Novel selective thiazoleacetic acids as CRTH2 antagonists developed from in silico derived hits. Part 2

Article abstract of DOI:10.1016/j.bmcl.2009.12.015

Structure-activity relationships have been established by exploring the eastern and western side of 5-thiazolyleacetic acids as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists. Benzhydryl motifs in the 2-position of

Full text of DOI:10.1016/j.bmcl.2009.12.015

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1181–1185
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel selective thiazoleacetic acids as CRTH2 antagonists developed
from in silico derived hits. Part 2
Marie Grimstrup, Øystein Rist, Jean-Marie Receveur, Thomas M. Frimurer, Trond Ulven ,
à
*
Jesper M. Mathiesen, Evi Kostenis , Thomas Högberg
7TM Pharma A/S, Fremtidsvej 3, DK-2970 Hørsholm, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history:
Structure–activity relationships have been established by exploring the eastern and western side of
5-thiazolyleacetic acids as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2
cells) antagonists. Benzhydryl motifs in the 2-position of the thiazole was found to be most advanta-
geous. The 4-thiazole position should either carry 3- or 4-fluorophenyl rings or a 4-pyridyl suitably
substituted in the flanking 2-position. Several compounds with single digit nanomolar binding affinity
and full antagonistic efficacy for human CRTH2 receptor were obtained. The compound series display a
good PK profile and selectivity over a large number of other targets.
Received 1 November 2009
Revised 2 December 2009
Accepted 2 December 2009
Available online 6 December 2009
Keywords:
CRTH2 antagonists
Chemoattractant receptor-homologous
molecule expressed on Th2 cells
PGD2
Ó 2009 Elsevier Ltd. All rights reserved.
Chemical libraries
Hit-to-lead
Structure–activity relationships
Molecular modeling
Prostaglandin D2 (PGD2) and one of its receptors CRTH2 (che-
moattractant receptor-homologous molecule expressed on Th2
cells) have been implicated in the pathogenesis of various inflam-
matory conditions.1 The CRTH2 receptor is expressed on various
inflammatory cells, including Th2 cells, mediating their chemo-
taxis in response to PGD2 and a number of other arachidonate
tion of the thiazole derivatives 2–4 into selective and orally avail-
able compounds.
The compounds 2 and 3 have large lipophilic moieties on the
western side whereas 4 on the eastern side. Superimpositions of
the molecules when 2 and 3 are rotated around the thiazole-
metabolites such as 13,14-dihydro-15-keto-PGD2, PGJ2,
D
12PGJ2,
15-deoxy-PGJ2 and 11-dehydro-TXB2.1–3 The Th2 cells play a cen-
tral role in allergic asthma, driving IgE response, eosinophilia and
release of proinflammatory cytokines.1,4 Activation of the CRTH2
O
N
N
Cl
receptor also mediates the release of histamine from basophils1,5
,
O
N
induces respiratory burst and degranulation of eosinophils.1,6 and
affects apoptosis of Th2 cells.7 Thus, CRTH2 antagonists are under
development for the treatment of asthma and allergic disease.8–10
We have earlier described the hit-to-lead process of hits
obtained from screening an in silico derived library that success-
fully delivered some novel chemotypes of CRTH2 antagonists
(Fig. 1).11–13 In this communication we describe and extension of
the structure–activity relationships and the subsequent optimiza-
O
COOH
S
HOOC
F
2
Br
1
N
N
S
HOOC
S
* Corresponding author. Tel.: +45 3925 7760; fax: +45 3925 7776.
E-mail address: th@7tm.com (T. Högberg).
HOOC
4
3
Present address: Department of Physics and Chemistry, University of Southern
Denmark, Campusvej 55, DK-5230 Odense, Denmark.
