7-Azaindole-3-acetic acid derivatives: Potent and selective CRTh2 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2009.06.042

High throughput screening identified a 7-azaindole-3-acetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a highly selective compound with good functional potency for inhibition of human eosinophil shape change in whole blood and oral bioavailability in the rat.

Full text of DOI:10.1016/j.bmcl.2009.06.042

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4794–4798
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
7-Azaindole-3-acetic acid derivatives: Potent and selective CRTh2
receptor antagonists
a
a
b
b
b
David A. Sandham a, , Claire Adcock , Kamlesh Bala , Lucy Barker , Zarin Brown , Gerald Dubois ,
David Budd b, Brian Cox a, Robin A. Fairhurst a, Markus Furegati c, Catherine Leblanc a, Jodie Manini b,
Rachael Profit b, John Reilly a, Rowan Stringer b, Alfred Schmidt c, Katharine L. Turner a, Simon J. Watson a,
Jennifer Willis b, Gareth Williams b, Caroline Wilson b
*
a Global Discovery Chemistry, Novartis Institutes of Biomedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom
b Respiratory Diseases Area, Novartis Institutes of Biomedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom
c Global Discovery Chemistry, Novartis Institutes of Biomedical Research, Postfach CH-4002, Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
High throughput screening identified a 7-azaindole-3-acetic acid scaffold as a novel CRTh2 receptor
antagonist chemotype, which could be optimised to furnish a highly selective compound with good func-
tional potency for inhibition of human eosinophil shape change in whole blood and oral bioavailability in
the rat.
Received 29 May 2009
Revised 10 June 2009
Accepted 11 June 2009
Available online 14 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
CRTh2
Prostaglandin D2
Azaindole
Eosinophils
Allergic diseases
Prostaglandin D2 (PGD2), a product of the arachidonic acid
cascade, is synthesized primarily by mast cells, as well as by mac-
rophages and Th2 lymphocytes. PGD2 has long been associated
with the allergic inflammatory response, being found at high con-
centrations in the lungs of asthmatic patients.1 PGD2 was initially
believed to act solely through the DP receptor, although more
recently a second receptor for PGD2, known as CRTh2 or DP2 has
been identified.2 CRTh2 shows minimal homology with DP and is
expressed on inflammatory cells, in particular showing selective
expression on Th2 over Th1 cells. Using specific agonists, it has
been demonstrated that the PGD2-mediated activation and migra-
tion of eosinophils, basophils and Th2 cells in vitro proceeds selec-
tively via CRTh2 receptor activation. An emerging body of evidence
of the activity of selective CRTh2 antagonists in pre-clinical rodent
models supports this mechanism as a new therapeutic modality for
treatment of asthma and other allergic diseases.3a,3b
CRTh2.5a,b Subsequently, related indoleacetic acid CRTh2 antago-
nist scaffolds have been reported such as 36 and 47 which were ob-
tained by morphing approaches from indomethacin. A similar
chemotype 5 was identified by optimisation of high throughput
screening (HTS) hits.8 A variety of other CRTh2 antagonist chemo-
types have also been disclosed.9 We conducted our own HTS to
search for novel CRTh2 antagonists and have recently disclosed a
series of 2-cycloalkylphenoxyacetic acids exemplified by 6 opti-
mised from one hit series.10 In this publication, we describe the
optimisation of a 7-azaindole-3-acetic acid HTS hit 7 leading to
compounds with improved potency and selectivity compared to 6.
Compound 7 was identified as a potent ligand for the CRTh2
receptor in a [3H]–PGD2 radioligand binding assay using CHO cells
stably transfected with the human CRTh2 receptor. Functional
activity was initially assessed using an isolated human eosinophil
shape change (SC) assay as described previously.10 An excellent
level of selectivity was found for binding to the CRTh2 over the
human DP and TP prostanoid receptors (Table 1). Most encourag-
ingly, despite the structural similarity to indomethacin, less than
50% inhibition of ovine COX-1 or human COX-2 enzymes at
Known drugs have been reported as ligands for the CRTh2
receptor (Fig. 1): ramatroban 1 is a thromboxane A2 (TP) receptor
antagonist used for treatment of allergic rhinitis in Japan which
was shown to also exhibit CRTh2 antagonist activity4 and the anti-
inflammatory drug indomethacin 2 was described as an agonist of
10
pled receptors (GPCRs) and 23 kinases no inhibition >50% at
10 M concentration was noted. Initial assessment of biopharma-
ceutical properties (Table 2) indicated good solubility combined
lM was observed. Against a broad panel of 46 G-protein cou-
l
* Corresponding author.
