Discovery of a novel series of CRTH2 (DP2) receptor antagonists devoid of carboxylic acids

Article abstract of DOI:10.1021/ml200223s

Antagonism of the CRTH2 receptor represents a very attractive target for a variety of allergic diseases. Most CRTH2 antagonists known to date possess a carboxylic acid moiety, which is essential for binding. However, potential acid metabolites O-acyl gluc

Full text of DOI:10.1021/ml200223s

Letter
pubs.acs.org/acsmedchemlett
Discovery of a Novel Series of CRTH2 (DP2) Receptor Antagonists
Devoid of Carboxylic Acids
Stefano Crosignani,* Catherine Jorand-Lebrun, Gordon Campbell, Adeline Pretre, Tania Grippi-Vallotton,
̂
Anna Quattropani, Gwenaelle Bouscary-Desforges, Agnes Bombrun, Marc Missotten, Yves Humbert,
Christele Fremaux, Mikael Paquet, Kamel El Harkani, Charles G. Bradshaw, Christophe Cleva, Nada Abla,
̀
́
̂
̈
Hamina Daff, Olivier Schott, Pierre-Andre Pittet, Jean-Franco
̧
is Arrighi, Marilene Gaudet, and Zoe Johnson
́
̀
̈
Merck Serono S.A., 9 chemin des Mines, CH-1202 Geneva, Switzerland
S
* Supporting Information
ABSTRACT: Antagonism of the CRTH2 receptor represents a very attractive target for a variety of
allergic diseases. Most CRTH2 antagonists known to date possess a carboxylic acid moiety, which is
essential for binding. However, potential acid metabolites O-acyl glucuronides might be linked to
idiosynchratic toxicity in humans. In this communication, we describe a new series of compounds that lack
the carboxylic acid moiety. Compounds with high affinity (Ki < 10 nM) for the receptor have been
identified. Subsequent optimization succeeded in reducing the high metabolic clearance of the first
compounds in human and rat liver microsomes. At the same time, inhibition of the CYP isoforms was
optimized, giving rise to stable compounds with an acceptable CYP inhibition profile (IC50 CYP2C9 and
2C19 > 1 μM). Taken together, these data show that compounds devoid of carboxylic acid groups could
represent an interesting alternative to current CRTH2 antagonists in development.
KEYWORDS: CRTH2 (DP2) receptor, antagonists, tetrazoles, asthma
Most CRTH2 antagonists known to date, with the only
rostaglandin D2 (PGD2) (1) (Figure 1) is the major
Pprostanoid species produced by mast cells in response to exception being tetrahydroquinolines such as 6,8 possess a
carboxylic acid moiety, which is essential for binding and which
mimics the same moiety found in prostaglandins. Carboxylic
acids can be metabolized in vivo into acyl-glucuronides. These
potentially reactive metabolites have been linked to instances
of idiosyncratic toxicity, which have led to the recall of several
drugs.9 Given the chronic nature of the diseases for which
CRTH2 antagonists could become useful drugs (e.g., asthma,
atopic dermatitis), removing the carboxylic acid group could
give rise to safer drug candidates.
A review of the literature on CRTH2 antagonists reveals that
several research groups have attempted to replace the
carboxylic acid moiety with a variety of groups that can be
considered as bioisosteres, for example, using the tetrazole
group. However, in all cases reported so far, a significant drop
in affinity for the CRTH2 receptor has been observed when
comparing tetrazole-containing compounds with the corre-
sponding carboxylic acids.10−13
stimulation by allergens and plays a key role in inflammatory
processes. PGD2 exerts its effect through two high-affinity G
protein-coupled receptors: the classical DP receptor, also called
DP1, and the more recently discovered chemoattractant homo-
logous receptor expressed on Th2 cells (CRTH2 also known as
DP2). In humans, CRTH2 is predominantly expressed by Th2
cells, eosinophils, and basophils, all known to play a key role in
allergic diseases.1 Activation of the Gi-coupled CRTH2 by
PGD2 or the selective agonist DK-PGD2 stimulates chemotaxis
of human Th2 cells, eosinophils, and basophils in vitro and in
vivo,2,3 suggesting that the CRTH2 receptor may directly
mediate the recruitment of inflammatory cells in allergic
diseases such as asthma, allergic rhinitis, and atopic dermatitis.
