Optimization of the central core of indolinone-acetic acid-based CRTH2 (DP2) receptor antagonists

Article abstract of DOI:10.1021/ml2001196

New spiroindolinone antagonists of CRTH2 are described. Following identification of insufficient stability in human plasma as an important liability of the lead compounds, replacement of the spirosuccinimide core with a spirohydantoin or spiropyrrolidinon

Full text of DOI:10.1021/ml2001196

LETTER
pubs.acs.org/acsmedchemlett
Optimization of the Central Core of IndolinoneꢀAcetic Acid-Based
CRTH2 (DP2) Receptor Antagonists
Stefano Crosignani,* Catherine Jorand-Lebrun, Patrick Page, Gordon Campbell, Vꢀeronique Colovray,
Marc Missotten, Yves Humbert, Christophe Cleva, Jean-Franc-ois Arrighi, Marilꢁene Gaudet, Zoe Johnson,
Pamela Ferro, and Andrꢀe Chollet
Merck Serono S.A., 9 chemin des Mines, CH-1202 Geneva, Switzerland
S Supporting Information
b
ABSTRACT: New spiroindolinone antagonists of CRTH2 are de-
scribed. Following identification of insufficient stability in human plasma
as an important liability of the lead compounds, replacement of the
spirosuccinimide core with a spirohydantoin or spiropyrrolidinone struc-
ture has yielded a compound that is fully stable in human plasma and with
good potency in a human whole blood assay (IC50 = 69 nM) but shows a
much lower oral bioavailability (6ꢀ9% in rodents) than the earlier
compounds. Successive optimization aimed at restoring an acceptable
oral bioavailability has yielded compound (S)-17a, which exhibits both
stability in human plasma and a good oral bioavailability in rat (37%) and
mouse (39%). This compound is also active in a mouse model of
ovalbumin-induced lung inflammation following oral dosing at 30 mg/kg.
KEYWORDS: CRTH2 receptor, prostaglandin D2, antagonist, indolinone, asthma, atopic dermatitis
rostaglandin D2 (PGD2) (1) (Figure 1) is the major
prostanoid species produced by mast cells in response to
In mouse models of allergic asthma and atopic dermatitis,
CRTH2 receptor activation promotes eosinophilia and exacer-
bates pathology.9 Intratracheal administration of PGD2 in rats,
pretreated or not with systemic IL-5 injection, induces eosinophil
trafficking into the airways. This effect is mimicked by selective
CRTH2 receptor agonists but not by a DP (DP1) selective
agonist.3,10 Furthermore, inhibition by selective small molecules
of the CRTH2 receptor but not of the DP or TP receptor
abolishes inflammatory responses in mouse models of acute and
chronic contact hypersensitivity as well as eosinophilic airway
inflammation.11ꢀ14 Recently, it has been postulated that DP and
CRTH2 might have opposing effects in complex inflammatory
processes, so that inhibition of CRTH2 may have the added
benefit of leaving the anti-inflammatory effects mediated by DP1
unopposed.15
PGD2 is enzymatically and nonenzymatically metabolized
into many different products, several of which are biologically
active.15,16 The thromboxane A2 antagonist ramatroban (2)
(Figure 1), a drug marketed for allergic rhinitis, has also been
shown to possess CRTH2 antagonistic properties. In addition,
the finding that indomethacin was able to activate CRTH2,
among other pharmacological actions, was the starting point for
the discovery of other indole acetic acid derivatives and further
spurred much effort in the pharmaceutical industry aimed at
discovering selective agents to modulate its action.17,18
P
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 PGD2-receptor (DP or
DP1) and the more recently discovered chemoattractant recep-
tor homologous expressed on Th2 lymphocytes (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 CRTH2 receptor is important in the
recruitment of Th2 in allergic diseases in humans.4 Indeed, atopic
dermatitis subjects or those with sensitivity to pollen or to dust
mite antigens have significantly increased levels of CD4þ T cells
expressing CRTH2 receptors,2,5 and severity of atopic dermatitis
has been correlated with increased numbers of circulating Th2
cells.6 Finally, sequence variants of the CRTH2 receptor that
confer increased mRNA stability are associated with a higher
degree of bronchial hyper-responsiveness and the occurrence of
fatal asthma.7
Further data in animal models likewise point to a central role
for CRTH2 in allergic disorders. CRTH2 receptor activation
induces the release of eosinophils from guinea pig bone marrow.8
Received: May 18, 2011
Accepted: June 9, 2011
Published: June 09, 2011
r
2011 American Chemical Society
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LETTER
Figure 1. Structures of prostaglandin D2 (PGD2) (1), ramatroban (2), representative CHTH2 antagonists (3ꢀ5), and the previously described lead
compounds [(R)-6a and (R)-6b].
during the pH stability studies were apparent, clearly indicat-
ing that the plasma degradation was also taking place on the
succinimide group.