Figure 1. Representative chemotypes identified after hit to lead process of in silico
screening hits. CRTH2 receptor binding IC50: 1 (4 nM)12, 2 (3.7 nM)13, 3 (38 nM) and
4 (24 nM).13
à
Present address: Institute of Pharmaceutical Biology, University of Bonn, Nussal-
lee 6, D-53155 Bonn, Germany.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.12.015

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M. Grimstrup et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1181–1185
Table 1
Binding affinity and functional antagonism on hCRTH2 of 4-(p-chlorophenyl)thiaz-
oleacetic acids
Cl
N
R
S
COOH
No.
R
IC50 binda
(
lM)
IC50 BRETb
(lM)
5
6
NH2
Me
>100
5.5
>100
41
Figure 2. Superimpositions of the CRTH2 antagonists 2 (light green), 3 (dark green
– kept in fixed position) and 4 (grey) in rotated low energy conformations (left) and
in receptor-bound conformations (right).
7
2-Furanyl
Ph
CH2-Ph
CH(Et)-Ph
5.1
3.8
0.96
4.1
8d
9d
10
0.55
0.18
0.19
>100
H
N
carboxyl axis show a reasonable overlap of the essential carboxylic
function interacting with 210Lys and the larger aromatic clusters
(Fig. 2 left). However, inspection of the likely receptor-bound con-
formations of 2–4 also invoking a critical interaction between the
thiazole nitrogen and 266Ser implies separate pharmacophoric fea-
tures in eastern and western sides (Fig. 2 right). Hence, we decided
first to explore the lipophilic eastern side pocket further by making
a diverse library of derivatives shown in Table 1.
The thiazoles were prepared from 3-bromo-4-oxo-butyric acid
derivatives and thioamides in accordance with the procedure de-
scribed earlier by microwave assisted heating in DMF (Scheme
1).13 The compounds were characterized with respect to binding
affinity and functional antagonistic activity using a biolumines-
cence resonance energy transfer (BRET) assay in HEK385-7 cells
(Table 2).12–14
11
2.9
>100
0.55
Ac
N
12
0.052
13d
14
15
16
17
18
19
NH-Ph
NH–CH2-Ph
NH–CH2–CH2-Ph
NH–CO-Ph
CH2–S-Ph
CH2–SO2–(p-Cl-Ph)
CH2–O–(p-Cl-Ph)
O
0.10
0.44
0.65
0.52
0.25
1.5
1.3
2.3
0.39
0.87
0.45c
0.73
0.37
0.032
20
0.50
0.15
2.0
The smaller eastern R groups NH2 (5), methyl (6) and 2-furanyl
(7) gives no or a poor activity. A phenyl and a benzyl moiety (8,9)
give submicromolar binding affinity, but ethyl substitution of the
benzyl carbon leads to loss of functional activity (10). Notably,
the piperidine substituted benzyl lacks functional activity whereas
the N-acetylated analogue displays good affinity and functional
activity (11 vs 12). The nitrogen derivatives 13–15 with different
linker length display activities comparable to benzyl derivative 9
and the amide 16 as well. The oxymethylene linked molecule 19
has considerable higher affinity than the sulfur analogues 17 and
18. Constraining the oxymethylene linker into the bicyclic 20 leads
to reduced potency. The naphthyl derivative 21 has affinity compa-
rable to the phenyl analogue 13, but it has a poor functional effi-
cacy. However, the corresponding carba analogue 22 has full
antagonistic efficacy. A number of compounds 23–27 having two
phenyl rings attached in conformationaly less constrained combi-
nations display good binding affinities with the benzydryl 27 being
a potent and full functional antagonist. Notably, changing one phe-
nyl with a cyclohexyl (28) leads to a considerable loss in affinity
and a complete loss in functional activity This finding is corrobo-
rated by docking a compound with benzhydryl showing a tight
O
21
0.096c
NH
22d
0.041
0.57
23d
24d
0.041
0.093
0.51
1.3
O
25
26
0.34
32c
0.056
0.51
´
interaction with aromatic residues (Phes, Trp, Tyr) in the hydro-
phobic pocket (vide infra Fig. 3).