CRTH2 is expressed by antigen-specific Th2 cells in allergic
individuals supporting this notion that the CRTH2 receptor is
important in the recruitment of Th2 in allergic diseases in
humans.4 Further data in animal models likewise point to a
central role for CRTH2 in allergic disorders and support the
promise of CRTH2 as a target for the treatment of atopic
diseases.1 Moreover, the thromboxane A2 antagonist rama-
troban, a drug marketed for allergic rhinitis, also has beeen
shown to possess CRTH2 antagonistic properties;5 yet, it is not
clear whether its clinical efficacy in allergic rhinitis is due to
inhibition of TP, CRTH2, or both receptors. The relevance of
CRTH2 as a target for allergic diseases spurred much effort in
the pharmaceutical industry aimed at discovering selective
agents to modulate its action.6,7
During a recent high-throughput screening (HTS) campaign,
we identified a series of potent CRTH2 antagonists that do not
contain a carboxylic acid group and that on the other hand
bear a tetrazole group. Even if tetrazoles can be metabolized
to glucuronides in vivo, the adducts are not chemically reactive
and have not been linked to toxic effects in man. As such, this
Received: September 14, 2011
Accepted: October 10, 2011
Published: October 10, 2011
© 2011 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
Figure 1. Structures of prostaglandin D2 (PGD2) (1), some CRTH2 antagonists in clinical development (2−5), and a tetrahydroquinoline
derivative (6).
chemical series was considered as being an interesting starting
point for our drug discovery effort.
The tetrazoles 11−19 of the HTS pool were prepared as
previously described.14 New analogues 20−67 were easily pre-
pared as outlined in Scheme 1. Tetrazoles were prepared from
in the 4-position. These findings could be confirmed when new
analogues were tested. Chain lengths of three or four carbon
atoms were optimal for potency, while the two-carbon chain led
to a decrease in potency (39 and 38 vs 37), although not as
marked as for the methyl group. The positive effect of the
halogen atom could be confirmed with several analogues, with a
particularly positive effect seen when the halogen was introduced
at the 5-position (24 and 28). Appropriately substituted
aromatic groups were favored in the R2 position. In particular,
3- and/or 4-alkoxy-substituted groups were found to confer
additional affinity as compared to an unsubstituted phenyl (21,
22, or 37 vs 20). On the contrary, halogen-substituted aromatics
(see, for example, 30−32) and heteroaromatics (ortho-, meta-,
and para-pyridine, 1- and 2-thiophene, isoxazole, and oxazole,
data not shown) did not increase the affinity. One notable
exception was substitution with a benzofuran group (35).
Substituting the tetrazole group with either a carboxylic acid
or an acetic acid group led to compounds with Ki > 1 μM, with
a loss of affinity of at least 2 orders of magnitude versus the
corresponding tetrazoles with the same substitution (Figure 2,
Ki = 4300 nM for 68 vs Ki = 7 nM for corresponding tetrazole
39, and Ki = 8000 nM for 69 vs Ki = 44 nM for tetrazole 23),
confirming that for the purpose of CRTH2 antagonism
tetrazoles and carboxylic acids cannot be considered as really
bioisosteric.
Some of the most potent analogues were also tested to test
the functional activity of the compounds in physiological
conditions, including the presence of plasma proteins. The
assay selected was a flow cytometry-based detection of the
change of shape of eosinophils in response to challenge with
PGD2 (at a concentration of 10 nM) in whole blood from
healthy volunteers.15,16 In this assay, compound 43 was the
most potent of the series, with an IC50 of 40 nM. Several
compounds of this series were also shown to be inverse
agonists in a GTPγS binding assay (Table 3, entries 1−6).
Unfortunately, all of the alkoxy-substituted compounds were
found to be highly unstable in human microsomes and
moderately unstable in rat microsomes (see, for example, 16,
29 ,and 39, Table 2). Analysis by LC-MS/MS of the
metabolites obtained after treatment of compound 15 in
human liver microsomes confirmed the prediction that
oxidative metabolism was taking place on the alkoxy substituent
a
Scheme 1.
a
Reagents: (a) R1COCl, N-methyl-morpholine, CH2Cl2, −10 °C, 75−
99%. (b) NaH, R2CH2Br, N,N′-dimethylformamide, 0 °C, 32−90%.