E-mail address: david.sandham@novartis.com (D.A. Sandham).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.06.042

D. A. Sandham et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4794–4798
4795
F
H
O
O
N
S
O
O
F
OH
O
OH
N
O S
O
N
N
SO2Me
O
Cl
OH
O
1
2
3
O
O
O
N
OH
N
OH
HO
OH
O
O
Cl
O
N
O S
O
N
O
N
O
Cl
N
Cl
F
7
6
5
4
Figure 1. Selected ligands for the CRTh2 receptor.
Table 1
On target and initial selectivity profiling of HTS hit 7
CRTh2 binding
Eosinophil SC
DP binding
Ki ( M)
TP binding
COX-1 enzyme
COX-2 enzyme
Ki ( M) IC50 M)
l
(l
l
Ki (lM)
IC50
(l
M)
IC50
(l
M)
0.103 0.108
>10
>10
>10
>10
Ki and IC50 values represent the mean of at least two experiments.
Table 2
iii)
i)
ii)
Biopharmaceutical properties of HTS hit 7
N
H
N
O S
O
N
O S
O
N
N
N
pH 6.8
Solubility (g/L)
HLM Clint
L min mgÀ1
RLM Clint
L min mgÀ1
)
Caco-2 permeability
A–B/B–A (10À6 cm/s)
(l
)
(l
0.877
20
27
8.9/11.2
8
10
9
HLM: human liver microsomes; RLM: rat liver microsomes.
O
O
iv)
v), vi)
OH
O
with moderate clearance and permeability. Taken together with
the potency and selectivity data, this favourable profiling outcome
encouraged us to initiate an optimisation programme to explore
the structure–activity relationship (SAR) of the 7-azaindole-3-ace-
tic acid scaffold.
N
H
N
N
N
N
N
H
O S Ar
O
11
13a-13n
12
Scheme 1. Representative syntheses of final compounds. Reagents and conditions:
(i) PhSO2Cl, BnEt3NCl, NaOH, CH2Cl2, rt, 80%; (ii) LDA, THF, MeI, À78 °C, 90%; (iii)
TBAF, THF, rt, 75%; (iv) n-BuLi, THF, 0 °C; ZnCl2, 0 °C; evaporate; methyl bromo-
acetate, toluene, 95 °C, 33%; (v) ArSO2Cl, DMF, BEMP, rt or ArSO2Cl, NaH, THF, 0 °C;
(vi) aq NaOH or BBr3, CH2Cl2, rt.
An optimised route to the core structure is depicted in Scheme
1. Commercial 7-azaindole 8 was readily metallated and alkylated
in the 2-position after N-sulfonylation. The activating group could
be subsequently cleaved under mild conditions as described.11
Installation of the acetate side chain was achieved directly by
alkylation of a zincate species derived from 11 in a one pot proce-
dure.12 The resultant building block 12 was amenable to parallel
array chemistry using a one pot sulfonylation–saponification pro-
tocol employing the phosphazene base BEMP. Upon scale-up of
selected compounds for further profiling (e.g., 13l), it was found
that the use of NaH as base for sulfonylation and isolation of the
resultant sulfonyl ester followed by Lewis acid-mediated ester
cleavage gave improved yields.
addition, the compound displayed reasonable flux across human
Caco-2 cells. It could be speculated that the prolonged terminal
half life (Fig. 2) and high volume of distribution were consequences
of enterohepatic recirculation of either a putative acyl glucuronide
metabolite or unchanged drug,14 although the metabolism of 13f
was not subjected to characterisation.
Because of the moderate throughput of the eosinophil shape
change assay, we introduced a CRTh2 whole CHO cell cAMP func-
tional assay as a pre-screen in our compound profiling flow chart.