We decided to further explore the benzhydryl series by making a
large set of compounds with substitutions that could affect physico-
chemical properties and metabolic behavior (Table 2). The com-
pounds were synthesized according to the method in Scheme 1
from the appropriate 3-bromo-4-oxo-buturic acid derivative or by
Suzuki coupling of the 4-thiazolyltriflate as outlined in Scheme 2.
The required 4-hydroxy-thiazol-5-ylacetic acid was obtained by
condensation with 2-mercapto-succinic acid and bis(4-fluoro-
phenyl)acetonitrile in a modest yield.
Initially, the 27 lead compound was modified by making para
chloro, fluoro and methoxy derivatives (29–32), which showed
retained affinity and functional activity in contrast to the 2-pyri-
dyl modification 33 that lost in activity. Introduction of a pyridyl
system in the methoxy compound (34) gave a reduced activity
27
28
0.014
0.53
0.060
>100
[3H]PGD2 equilibrium competition binding in hCRTH2 transfected HEK385-7
cells; except for 6, 7 and 9 which were tested in hCRTH2 transfected COS7 cells.
a
b
Antagonistic activity as inhibition of b-arrestin translocation measured in a
bioluminescence resonance energy transfer (BRET) assay in HEK385-7 cells. All
compounds displayed efficacy above 50% unless noted. All values are single or mean
of double determinations.
c
Compounds having 30–35% antagonistic efficacies.
Compounds described in Part 1.13
d

M. Grimstrup et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1181–1185
1183
Cl
Cl
O
Br
H2N
R
N
DMF
100ºC
+
R
OH
S
S
O
OH
O
Scheme 1.
Table 2
Binding affinity and functional antagonism on hCRTH2 of (2-benzhydryl-4-phenyl-
thiazol-5-yl)acetic acids
R1
R2
R3
N
S
COOH
No.
R1
R2
R3
IC50 binda
(nM)
IC50 BRETb
M)
(
l
Figure 3. Docking of 4-pyridyl derivative 67 in hCRTH2 receptor.
27
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
H
H
4-F
3-F
4-OMe
3,4-F2
4-CF3
2-OMe, 5-Cl
2,5-OMe2
4-F
4-F
4-F
4-F
4-F
4-F
3-F
3,4-F2
3,5-F2
4-CN
3-CN
4-F, 3-CN
4-H2NSO2
3-H2NSO2
3-MeSO2
3-MeSO2NH
H
4-Cl
4-F
H
H
H
4-F
H
14
45
17
0.060
0.075
0.036
0.18
F
4-F
9.7
8.4
810
61
3200
570
16
8.7
2.9
370
4.1
1100
9400
>105
14
4-OMe
2-pye
2-pye
6-Cl, 2-pye
H
4-F
H
H
H
H
H
H
H
4-Cl
3,4-F2
4-OMe
4-OH
4-OMe
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
0.076
1.9c
O
H
OH
pyridine / 100ºC
34 %
4-OMe
H
H
4-F
H
H
H
H
H
H
0.31
>100
0.37
NC
HO
+
HO
F
O
SH
0.24
0.077
0.029
0.91c
0.043
>100
>100
>100
0.079
0.064
0.031
0.030
0.031
0.072
0.018
0.041
0.34
F
F
F
1) Tf2O / CH2Cl2
67 %
Ar
N
N
S
S
2) Ar-B(OH)2
Pd(PPh3)4
H
H
H
H
COOH
COOH
dioxane/aq K2CO3
40-70 %
10
F
3.6
3.4
3.9
7.5
1.4
3.5
35
150
20
57
H
4-OMe
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
Scheme 2.
positions of the eastern phenyl rings. The 3,4-difluorinated com-
pound 52 displays comparably high activity whereas a 10-fold
is lost for the 3,5-diflouro derivative 53. A p-cyano compound
54 drops more in activity than the m-cyano compounds 55 and
56. The difference in meta and para substitution with polar
groups are also shown by comparing the aminosulfonyl deriva-
tives 57 and 58. The corresponding methylsulfone 59 displays a
poor functional and only partial activity, but the sulfonamide 60
is reasonably active.