(c) R2CHO, p-toluenesulfonic acid, toluene, then NaBH4, MeOH,
CH2Cl2, 41−84%. (d) R1COCl, N-methyl-morpholine, N,N′-dime-
thylformamide, 50 °C, 38−92%. (e) Trimethylsilyl azide, Cu2O, N,N′-
dimethylformamide, MeOH, 80 °C or trimethylsilyl azide, Bu2SnO,
toluene, 110 °C, 31−95%.
the corresponding nitriles 9 at the final step, as this was generally
found to make the purification of intermediates more straight-
forward. For this transformation, the reaction using the less toxic
copper(I) oxide was generally preferred over the use of dibutyltin
oxide.
Some early structure−activity relationship (SAR) could be
gathered from the affinity data of the compounds present in the
HTS pool (Table 1, 11−19): A longer, more lipophilic alkyl chain
as R1 seemed to be more favorable than a smaller methyl group
(see, for example, 13 vs 11 or 14 vs 12). The comparison of these
pairs also showed that additional substitution with a halogen on
the central aromatic also seemed to have a positive effect, at least
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ACS Medicinal Chemistry Letters
Letter
Table 1. SAR of Tetrazole Compounds 11−67
compd
R1
R2
X
Ki (nM)
cLog D (pH 7.4)
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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
61
62
63
64
65
66
67
methyl
methyl
butyl
butyl
butyl
butyl
butyl
butyl
butyl
ethyl
ethyl
ethyl
butyl
butyl
ethyl
ethyl
butyl
butyl
ethyl
ethyl
ethyl
ethyl
ethyl
butyl
butyl
ethyl
ethyl
propyl
butyl
ethyl
3-alkynyl-phenyl
3-alkynyl-phenyl
3-alkynyl-phenyl
3-alkynyl-phenyl
benzodioxane-6-yl
4-methoxyphenyl
2-naphthyl
H
400
140
45
1.2
1.6
4-F
H
2.7
4-F
4-F
H
10
3.1
3.3
50
2.1
1.9
H
39
3.2
6-isoquinyl
H
330
620
1800
360
220
44
1.7
2-thienyl
H
1.8
phenyl
H
1.0
3-OMe-phenyl
4-OMe-phenyl
3-OMe-phenyl
3-OMe-phenyl
3-OMe-phenyl
4-OMe-phenyl
4-OMe-phenyl
4-OMe-phenyl
3-isopropoxyphenyl
2-F-phenyl
H
1.1
H
0.9
H
2.1
5-F
5-F
5-F
5-F
5-Cl
5-F
H
3.0
8.2
7.6
3.0
3.6
6.4
950
1400
1200
580
18
1.4
0.4
0.1
1.1
2.6
1.2
1.1
3-F-phenyl
H
1.0
4-F-phenyl
H
1.1
3-methylphenyl
2-naphthyl
H
1.5
4-F
4-F
5-F
H
3.6
2-benzofuranyl
2-quinolyl
7.1
56
3.3
0.3
1,4-benzodioxane-6-yl
1,4-benzodioxane-6-yl
1,4-benzodioxane-6-yl
1,4-benzodioxane-6-yl
1,4-benzodioxane-6-yl
1,4-benzodioxane-6-yl
1,4-benzodioxane-6-yl
1,4-benzodioxane-6-yl
1,3-benzodioxol-5-yl
3-CF3-phenyl
42
0.8
H
12
1.3
H
7.0
11
1.8
4-F
4-F
4-F
5-F
1.1
isobutyl
propyl
butyl
5.6
4.9
2.0
45
2.0
1.6
1.0
butyl
4,6-difluoro
H
1.7
ethyl
130
220
110
5.7
2.4
4.5
6.9
7.7
19
1.0
ethyl
H
1.8
ethyl
4-CF3-phenyl
H
1.8
ethyl
4-CF3-phenyl
5-F
5-F
5-F
5-F
5-F
5-Cl
5-F
5-F
5-F
H
1.1
butyl
4-CF3-phenyl
2.1
butyl
3-OCF3-phenyl
4-OCF3-phenyl
4-OCF3-phenyl
4-OCF3-phenyl
4-CF3SO2-phenyl
3-hydroxyphenyl
4-hydroxy-phenyl
4-MeSO2-phenyl
4-MeSO2-phenyl
4-MeSO2-phenyl
4-MeSO2-phenyl
4-MeSO2-phenyl
4-MeSO2-phenyl
4-MeSO2-phenyl
4-MeSO2-phenyl
4-MeSO2-phenyl
4-MeSO2-phenyl
4-MeSO2-phenyl
2.4
ethyl
1.2
butyl
2.2
butyl
3.6
ethyl
5.2
26
1.2
ethyl
−0.3
−0.4
−0.2
−0.9
−0.6
−0.1
0.0
ethyl
22
ethyl
69
ethyl
5-F
5-F
5-F
5-F
5-F
5-F
5-F
5-F
5-F
5-F
3.1
17
isopropyl
isobutyl
cyclopentyl
phenyl
benzyl
2-(4-tolyl)-ethyl
dioxolan-4-yl
3-pyridyl
4-pyridyl
3.2
5.4
2.2
0.9
2.5
28
−0.8
−0.8
0.2
−1.4
−1.5
−1.4
4.0
17
(see the Supporting Information). To reduce oxidative
metabolism, our first strategy involved blocking this weak
spot. Compounds 50 and 51, bearing a trifluoromethoxy group,
were found to retain potency on the target but were
significantly less metabolized, in particular those with a C-2
chain on the acyl group, probably due to the lower overall
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ACS Medicinal Chemistry Letters
Letter
exposure after oral dosing (AUC 11212 h ng/mL after a dose
of 5 mg/kg), identifying the compound as a possible tool
compound for pharmacology experiments.