To obtain new analogues with substantially improved stability
in human plasma, two strategies to stabilize the COꢀN bonds of
the succinimide ring were envisioned, removal of either of the
carbonyl groups of the succinimide to give more stable spiro-
pyrrolidinones or replacement of the succinimide ring with a
hydantoin. The synthesis of the spiropyrrolidinones 9 and 10 has
been described in our previous work.19 Spirohydantoins 11aꢀc
Figure 2. Degradants of 6a at pH > 6.
could be prepared as described in Scheme 1.
In a preceding paper of this series,19 we disclosed two novel,
potent DP2 antagonists. Spirosuccinimides (R)-6a and (R)-6b
showed not only excellent potencies on CRTH2 in both binding
as well as functional assays but also showed a good pharmaco-
kinetic (PK) profile in rodents and dog. These two compounds
were further profiled to establish their potential for use as
therapeutic agents for atopic diseases. A key weakness was soon
identified: pH stability studies demonstrated that the compounds
were prone to significant degradation at neutral and basic pH
[25% degradation after 24 h at pH 7.4 and 50% degradation after
24 h at pH 8 for (R)-6a]. The two main degradants were
identified as being products 7 and 8, both derived from opening
of the succinimide ring, with subsequent decarboxylation for
derivative 8 (Figure 2). It was hypothesized that the succinimide
moiety was particularly prone to ring opening due to the strain
caused by the spiro system.
This chemical instability had a negative impact on the devel-
opment potential of the compounds, since the preparation of
different salts [potassium or 4-(2-hydroxyethyl)-morpholine
salts, for example] led to an unacceptable level of degradation,
leaving only the parent form of the compound as suitable for
preclinical and clinical studies. However, no significant impact
had been determined in the rodent and dog PK experiments,
which exhibited medium/low clearance values, in keeping with
the good stability exhibited by the compounds in the presence of
rat and mouse plasma. In contrast, the compounds were found to
have low stability (t1/2 ∼ 1 h) in the presence of human plasma,
precluding the possibility of the compounds showing a favorable
PK profile in humans. The same degradation products found
Following alkylation of chloroisatin with tert-butyl bromoace-
tate, the hydantoin ring could be assembled in one step by reac-
tion with KCN and (NH4)2CO3. Alkylation with various benzyl
bromides using NaHCO3 in N,N0-dimethylformamide (DMF)
was found to exclusively alkylate on the most acidic NH group,
giving the desired intermediates 15aꢀc. Deprotection with
trifluoroacetic acid afforded the desired spirohydantoin com-
pounds. Separation of the two enantiomers was accomplished for
the most potent analogues by preparative high-performance
liquid chromatography (HPLC) on a chiral stationary phase.20
Comparison of the activities of these compounds showed that
two of the succinimide replacements maintained a good level of
potency on the receptor. Hydantoins 11aꢀc were found to be
active, as well as one of the pyrrolidinone regioisomers (9). In
contrast, the other pyrrolidinone regioisomer (10) was found to
be significantly less active than its succinimide counterpart,
suggesting that the carbonyl in the 5-position of the succinimide
ring is important for the binding to the receptor. Both new
scaffolds proved to be more stable than the corresponding
succinimides: Both (S)-11b and (S)-9b were found to be stable
in human plasma (<15% degradation after 24 h). In pH stability
experiments, (S)-9b proved to be completely stable (<5%
degradation) up to pH 9, whereas (S)-11b was stable at pH 8
(<5% degradation) but not at pH 9 (45% degradation). The
improved stability allowed for the development of salt forms for
both types of compounds, and both were found stable in a
number of formulations.