1.5d
0.22
0.52
>100
0.71c
6.3d
1500
140
590
40
0.37
a
b
c
As in Table 1, but all compounds displayed efficacy above 80% unless noted.
As in Table 1, but all compounds displayed efficacy above 80% unless noted.
Compound having 55–60% antagonistic efficacy.
As an extension of the exploration the western side we made a
number of aromatic heterocyclic five- and six-ring systems using
the Suzuki coupling method in Scheme 2 (Table 3). The 2-and 3-
furanyl derivatives 61 and 62 had reasonable activity comparable
to the 4-pyrazole derivative 63. The methyl substituted 4-pyraz-
olyl 64 and the 3-pyrazolyl 65 were less active. The 3-pyridyl
66 was comparable to the best five-membered heterocycles
whereas the 4-pyridyl compound 67 showed superior potency
and full functional antagonistic activity. Docking studies also indi-
cate the 4-pyridyl to be better positioned than 3-pyridyl to inter-
act with 269Glu in the receptor (cf. Fig. 3). Hence, we explored the
4-pyridyl subclass further by making modifications especially in
the 2-position ortho to the pyridyl nitrogen (68–80). The 2-chloro
69 is comparable to the unsubstituted compound 67 whereas the
2-fluoro 68 is a 10-fold more active with subnanomolar binding
affinity and 5 nM full functional antagonistic activity. Although,
d
e
Compound having 30–35% antagonistic efficacy.
One phenyl ring replaced with 2-pyridyl system.
and the chloropyridyl derivative 35 lost substantially in activity.
The importance of the halogen substituent in the western ring
was evidenced by comparing the unsubstituted 36 and the meth-
oxy 40 compounds with the chloro (27) and fluoro derivatives
(38, 39 and 41). Introduction of p-fluoro groups (37) gave an in-
crease in affinity but not functional activity over 36. The larger
pseudo halogen trifluoromethoxy derivative 42 and the ortho
methoxy derivatives (43, 44) are devoid of functional activity.
Thus, a set of western mono fluoro derivatives 45–51 all showed
very high binding affinity and full functional antagonistic activity.
Notably, methoxy and hydroxyl groups are allowed in the para

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M. Grimstrup et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1181–1185
Table 3
Binding affinity and functional antagonism on hCRTH2 of (4-aryl-2-benzhydryl-
thiazol-5-yl)acetic acids
F
N
F
F
F
F
N
N
F
R1
N
H
N
S
N
S
neat, 90 ºC
29 %
Ar
N
S
COOH
COOH
COOH
F
Scheme 3.
No.
Ar
R1
IC50 binda (nM)
IC50 BRETb
(lM)
61
62
2-Furanyl
3-Furanyl
N
H
H
18
14
0.14
0.13
Table 4
63
H
16
0.22
In vitro and in vivo ADME profile of representative compounds
HN
Me
N
N
27
47
64
H
1300
3.5
Aqueous solubility (PBS, pH 7.4)
Aqueous solubility (pH 1)
Log D (water/n-octanol, pH 7.4)
Plasma protein binding (rat)
Caco-2 (A to B)
154
30
2.6
l
M
197 lM
3.4
2.1
lM
lM
N
N
H
65
66
H
H
280
68
3.3d
0.51
98.5%
97.8%
69 Â 10À6 cm/s
24 Â 10À6 cm/s
N
Metabolic stab. (S-9, rat) Remain
Metabolic stab. (S-9, h) Remain
27%
n.d.