However, all CF3- and OCF3-containing compounds found
to be stable in the microsomes were also found to be potent
inhibitors of some CYP isoforms, in particular the 2C8, 2C9,
and 2C19 isoforms (IC50 < 300 nM; see, for example, 48
and 51, Table 2). In contrast, no significant inhibition (IC50
>
10 μM) was found on isoforms 1A2, 2B6, 3A4, and 2D6. This
could be rationalized as follows: modification to the structure
had reduced the capability of the metabolizing enzymes to
oxidize the compounds but not reduced the overall affinity
of the compounds for these CYP isoforms; the high affinity
coupled with the inability of the enzyme to process the
compound resulted in the strong inhibition.
Figure 2. Activity of carboxylic acid analogues.
Table 2. In Vitro Clearance in Human and Rat Liver
Microsomes and Human CYP Inhibition Data for Selected
Compounds
Given these results, two alternative strategies were pursued.
First, it was decided to verify if the metabolites of compounds
25−26 would retain activity on the receptor. Phenolic
compounds 55 and 56 were prepared, but their potency was
lower than the corresponding parent compounds, albeit the
CYP inhibition was indeed reduced.
a
Clint (HLM/RLM)
CYP inhibition (2C8/2C9/2C19)
compd
(μL/min/mg prot)
IC50 (μM)
16
29
39
48
51
55
58
60
61
63
>1000/43
1700/30
>1000/125
<10/<10
<10/12
55/10
0.32/0.84/0.26
0.47/0.34/0.90
0.57/0.64/0.68
0.086/0.28/0.038
0.043/0.20/0.051
0.97/2.0/3.7
As a second alternative, it was decided to increase the polarity
of the compounds, to decrease affinity to the CYP isoforms,
which in general show a preference for more lipophilic
compounds.17 In particular, it was decided to introduce polar
groups on the benzylic group, which is close to the main site of
metabolism. Good results were obtained in particular with
sulfone-containing compounds such as 58, which showed a low
level of metabolism in the microsomes, coupled with a reduced
level of inhibition of the CYP 2C9 isoform, as well as an
excellent potency on the receptor. Keeping this R2 group fixed,
we then examined a number of different R1 groups (59−67). A
number of groups retained an excellent affinity for the receptor.
The best combination in terms of in vitro profiling was the
isobutyl group (60), which retained moderate metabolic stability
and moderate 2C9 inhibition (IC50 = 1.7 μM) but also gave a
significant improvement on the inhibition of the 2C19 isoform
(IC50 = 7.5 μM), as compared to 58. All of these compounds
still inhibited CYP2C8 with IC50 < 1 μM; however, it is
interesting to note that an important asthma drug, Montelukast
(Singulair), is also reported as a very potent inhibitor of CYP
2C8.18
The introduction of the polar sulfone moiety also had an
effect on the functional behavior of the compounds. While
earlier compounds had shown an inverse agonist behavior in
the GTPγS assay, the sulfone-bearing compounds displayed
different behaviors: a neutral antagonist behavior for compound
60, with no significant effect on the assay in agonist mode, even
though the slightly reduced level of inhibition at the highest
concentration in antagonist mode might suggest a weak partial
agonist effect; compound 61 behaved as a weak partial agonist
(7% Emax in agonist mode, with a corresponding reduction in
the maximum inhibition in the assay in antagonist mode),
whereas 63 had an inverse agonist behavior. This tendency for
switch of functional behavior for CRTH2 agonists/antagonists,
even with small structural changes such as methyl to ethyl, has
been described in the literature.13,19
<10/<10
17/17
0.054/>20/0.15
0.079/1.7/7.5
0.22/7.4/12
92/40
28/20
0.050/0.29/0.17
a
HLM, human liver microsomes; RLM, rat liver microsomes.