Given the carboxylic acid functionality present in this chemotype,
we were also aware of the potential for plasma protein binding to
impact potency.15 We therefore included a protocol to spike the
assay medium with 0.1% human serum albumin (HSA) as an indi-
rect measure of plasma protein binding. As shown in Figure 3, post
A Topliss tree type13 optimisation approach (Table 3) indicated
a preference for electron deficient substituents on the aromatic
ring and quickly lead us to 13f as a candidate for further profiling.
This compound retained antagonist activity in the eosinophil SC
assay (IC50 0.112 lM). The results of rat pharmacokinetic (PK)
studies on 13f are shown in Table 4 and Figure 2, in which we were
pleased to note low clearance and excellent oral bioavailability. In

4796
D. A. Sandham et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4794–4798
Table 3
Optimisation of CRTh2 binding potency
O
OH
13a-13h
N
N
O S Ar
O
Ar
*
*
*
*
*
*
*
*
Cl
O
Cl
NO2
Cl
CF3
Cl
Cl
13f
13c
13b
13e
13d
13a
13h
13g
CRTh2 Ki (
l
M)
0.377
3.22
0.282
2.619
0.619
0.052
1.171
0.048
Ki values represent the mean of at least two experiments.
Table 5
Table 4
Comparison of 13f with previous lead 6 and ramatroban 1
Rat PK and human permeability profile of compound 13f
6
13f
1
T
½
44.3 h
(iv, 1 mg/kg)
Cl
Vss
F(po,
AUC
Cmax
4.0 mL/min/kg
9.8 L/kg
100%
CRTh2 binding Ki (
CRTh2 cAMP IC50
CRTh2 cAMP + HSA, potency shift
Eosinophil SC IC50 M)
l
M)
M)
0.059
0.148
24
0.248
>10
0.052
0.354
3.4
0.112
0.629
93.4%
0.8
0.073
0.210
1.6
0.021
0.195
96.1%
1.1
(
l
3
mg/kg)
2622
1.5
l
M
M min
(0–48 h)
(
l
l
HWB SC IC50
(lM)
Caco-2 A–B/B–A (10À6 cm/s)
8.7/19.3
Human PPBa
99.4%
1.5
b
log D6.8
a
Determined by HSA column HPLC method.16
Determined from clog P17 and predicted pKa values.
b
18
eosinophil shape change assay was implemented by conducting
the assay in human whole blood (HWB). This delivered a more
physiologically relevant environment, factoring in binding of
compounds to plasma and other proteins, as well as providing a
potential ex-vivo receptor occupancy assay suitable for a clinical
setting. In this context, 13f was compared with 7 from our earlier
CRTh2 antagonist chemotype10 and the reference dual CRTh2-TP
antagonist ramatroban. We were encouraged to note that 13f
showed greatly improved functional potency in whole blood,
despite similar binding and reduced functional cAMP activity com-
pared to 6, although it was inferior to ramatroban in both isolated
and HWB eosinophil shape change assays (Table 5).
We speculated that reducing plasma protein binding (PPB)
within the azaindole chemotype might be a key factor in delivering
optimal whole blood potency. Within congeneric series of acidic
compounds, there is thought to be a correlation between the
extent of plasma protein binding and lipophilicity.19 Accordingly,
a small array of 3,4-disubstituted analogues of 13f with reduced
lipophilicity was prepared to probe this hypothesis. As shown in
Table 6, reduction of log D maintained binding activity, attenuated
to some extent the potency loss in the presence of HSA, and
improved isolated eosinophil SC potency. In the HWB eosinophil
SC assay, we were pleased to identify 13l, 13m and 13n with
greatly improved potency compared to ramatroban.
Figure 2. Rat intravenous PK plasma timecourse for compound 13f. Data represents
n = 3, SEM; lower limit of quantitation 10 nM.
facto analysis of a broader set of 7-azaindole-3-acetic acid ana-
logues indicated a good correlation between eosinophil shape
change and cAMP (+HSA) potency. A further development of the
10
1
0.1
0.01
Compounds 13l–n were selected for further profiling in rat PK
experiments (Table 7). The clearance of all compounds was
increased compared to 13f, and while 13l showed moderate
bioavailability, 13m had poor exposure and 13n could not be de-
tected in plasma after oral dosing. For both 13l and 13m, significant
0.00001
0.0001
0.001
0.01
0.1
1
levels of parent compound (9.1 lM and 0.6 lM, respectively) were
Human eosinophil shape change IC50 (µM)
found in urine collected up to 6 h post iv dosing, suggesting that oxi-
dative metabolism played a minor role in their clearance. These
compounds were also stable in rat plasma over 2 h, whereas 13n
Figure 3. Correlation of eosinophil shape change potency with cAMP functional
potency in the presence of HSA.