A comparison of the profiles of two of the most potent
analogues for each of the spiropyrrolidinone and spirohydantoin
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Scheme 1a
a Reagents: (a) K2CO3, tert-butyl bromoacetate, room temperature, 65%. (b) KCN, (NH4)2CO3, EtOH/H2O, reflux, 92%. (c) NaHCO3, R1CH2Br,
59%. (d) CF3COOH, CH2Cl2, 0 °C to room temperature, 93%. (e) Chiral HPLC for 11b.
Table 1. Comparison of (S)-9b and (S)-11b
for (S)-9b. This was in keeping with low clearance values in
both human microsomes (<1 μg/mL/h) and human hepatocytes
(2 μg/mL/h) for (S)-11b. Both compounds showed low oral
bioavailability (Fz), 6% for (S)-11b vs 5% for (S)-9b.
(S)-9b
(S)-11b
15
Ki (hCRTH2) (nM)
13
PK experiments in various animal species (mouse, dog, guinea
pig, and monkey) confirmed that (S)-11b could be considered as
a low-clearance compound. However, the low oral bioavailability
observed in the rat was confirmed in mouse (9%), guinea pig
(7%), and monkey (10ꢀ15%), while the dog, with an oral
bioavailability of 71%, was an outlier. The in vitro profiling of
(S)-11b identified two parameters that could explain the poor
oral bioavailability. First, the compounds exhibited a very low
solubility in simulated gastric fluid (SGF) of 0.01 mg/mL (vs
a solubility in fasted state simulated intestinal fluid, Fassif, of
1.5 mg/mL). Even more importantly, (S)-11b had a very poor
permeability in the Caco-2 assay (Papp = 0.2 ꢁ 10ꢀ6 cm/s), ca.
100-fold lower than the corresponding succinimide (R)-6b
(Papp = 26 ꢁ 10ꢀ6 cm/s), which showed a more satisfactory
Fz of 32% in rat. To determine the cause for the low oral
bioavailability, an experiment was performed in rats by admin-
istering the compound via different routes. The high bioavail-
ability after portal vein administration (90%) ruled out the possi-
bility that first-pass metabolism could play a major role in
reducing oral bioavailability. In contrast, the low bioavailabil-
ity after intraduodenal administration (11%) confirmed that
low permeability of the compound, and not a possible pre-
cipitation in the stomach, was the main determinant of the low
oral bioavailability.
eosinophil chemotaxis IC50 (nM)
hWB assay IC50 (nM)
62
7.4
1800
69
Fu (h, r, m, %)
<1%/ ND/ND
2.3/3.0/6.3
0.2 ꢁ 10ꢀ6
0.15
Caco-2 permeation Papp (cm/s)
clearance in rat (L/kg/h)
oral bioavailability in rat (Fz, %)
1.8 ꢁ 10ꢀ6
0.72
5
6
series can be found in Table 1. For both series, the compounds
substituted with an isoxazole substituent (9d and 11c) were
found to be highly potent on the receptor and showed excellent
activities in a human whole blood assay (hWB assay, inhibition of
eosinophil shape change induced by 10 nM PGD2) but had very
high clearance in rodent PK experiments and were not further
characterized. The (2-fluoro-4-chloro)benzyl-substituted com-
pounds showed similar potencies in the binding assay but diffe-
rent activities in the functional assays, with hydantoin (S)-11b
being significantly more potent in both the eosinophil chemo-
taxis assay (7.4 vs 62 nM) and especially in the hWB assay (69 vs
1800 nM). The difference in activity in human whole blood could
be at least in part attributed to the higher unbound fraction in
human plasma [Fu 2.3% for (S)-11b vs Fu <1% for (S)-9b]. The
rat PK data also showed that among the two compounds (S)-11b
had the better profile, with a low clearance of 0.15 vs 0.72 L/kg/h
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Scheme 2a
a Reagents: (a) tert-Butyl N,N0-diisopropylimidocarbamate, THF, room temperature, 61%. (b) R2I, K2CO3, DMF, room temperature. (c) CF3COOH,
CH2Cl2, 0 °C to room temperature. (d) CH3I, [(CH3)3Si]2NLi, THF, 0 °C to room temperature, 47%. (e) R1CH2Br or R1CH2Cl, NaHCO3, KI, DMF,
80 °C. (f) HCl, dioxane, 0 °C to room temperature.
