesised by Schöllkopf methodology16,17
and then esterified.
O
O
1
Changes to the phenoxy group had to be made at the start of the
synthetic sequence. Synthesis of the phenoxypiperidines was car-
ried out as previously described; however the 2-methyl analogue
69 required a previously unknown fluorobenzene. Lithiation of
3,4-dichlorofluorobenzene 66, with careful control of the base stoi-
chiometry, gave the desired 3,4-dichloro-2-methylfluorobenzene
67 contaminated by small amounts of residual 66 and dimethylat-
ed product 68. Switching from iodomethane to dimethyl sulfate as
methylating agent and carefully controlling the temperature max-
imised the yield of 67 that was then purified by fractional distilla-
tion. Displacement of fluoride with the potassium alkoxide of 4-
hydroxypiperidine proceeded uneventfully to give 69 (see
Scheme 4).
At the start of this programme we decided to continue to make
zwitterions in order to maintain the required selectivity against
the hERG channel, thus we started to evaluate other zwitterionic
compounds we had made during the programme that led to 1.
One such compound was the racemic amino acid 8. This compound
had moderate CCR3 potency,18 good in vitro metabolic stability, a
respectable half-life in rat and measurable bioavailability; it was
also only weakly active at the hERG channel (pIC50 5.3 in an ion
flux assay) (Table 1). Our previous experience that led to the dis-
covery of (1) had shown that the anionic centre was tolerated in
only a limited range of positions without a significant negative im-
pact on the CCR3 potency and that small changes could have large
effects. We decided to evaluate related ring-systems to investigate
the effects on potency. 3-Piperidinyl methyl 9 (racemic mixture of
diastereomers), showed no advantage. The morpholine analogues
10, 11, (both a mixture at the carboxylate centre) showed differing
effects on CCR3 and H1 potencies with (11) being more potent at
CCR3 and having moderate bioavailability in rats. The 4-piperidinyl
methyl 12 showed the best potency at CCR3, close to the levels ob-
tained for 1. H1 activity was broadly consistent across the series
with the most potent compound being the weakest at CCR3 (10).
The compounds from these series were only weakly active at the
hERG channel, encouraging the belief that zwitterions could pro-
vide a general solution to this problem. The separated enantiomers
of 12 (26, 27) showed again a divergent effect on CCR3 and H1
potencies. The enantiomer with the higher CCR3 potency 27 (ste-
reochemistry initially unknown) was taken to in vivo rat PK and
had a good half-life but poor bioavailability. The factors that gov-
erned bioavailability were not clear to us as, although 8 and 27
were poorly bioavailable, the closely related compound 11 was
acceptably bioavailable (target >30%). We chose to explore the
Synthetically the 4-piperidinylmethyl-4-piperidinyl system was
attractive because of the simplicity of the achiral core. We had pre-
viously shown that carboxylate groups on the piperidine rings were
disfavoured so we investigated alternative positions that a carbox-
ylate could be attached close to the second (right-hand as drawn)
aromatic ring (Table 2). This table shows that most of these com-
pounds had CCR3 potencies in the 7.0–7.7 range with one notable
exception; compound 13 is a log unit more potent at CCR3 (pKi
8.7) and also has high potency at H1 (pKi 8.2). Additionally 13 had
a reasonable half-life and good bioavailability when dosed to rats
(t1/2 4.1 h; F = 58%). Unfortunately hERG activity was also much
higher. It is noticeable that 13 has higher lipophilicity than the
other compounds shown, we attributed this to charge-pairing be-
tween the adjacent positive and negative ions in the zwitterion
reducing the hydrophilicity (it is also noteworthy that 13 is doubly
basic implying that the aromatic ring is not coplanar with the piper-
idine; data not shown). We synthesised the pyridine analogue 25
which indeed was much weaker at hERG, however the CCR3 activity
was almost abolished though H1 activity was little changed. Exten-
sive further studies on this series failed to deliver a compound with
both good CCR3 potency and low hERG activity.
Our breakthrough came when we made the homologated ana-
logues of 12; 33 & 34; the CCR3 and H1 potency values for 33 com-
pare favourably to those of 12 and 27; interestingly
S
stereochemistry was now favoured for potency at CCR3. More
importantly 33 showed excellent bioavailability (62%) and long
half-life (12 h) in rat whilst retaining only weak activity at hERG.
Exploration of substitution on the phenyl ring 33 showed only
small effects on CCR3 and H1 activity with meta substitution being
generally disfavoured and ortho substitution having a small po-
tency boost (43, 46). Amongst substituted phenyl groups lipophil-
icity did not appear to be a significant factor driving potency
against either CCR3 or H1. Heterocyclic analogues showed a reduc-
tion in potency at both CCR3 and H1 and had poorer metabolic sta-
bility in general (data not shown) (Table 3, Chart 1).