D. A. Sandham et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4794–4798
4797
Table 6
Optimisation of eosinophil shape change potency
O
OH
13i-13n
N
N
O S Ar
O
Ar
Cl
*
OMe
F
OEt
CN
F
F
CN
Cl
CN
F
*
*
*
*
*
F
13j
13m
13l
13k
13i
13n
CRTh2 Ki (
cAMP IC50
HSA shift
l
M)
M)
0.158
0.311
1.8
0.056
0.091
2.4
0.043
0.031
1.7
0.031
0.060
1.3
0.035
0.041
1.8
0.036
0.101
1.0
(l
Eosinophil SC IC50
(lM)
0.050
nd
0.3
0.018
0.156
0.1
0.005
nd
À0.3
0.009
0.017
À0.3
0.006
0.056
À0.6
0.008
0.040
À1.0
HWB SC IC50
(l
M)
a
log D6.8
Ki and IC50 values represent the mean of at least two experiments.
nd not determined.
a
18
Determined from clog P17 and predicted pKa values.
Compound 13l22 was further profiled as an advanced lead
candidate and showed IC50 >10 M against a prostanoid receptor
panel (DP, EP2, EP3, EP4, FP and TP receptors) and was also inactive
(IC50 >10 M) in COX-1 and COX-2 enzyme inhibition assays. The
only significant activity in a broader panel of 46 GPCRs and 19
kinases was on CCKa (IC50 8.1 M). In addition, the compound
Table 7
l
Rat PK and permeability profiles of 13l–n
13l
13m
13n
l
T
½
(h)
(iv, 1 mg/kg)
1.8
20
4.9
54%
222
0.32
>120
9.5/8.8
0.17
67
0.3
8%
12
0.30
>120
1.0/4.4
0.21
52
4.1
0%
—
—
Cl (mL/min/kg)
Vss (L/kg)
F(po,
l
was tested for activity at the murine CRTh2 receptor stably trans-
3
mg/kg)
AUC
(
l
M min)
fected into K562 cells, where a Ki value of 28 nM for displacement
(0–48 h)
of 3[H]-PGD2 was determined. In a GTP-
cS functional assay using
Cmax
(
lM)
Rat plasma T (mins)
55
1.4/0
½
the same cell line, 13l behaved as a functional antagonist (IC50
167 nM), confirming its suitability for potential use in mouse mod-
els of CRTh2-driven diseases. Further characterisation data was
obtained as indicated in Table 8, indicating minimal potential for
cardiotoxicity via hERG blockade and a low risk for drug–drug
interactions arising from inhibition of the major cytochrome-
P450 (CYP) isoforms. In addition, there was no activity found in
the standard pre-clinical genetic toxicology assays, human plasma
protein binding was relatively low, the compound was stable in a
human liver microsomes clearance assay, as well as being highly
soluble.
In conclusion, HTS identified a novel 7-azaindole-3-acetic acid
chemotype as selective CRTh2 antagonists. The SAR of the scaffold
was explored, and further optimisation based on reducing lipophil-
icity and plasma protein binding resulted in identification of
compound 13l as a potent and highly selective functional antago-
nist of the human CRTh2 receptor in human whole blood, exhibit-
Caco-2 A–B/B–A (10À6 cm/s)
exhibited significant instability in rat plasma in vitro, which may
have contributed to the lack of exposure of the latter compound. In
addition, the decreased lipophilicity of 13m and 13n may also have
led to the observed reduced flux across Caco-2 cells20 as a further
contributory factor in the poor PK profiles of these compounds.