Table 2. Comparison of (S)-17a and (S)-11b
R1 substituent (Scheme 2), a position that had been extensively
studied on the succinimide derivatives. A number of groups were
explored, but only the phenyl thiazole derivative 20d showed
potency comparable to (S)-17a. Further profiling of 20d showed
that potency in the hWB assay (IC50 = 3940 nM) as well as
mouse PK parameters (Cl 3.63 L/kg/h, Fz <5%) were unfavor-
able, and further development of this compound was not
pursued.
Characterization of (S)-17a (Table 2) showed that the
compound retained stability in human plasma as well as in
human and rat microsomes (Clint <10 μL/min/mg in both
species). In the Caco-2 experiment, (S)-17a was still found to be
poorly permeable, with a Papp <1 ꢁ 10ꢀ6 cm/s, far below the
corresponding succinimide (R)-6b (Papp = 26 ꢁ 10ꢀ6 cm/s).
However, in a mouse PK experiment, (S)-17a had a similar,
moderate clearance (Cl = 0.8 L/kg/h) as shown by (S)-11a in the
same species but with an improved oral bioavailability (Fz = 39%
vs Fz = 9% for (S)-11a in mouse), resulting in a much-improved
AUC after oral dosing (2400 vs 580 h ng/h/mL at 5 mg/kg po).
A similar improvement of the oral bioavailability was observed in
the rat [Fz = 37% vs Fz = 6% for (S)-11a]. The stability in human
and rodent plasma was retained. The protein binding of (S)-17a
was found to be very similar to that of (S)-11a, so rather
unsurprisingly the potency in the hWB assay was found to follow
the same trend as the affinity for the receptor, with an IC50 ca.
2-fold higher than for (S)-11a (IC50 = 150 vs 69 nM). The
combination of good potency in the hWB assay and favorable PK
(S)-17a
(S)-11b
15
Ki (hCRTH2) (nM)
35
eosinophil chemotaxis IC50 (nM)
hWB assay IC50 (nM)
47
7.4
150
69
Fu (h, r, m, %)
2.0/1.9/5.0
0.6
2.3/3.0/6.3
Caco-2 permeation Papp (cm/s)
clearance in mouse (L/kg/h)
oral bioavailability in mouse (Fz, %)
AUC po (5 mg/kg) (h ng/mL)
0.2 ꢁ 10ꢀ6
0.8
9
0.8
39
2400
580
Comparing the structures of (R)-6b and (S)-11b, the impor-
tant difference in permeability could be tentatively attributed
to the presence of an extra hydrogen bond donor (HBD) in
hydantoin (S)-11b. To obtain compounds combining the plasma
and pH stability of the hydantoin compounds and the perme-
ability of the succinimide compounds, it was decided to mask the
HBD function by alkylating the second hydantoin nitrogen atom.
A small series of N-alkyl derivatives (S)-17aꢀc could be prepared
by alkylation of the tert-butyl ester (S)-16 (Scheme 2).
Compound (S)-17a showed an activity on the receptor,
which, albeit slightly reduced as compared to (S)-11a, was still
acceptable (Table 2). In contrast, introducing even slightly larger
substituents, such as ethyl and propyl, quickly led to compounds
having Ki over 100 nM. A limited SAR was also performed on the
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in mice indicated that (S)-17a should be active in CRTH2-
dependent animal models after oral dosing. This was verified by
testing the compound in a lung eosinophilia model in mice: (S)-
17a was found to inhibit lung eosinophilia induced by aero-
solized ovalbumin (67 ( 11% inhibition following oral dosing at
30 mg/kg, P < 0.05, vs 83 ( 8% inhibition by dexamethasone
dosed at 1 mg/kg ip, P < 0.01).
The undesirable off-target activity of (S)-17a (at a concentra-
tion of 10 μM) was also evaluated; among other prostanoid
receptors, EP1 and EP2 were weakly inhibited (respectively, 32
and 34% inhibition in a binding assay). Inhibition of PGD2
binding to DP1 or of PGD2-mediated cyclic adenosine mono-
phosphate (cAMP) increase in DP1-expressing human embryo-
nic kidney cells was found to be of less than 30% [up to 20 μM of
(S)-17a]. No significant activity was found on a panel of 50
different enzymes and receptors, including the Kv11.1 (hERG)
channel, with the exception of the enzyme aldose reductase
(IC50 = 150 nM). The compound was also tested in a cytotoxicity
assay, both on primary rat hepatocytes and on human hepato-
cellular carcinoma (HepG2) cells, and found to be noncytotoxic
up to the highest concentration tested (750 μM). Finally, no
significant inhibition of the major cytochrome P450 (CYP)
isoforms was observed (CYP1A2, -2C19, -2C8, -2C9, -2D6,
and -3A4; IC50 > 10 μM).