Substitution on the phenoxy ring was investigated through a
series of analogues 49–57 (Table 4, Chart 2). As was observed with
previous compounds there was a general trend of the potency at
both CCR3 and H1 having a significant relationship with lipophilic-
ity (Chart 1). Thus the two similar trisubstituted phenoxy com-
pounds 55 and 56 are very similar in potencies at CCR3 and H1.
Further profiling of these compounds showed that the 2-methyl
iii
Cl
Cl
F
Cl
Cl
O
Cl
Cl
F
Cl
Cl
F
i, ii
+
NH
66
67
68
69
Scheme 4. Synthesis of 4-(2-methyl-3,4-dichlorophenoxy)piperidine; (i) LDA (1.05 equiv), THF, À60 °C then warm to À40 °C for 30 min; (ii) MeI or Me2SO4, À60 °C, 30 min
then to ry 16 h; (iii) 4-hydroxypiperidine, KOBu-t, NMP, 67 °C, 18 h.

A. Bahl et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6694–6699
6697
Table 1
Data for Data for boron Mannich products 1, 8–12, 26, 27
19
Compound
CCR3 binding pKi
H1 binding pKi
hERG binding pIC50
4.6
Human microsomes CLint ml/min/kg
Rat t1/2 iv (h)
Ratbioavailability F (%)
1
8.2
7.4
7.1
6.9
7.5
7.9
7.5
8.0
7.5
7.2
7.2
7.7
7.0
7.3
7.6
7.0
1
6
<3
<3
2.7
2.4
30
13
8a
9b
4.6
10c
11c
12a
26d
27e
<4.5
<4.5
4.6
1.9
4.8
36
5
<3
<3
<3
4.8
a
b
c
Racemic.
Racemic mixture of diastereomers.
Chiral morpholine, mixture of isomers at amino acid.
Later shown to be S.
Later shown to be R (26 & 27 are the 2 enantiomers of 12).
d
e
Table 2
Data for benzoic and phenylacetic acids 13–25
R1
O
Y
R2
R3
Cl
Cl
N
N
X
Compound
R1
R2
R3
X
Y
CCR3 binding pKi
H1 binding pKi
hERG binding pIC50
LogD7.4
13
14
15
16
17
18
19
20
21
22
23
24
25
CO2H
H
H
CH2CO2H
H
H
OCH2CO2H
H
H
CO2H
H
H
CO2H
H
H
CH2CO2H
H
H
OCH2CO2H
H
H
CO2H
H
H
H
CO2H
H
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
Bond
Bond
Bond
Bond
Bond
Bond
Bond
Bond
Bond
CH2
8.7
7.0
6.8
7.7
7.4
7.6
7.5
7.4
7.0
7.7
6.6
6.2
6.2
8.2
8.3
7.2
7.8
8.3
7.7
7.8
8.3
7.4
7.2
7.3
6.9
8.0
5.8
4.5
4.5
4.9
4.5
4.5
4.5
5
2.8
2.2
2.3
H
1.6
1.8
2
CH2CO2H
H
H
OCH2CO2H
H
H
CO2H
H
2
5
4.9
4.7
4.5
4.5
2.5
1.3
1.1
1.7
CH2
CH2
Bond
H
CO2H
H
of 56 was much less susceptible to metabolism than the 3-methyl
of 55 (rat hepatocyte CLint <3 vs 13
L/ml/106 cells; rat in vivo t1/2
10 vs 0.8 h). The four disubstituted compounds 49, 51, 52 and 54
lipophilic 53 is however markedly more potent than the monosub-
stituted 50. Cyano substitution on the phenoxy ring (57) resulted
in the only compound with a significant deviation from the
lipophilic trend exhibiting good potency at CCR3 and only weak
l
with similar lipophilicities are very similar in profile; the less
Table 3
Effects of substitution on phenyl ring
O
N
OH
X
O
Cl
Cl
N
Compound
X
CCR3 binding pKi
H1 binding pKi
hERG binding pIC50
LogD7.4
Human microsomes CLint ll/min/mg
33
34a
35
36
37
38
39
40
41
42
43
44
45
46
47
48
H
H
2-Cl
4-Cl
2-F
8.0
7.5
8.0
7.7
8.0
7.6
8.1
8.3
7.7
8.1
8.3
7.7
7.7
8.4
7.6
7.7
7.3
7.0
7.3
7.5
7.3
6.9
7.3
7.8
7.6
7.8
7.5
7.8
7.1
7.2
7.2
6.8
4.8
5.2
<5
5.4
<4.5
<5
2.5
2.5
<3
<3
<5
<3
4
8
10
6
<5
<3
<3
<6
14
8
2.9
2.6
2.7
3
2.1
2.3
2.2
2.5
2.8
3
3-F
4-F
5
2-CN
3-CN
4-CN
2-Me
3-Me
4-Me
2-MeO
4-MeO
3-CF3
4.6
4.9
5.3
<4.6
5.2
5.2
5
2.8
5
5.2
7
a
R stereochemistry.