Table 3. Activity of Selected Compounds in Functional
Cellular Assays in Agonist
a
b
GTPγS agonist mode
(Emax at 20 μM)
GTPγS antagonist mode
entry
compd
(IC50/inhibition at 2 μM)
1
2
3
4
5
6
7
8
9
25
28
43
48
53
55
60
61
63
−11%
−10%
−15%
−8%
−10%
−17%
64 nM/107%
10 nM/110%
2.8 nM/102%
37 nM/105%
20 nM/112%
85 nM/106%
46 nM/85%
57 nM/80%
3.7 nM/94%
c
no effect
+7%
−10%
a
In the absence of PGD2, 100% represents the level of stimulation
given by 2 μM PGD2. In the presence of 80 nM PGD2. No
statistically significant effect (−5% < effect < 5%).
b
c
lipophilicity. Quite surprisingly, considering the lower activity
of the halogen-substituted compounds was the fact that the
trifluoro-substituted 46−49 were also found to be highly
potent. The stability in human and rat microsomes was also
good (Table 2). Compound 48 was also tested in a mouse PK
experiment and showed a low clearance (0.3 L/kg/h), with an
acceptable half-life (1.4 h after intravenous dosing) and a
medium volume of distribution (Vss 0.9 L/kg). The low in vivo
clearance of this compound might indicate that limited
conjugative metabolism might be taking place, at least in
mouse. However, we have not studied the behavior of these
compounds in hepatocytes (neither rodent nor human), so
further studies would be warranted to make a definite statement
on the matter. Despite a moderate permeability in a Caco-2
assay (Papp 3.0 × 10−6 cm/s), the oral bioavailability in mouse
was found to be good (Fz 76%), resulting in an excellent
In conclusion, the results presented in this communication
show that it is possible to design potent tetrazole-based
CRTH2 antagonists as a potentially safer alternative to the
traditional carboxylic acid antagonists. Further investigations,
aimed at further improving the metabolic stability, at improving
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ACS Medicinal Chemistry Letters
Letter
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cellular functional behavior, and at further reducing the CYP
inhibition, are ongoing and will be communicated in due time.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details for biological assays and for the synthesis
and characterization of all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) Desforges, G.; Bombrun, A.; Quattropani, A. An efficient and
expeditious synthesis of di- and trisubstituted amino-phenyl and
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Chem. 2008, 10, 671−680.
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eosinophil chemokine signaling via CCR3 and non-CCR3 pathways.
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B. A. Delta 12-prostaglandin J2, a plasma metabolite of prostaglandin
D2, causes eosinophil mobilization from the bone marrow and primes
eosinophils for chemotaxis. J. Immunol. 2003, 170, 4752−8.
(17) Lewis, D. F. V.; Jacobs, M. N.; Dickins, M. Compound
lipophilicity for substrate binding to human P450s in drug metabolism.
Drug Discovery Today 2004, 9, 530−537.
(18) Walsky, R. L.; Gaman, E. A.; Obach, R. S. Examination of 209
drugs for inhibition of Cytochrome P450 2C8. J. Clin. Pharmacol.
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(19) Crosignani, S.; Pretre, A.; Jorand-Lebrun, C.; Fraboulet, G.;
Seenisamy, J.; Augustine, J. K.; Missotten, M.; Humbert, Y.; Cleva, C.;
Abla, N.; Daff, H.; Schott, O.; Schneider, M.; Burgat-Charvillon, F.;
Rivron, D.; Hamernig, I.; Arrighi, J.-F.; Gaudet, M.; Zimmerli, S. C.;
Juillard, P.; Johnson, Z. Discovery of potent, selective and orally
bioavailable alkynyl-phenoxyacetic acid CRTH2 (DP2) receptor
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AUTHOR INFORMATION
Corresponding Author
*Tel: +41 22 414 9618. Fax: +41 22 414 9565. E-mail: stefano.
crosignani@merckgroup.com.
■
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