In conclusion, the lack of stability of the initial lead com-
pounds in neutral and mildly basic conditions and especially in
human plasma could be substantially improved by modifying the
succinimide ring. Of the modifications attempted, both yielded
compounds with good affinity for the receptor, but only the use
of a hydantoin group allowed the discovery of an antagonist with
high potency in the human whole blood assay, but its low oral
bioavailability across several species prevented its development
as an oral agent for atopic dermatitis or asthma. Further opti-
mization to improve the oral bioavailability led to the identifica-
tion of compound (S)-17a, which shows good potency in the
hWB assay as well as good PK parameters in rodents, including
a acceptable oral bioavailability, translating to activity in a mouse
model of ovalbumin-induced lung inflammation following oral
dosing.
(2) Hirai, H.; Tanaka, K.; Yoshie, O.; Ogawa, K.; Kenmotsu, K.;
Takamori, Y.; Ichimasa, M.; Sugamura, K.; Nakamura, M.; Takano, S.;
Nagata, K. Prostaglandin D2 selectively induces chemotaxis in T helper
type 2 cells, eosinophils and basophils via 7-transmembrane receptor
CRTH2. J. Exp. Med. 2002, 193, 255–261.
(3) Shiraishi, Y.; Asano, K.; Nakajima, T.; Oguma, T.; Suzuki, Y.;
Shiomi, T.; Sayama, K.; Niimi, K.; Wakaki, M.; Kagyo, J.; Ikeda, E.; Hirai,
H.; Yamaguchi, K.; Ishizaka, A. Prostaglandin D2-induced eosinophilic
airways inflammation is mediated by CRTH2 receptor. J. Pharmacol.
Exp. Ther. 2005, 312, 954–960.
(4) Cosmi, L.; Annunziato, F.; Galli, M. I. G.; Maggi, R. M. E.;
Nagata, K.; Romagnani, S. CRTH2 is the most reliable marker for the
detection of circulating human type 2 Th and type 2 T cytotoxic cells in
health and disease. Eur. J. Immunol. 2000, 30, 2972–2979.
(5) Hammad, H.; de Heer, H. J.; Soullie, T.; Hoogsteden, H. C.;
Trottein, F.; Lambrecht, B. N. Prostaglandin D2 inhibits airway dendritic
cell migration and function in steady state conditions by selective
activation of the D prostanoid receptor 1. J Immunol. 2003, 171,
3936–3940.
(6) Iwasaki, M.; Nagata, K.; Takano, S.; Takahashi, K.; Ishii, N.;
Ikezawa, Z. Association of a new type prostaglandin D2 receptor
CRTH2 with circulating T helper 2 cells in patients with atopic
dermatitis. J. Invest. Dermatol. 2002, 119, 609–616.
(7) Huang, J. L.; Gao, P. S.; Mathias, R. A.; Yao, T. C.; Chen, L. C.;
Kuo, M. L.; Hsu, S. C.; Plunkett, B.; Togias, A.; Barnes, K. C.; Stellato,
C.; Beaty, T. H.; Huang, S. K. Sequence variants of the gene encoding
chemoattractant receptor expressed on Th2 cells (CRTH2) are asso-
ciated with asthma and differentially influence mRNA stability. Hum.
Mol. Genet. 2004, 13, 2691–2697.
(8) Heinemann, A.; Schuligoi, R.; Sabroe, I.; Hartnell, A.; Peskar,
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, 4752–4758.
(9) Spik, I.; Brenuchon, C.; Angeli, V.; Staumont, D.; Fleury, S.;
Capron, M.; Trottein, F.; Dombrowicz, D. Activation of prostaglandin
D2 receptor DP2/CRTH2 incraeses allergic inflammation in mouse.
J. Immunol. 2005, 174, 3703–3708.
(10) Almishri, W.; Cossette, C.; Rokach, J.; Martin, J. G.; Hamid, Q.;
Powell, W. S. Effects of prostaglandin D2, 15-deoxy-delta12,14-prosta-
glandin J2, and selective DP1 and DP2 receptor agonists on pulmonary
infiltration of eosinophils in Brown Norway rats. J. Pharmacol. Exp. Ther.