6698
A. Bahl et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6694–6699
Chart 1. (a) pKi CCR3 versus LogD7.4; (b) pKi H1 versus LogD7.4 for compounds from Table 3 with measured LogD values; shape by substitution position H (j); H (R
stereochemistry, (d), ortho (N), meta (ꢀ), para (.).
Table 4
Effects of phenoxy substitution
F
O
N
OH
R3
R2
R1
O
N
Compound
R1
R2
R3
CCR3 binding pKi
H1 binding pKi
hERG binding pIC50
LogD7.4
Human microsomes CLint ll/min/mg
49
50
51
52
53
54
55
56
57
Cl
Cl
Cl
Cl
F
Cl
Cl
Cl
CN
Cl
H
H
H
H
Me
Me
Cl
Cl
H
H
Cl
Me
Me
H
Cl
Me
Me
8.0
7.3
8.3
8.4
7.9
8.1
9.3
9.3
8.9
7.3
6.4
7.0
7.1
6.8
7.0
7.4
7.5
6.3
<4.5
<4
<4.5
<4.5
<4
2.6
1.9
2.6
2.5
1.8
2.5
3.2
3.5
2.2
4
<3
<3
<3
<3
<3
<3
<3
6
<4
<4.5
<4.3
4.8
Substitution on the aliphatic chain of the phenylalanine had
mixed effects; b-substituted compounds were less active than
the parent (data not shown) but the a-methyl compounds gained
potency at CCR3 and the selectivity over H1 activity was increased
(Table 5). The most potent CCR3 antagonist 62 was highly lipo-
philic (logD7.4 3.0), but given the potency of this a-methylated sys-
tem we were able to attenuate lipophilicity within the phenoxy
ring (63–65) whilst retaining potency (Table 6).
Antagonism of the H1 receptor is a feature of the phenoxypi-
peridine moiety that characterises this series of CCR3 antagonists.
Since many asthmatics take H1 antagonist drugs there is a poten-
tial benefit to a dual antagonist. The SAR of H1 antagonism how-
ever did not parallel that for CCR3; in particular the changes that
improved activity at CCR3, 2-substitution on the phenoxy ring
and a-methylation of the amino acid, had little effect on H1 antag-
onism which appeared to be largely driven by lipophilicity. Many
later compounds had >100-fold selectivity for CCR3 over H1 and
thus could no longer be considered to be dual antagonists.
Several a-methylated compounds from this series received ex-
tended evaluation; ultimately 63 (AZ12436092) was selected for
development as a CCR3 selective antagonist. 63 has subnanomolar
CCR3 potency but only very weak activity at the hERG channel
thereby removing any cardiac liability via this mechanism. The
pharmacokinetics in rat and dog are excellent with long half lives
and high bioavailability (63 dog PK iv t1/2 12 h, oral F 83%). Further
Chart 2. pKi (CCR3 (N) or H1 (.)) versus LogD7.4 for the compounds of Table 4.
activity at H1. This cyano substituted compound however was less
stable to metabolism (human liver microsomes) than other
compounds.

A. Bahl et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6694–6699
6699
Table 5
Matched pairs showing effect of
a-alkylation on CCR3 and H1 binding
Z
HO
N
O
R3
R2
R1
O
R4
N
Compound
R1
Cl
R2
Cl
R3
H
Z
R4
CCR3 pKi
H1 pKi
Selectivity (CCR3—H1)
33
58
39
59
60
61
56
62
H
H
Me
H
Me
H
Me
H
8.0
8.5
8.1
9.1
8.7
8.8
9.3
9.7
7.3
7.0
7.3
7.1
7.2
6.7
7.5
7.5
0.7
1.5
0.7
2.0
1.5
2.1
1.8
2.2
Cl
Cl
Cl
Cl
Cl
Cl
H
F
Me
Me
H
F
Me
Table 6
Optimised compounds with moderate logD7.4 and balanced properties
F
HO
O
R3
R2
R1
O
N
N
Compound
R1
R2
R3
CCR3 binding pKi
H1 binding pKi
hERG binding pIC50
LogD7.4
Rat t1/2 iv (h)
Rat bioavailability F (%)
63
64
65
Cl
Cl
F
H
Me
H
Me
H
Me
9.2
8.9
8.7
6.8
7.3
7.1
4.5
<4
<4
2.6
2.1
2.0
8.7
7.3
4.5
52
84
24
screening of 63 in a panel of >140 other assays (MDS Pharma), of
References and notes
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macokinetics meant that this compound was suitable for further
evaluation.
In conclusion we took a moderately active starting point and
investigated a series of changes to the core scaffold which identi-
fied that the addition of 2 methylene units, one between the 2
piperidine rings, the other between the amino acid and the phenyl
ring that made a marked difference to the potency, pharmacokinet-
ics and bioavailability of these compounds. Optimisation of the
substitution patterns generated compounds with excellent po-
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consistent bioavailability, and low hERG risk.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.08.
103. These data include MOL files and InChiKeys of the most
important compounds described in this article.
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