Mindful of the potential for ipso aromatic substitution on the 4-
halobenzenesulfonamide moiety as a potential source of covalent
adduct formation and possible toxicity,21 we screened for the reac-
tivity of 13l and 13m with n-butanethiol (Scheme 2). No reaction
with either compound was observed in the absence of base, while
in the presence of K2CO3, 13l remained inert over 6 h, whereas
13m showed 87% conversion by LC–MS to the sulfide adduct 14.
Interestingly, when 13l and 13m were incubated with human liver
microsomes in the presence of the physiological sulfur nucleophile
glutathione, no evidence of adduct formation with either com-
pound could be detected by LC–MS.
Table 8
Further profiling of compound 13l
hERG patch clamp
CYP1A2
CYP2C9
CYP2C19
CYP2D6
16% Inhibition (10 lM)
IC50 >10
IC50 >10
IC50 >10
IC50 >10
IC50 >10
Negative
Negative
89.8%
l
l
l
l
l
M
M
M
M
M
O
O
OH
OH
i)
R1
CYP3A4
N
S
O
R1
R2
N
Ames testa
N
S
O
N
O
S
TK6 human micronucleus assay
Human plasma protein bindingb
Human liver microsomes Clint
pH 6.8 buffer thermodynamic solubility
O
0
l
L minÀ1 mgÀ1
>6 g/L
13l R1=R2=F
13m R1=CN; R2=Cl
14 R1=CN
a
In the presence and absence of S9 liver microsomes.
b
By HSA column method.17
Scheme 2. Reagents and conditions: (i) butanethiol, K2CO3, MeCN, rt, 6 h.

4798
D. A. Sandham et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4794–4798
10. Sandham, D. A.; Aldcroft, C.; Baettig, U.; Barker, L.; Beer, D.; Bhalay, G.; Brown,
Z.; Dubois, G.; Budd, D.; Bidlake, L.; Campbell, E.; Cox, B.; Everatt, B.; Harrison,
D.; Leblanc, C. J.; Manini, J.; Profit, R.; Stringer, R.; Thompson, K. S.; Turner, K. L.;
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Wilson, C. Bioorg. Med. Chem. Lett. 2007, 17, 4347.
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properties. Further optimisation of 13l and analogues23a–c towards
clinical candidates will be disclosed in due course.
11. Desarbre, E.; Coudret, S.; Meheust, C.; Merour, J.-Y. Tetrahedron 1997, 53, 3637.
12. McKew, J. C.; Foley, M. A.; Thakker, P.; Behnke, M. L.; Lovering, F. E.; Sum, F.-W.;
Tam, S.; Wu, K.; Shen, M. W. H.; Zhang, W.; Gonzalez, M.; Liu, S.; Mahadevan,
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17. Values calculated using CLOGP v4.71, BioByteCorp, Claremont, CA, USA.
18. Jelfs, S.; Ertl, P.; Selzer, P. J. Chem. Inf. Model. 2007, 47, 450.
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22. Selected data for 13l: dH (400 MHz, DMSO-d6) 2.62 (3H, s), 3.69 (2H, s), 7.28 (1H,
dd, J 7.8, 4.8), 7.69 (1H, dd, J 17.6, 9.1), 7.92 (1H, dd, J 7.8, 1.5), 8.06 (1H, m),
8.26 (1H, ddd, J 9.8, 7.2, 2.4), 8.32 (1H, dd, J 4.8, 1.5) (12.48, 1H, br s); dF {1H}
(377 MHz, DMSO-d6) À134, À128; m/z (APCI +ve) 367; C16H12F2N2O4S requires
C, 52.38; H, 3.1; N, 10.78; S, 8.23. Found C, 52.76; H, 3.353; N, 10.46; S, 8.053.
23. (a) Bala, K.; Leblanc, C.; Sandham, D.A.; Turner, K. L.; Watson, S.J.; Brown, L.N.;
Cox, B. PCT Int. Appl. WO2005123731, 2005; Chem. Abstr. 2005, 144, 88269.; (b)
Brown, L.N.; Leblanc, C.; Sandham, D.A; Singh, H.P.; PCT Int. Appl. WO
2007065683, 2007; Chem. Abstr. 2007, 147, 72640.; (c) Sandham, D.A. PCT Int.
Appl. WO2007065684, 2007; Chem. Abstr. 2007 147, 72634.
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