62%
40%
6
5
2
N
CYP2D6 inhibition (1
CYP3A4 inhibition (1
Half-life (rat)
Clearance (rat)
Bioavailability (rat)
l
M)
3%
0%
6%
0%
lM)
3.3 h
4.4 mL/min/kg
70%
5.8 h
8.5 mL/min/kg
81%
67
H
5.3
0.040
6
68
69
70
71
72
73
74
75
76
77
4-Pyridyl
4-Pyridyl
4-Pyridyl
4-Pyridyl
4-Pyridyl
4-Pyridyl
4-Pyridyl
4-Pyridyl
4-Pyridyl
4-Pyridyl
2-F
2-Cl
2,6-F2
2-Me
2-MeO
2-OH
0.48
3.1
5.4
3.1
29
0.0047
0.039
0.11
0.053
0.38c
0.89c
0.064
1.4d
68
The compound 27 having only a p-chlorophenyl group in the
western side was further characterized with respect to its receptor
selectivity showing less than 33% inhibition towards 41 receptors
and transporters at 10
less than 20% inhibition of the lipid mediator converting enzymes
PLA2, COX-1, COX-2, 12-LO and 15-LO at 10 M concentration. The
IC50 value for the other PGD2 receptor DP1 was over 100 M.
2-NH2
4.8
220
25
6-F, 2-NH2
2-NHMe
2-NMe2
0.17
>100
380
lM concentration. Furthermore, it showed
e
78
79
4-Pyridyl
4-Pyridyl
660
230
>100
>100
N
l
e
N
l
Importantly no affinity was seen for the physicogenetically related
AT1 and AT2 receptors that provided input to the pharmacophore
used for the in silico generation of hits.11,12 The ADME properties
for 27 and 47 having an eastern 4-methoxy substituted are shown
in Table 4. Both compounds display a favorable in vitro profile with
good membrane permeability and physicochemical properties. The
oral bioavailability and half-life are appreciable for both com-
pounds, indicating that the methoxy group represents no meta-
bolic liability as supported by a hepatic clearance of about 10% of
hepatic blood flow for 47. No CYP inhibitions were indicated for
the 2D6 and 3A4 isoforms.
Ac
N
e
80
4-Pyridyl
360
>100
N
81
82
83
3-Pyridyl
3-Pyridyl
3-Pyridyl
6-NH2
5-Me, 6-NH2
5-F
100
880
71
0.50c
>100
0.30
a
b
c
As in Table 1, but all compounds displayed efficacy above 80% unless noted.
As in Table 1, but all compounds displayed efficacy above 80% unless noted.
Compound having 60–70% antagonistic efficacy.
Compound having 30–35% antagonistic efficacy.
Substituent in 2-pyridyl position.
d
e
In summary, we have extensively explored the eastern and wes-
tern side of 5-thiazolyleacetic acids. Functionalisation with substi-
tuted benzhydryl motifs in the 2-position of the thiazole was found
to be most advantageous. The docking of this benzhydryl series
also fit nicely into a pocket containing several aromatic residues.
The 4-thiazole position should either carry 3- or 4-fluorophenyl
rings or a 4-pyridyl suitably substituted in the flanking 2-position
with a methyl group. The series display a good PK profile warrant-
ing further in vivo PD studies in inflammation and allergy models
that will be described in subsequent reports.
we cannot explain the dramatic potency increase at present, it
may be speculated that an irreversible binding mode is a contrib-
uting factor. This reactivity was also utilized by making some of
the 2-substituted derivatives exemplified by the pyrrolidine
derivative 79 (Scheme 3).
The 2-chloro derivative is also potentially subject to chemical
instability which makes the potent 2-methyl 71 more attractive
also with respect to masking the pyridyl against potential CYP
interactions. The 2-methoxy (72) and 2-hydroxy (73) show 10-
fold lower activity. The activity of the amines ranks according
to alkylation degree with the primary amine 74 being more po-
tent than the secondary amine 76 while the tertiary amines
(77–80) lack functional activity. Finally, we explored some 3-pyr-
idyl derivatives with 6-amino (81, 82) with rather poor functional
activity. The 5-flouro compound 83 was equipotent with the par-
ent compound 66.
Acknowledgments
The authors thank Joan Gredal, Stina Hansen, Rokhsana Ander-
sen, Ann Christensen and Helle Zancho Andresen, for excellent
technical assistance.

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