2005, 313, 64–69.
(11) Takeshita, K.; Yamasaki, T.; Nagao, K.; Sugimoto, H.; Shichijo,
M.; Gantner, F.; Bacon, K. B. CRTH2 is a prominent effector in contact
hypersensitivity-induced neutrophil inflammation. Int. Immunol. 2004,
16, 947–959.
’ ASSOCIATED CONTENT
(12) Boehme, S. A.; Chen, E. P.; Franz-Bacon, K.; Sasik, R.; Sprague,
L. J.; Ly, T. W.; Hardiman, G.; Bacon, K. B. Antagonism of CRTH2
ameliorates chronic epicutaneous sensitization-induced inflammation
by multiple mechanisms. Int. Immunol. 2009, 21, 1–17.
(13) Boehme, S. A.; Franz-Bacon, K.; Chen, E. P.; Sasik, R.; Sprague,
L. J.; Ly, T. W.; Hardiman, G.; Bacon, K. B. A small molecule CRTH2
antagonist inhibits FITC-induced allergic cutaneous inflammation. Int.
Immunol. 2009, 21, 81–93.
(14) Uller, L.; Mathiesen, J. M.; Alenmyr, L.; Korsgren, M.; Ulven,
T.; Hoegberg, T.; Andersson, G.; Persson, C. G. A.; Kostenis, E.
Antagonism of the prostaglandin D2 receptor CRTH2 attenuates
asthma pathology in mouse eosinophilic airway inflammation. Respir.
Res. 2007, 8.
(15) Kostenis, E.; Ulven, T. Emerging roles of DP and CRTH2 in
allergic inflammation. Trends Mol. Med. 2006, 12, 148–158.
(16) Schuligoi, R.; Schmidt, R.; Geisslinger, G.; Kollroser, M.;
Peskar, B. A.; Heinemann, A. PGD2 metabolism in plasma: Kinetics
and relationship with bioactivity on DP1 and CRTH2 receptors.
Biochem. Pharmacol. 2007, 74, 107–117.
S
Supporting Information. Experimental details for biolo-
b
gical assays and for the synthesis and characterization of 11aꢀc,
17aꢀc, and 20aꢀg. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Tel: þ41 22 414 9618. Fax: þ41 22 414 9565. E-mail: Stefano.
crosignani@merckserono.net.
’ ACKNOWLEDGMENT
We are grateful to Cynthia Rocha, Manfred Schneider, Clive
Till, and Nada Abla for the PK assessment of the compounds.
’ REFERENCES
(1) Pettipher, R.; Hansel., T. T.; Armer, R. Antagonism of the
prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat
allergic diseases. Nature Rev. Drug Discovery 2007, 6, 313–325.
(17) Ly, T. W.; Bacon, K. B. Small-molecule CRTH2 antagonists for
the treatment of allergic inflammation: an overview. Expert Opin. Invest.
Drugs 2005, 14, 769–773.
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LETTER
(18) Ulven, T.; Kostenis, E. Novel CRTH2 antagonists: A review of
patents from 2006 to 2009. Expert Opin. Ther. Pat. 2010, 20, 1505–1530.
(19) Crosignani, S.; Page, P.; Missotten, M.; Colovray, V.; Cleva, C.;
Arrighi, J.-F.; Atherall, J.; Macritchie, J.; Martin, T.; Humbert, Y.;
Gaudet, M.; Pupowicz, D.; Maio, M.; Pittet, P.-A.; Golzio, L.; Giachetti,
C.; Rocha, C.; Bernardinelli, G.; Filinchuk, Y.; Scheer, A.; Schwarz,
M. K.; Chollet, A. Discovery of a New Class of Potent, Selective and
Orally Bioavailable CRTH2 (DP2) Receptor Antagonists for the
Treatment of Allergic Inflammatory Diseases. J. Med. Chem. 2008,
51, 2227–2243.
(20) While the absolute configuration for the enantiomers of 11b
could not be determined due to the difficulty to obtain crystals suitable
for X-ray diffraction, the absolute configuration of the most potent (on
CRTH2) enantiomer (þ)-11b was deduced by analogy with known
(R)-6a and (R)-6b to be of (S) configuration.
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