Thienopyrrole acetic acids as antagonists of the CRTH2 receptor

Article abstract of DOI:10.1016/j.bmcl.2011.01.008

The bioisosteric replacement of the indole core of CRTH2 antagonists using thienopyrroles was investigated, resulting in potent antagonists with good selectivity over DP1. Early ADME/PK assessment of this chemotype demonstrated bioavailability in mice.

Full text of DOI:10.1016/j.bmcl.2011.01.008

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1861–1864
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Thienopyrrole acetic acids as antagonists of the CRTH2 receptor
Dominique Bonafoux a, , Ayome Abibi a, Brian Bettencourt b, Andrew Burchat a, Anna Ericsson a,
⇑
Christopher M. Harris b, Tegest Kebede b, Michael Morytko a, Michael McPherson b, Grier Wallace a,
Xiaoyun Wu a
a Abbott Laboratories, 381 Plantation Street, Worcester, MA 01605, United States
b Abbott Laboratories, 100 Research Drive, Worcester, MA 01605, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The bioisosteric replacement of the indole core of CRTH2 antagonists using thienopyrroles was investi-
gated, resulting in potent antagonists with good selectivity over DP1. Early ADME/PK assessment of this
chemotype demonstrated bioavailability in mice.
Received 1 December 2010
Revised 28 December 2010
Accepted 3 January 2011
Available online 14 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
CRTH2 receptor
DP1 receptor
Thienopyrroles
PK
Bioavailability
Prostaglandin D2 (PGD2) is the major prostanoid released by
mast cells during allergic attacks.1,2 In human patients, allergen
challenge leads to a rapid increase in the production of PGD2 in
the airway of asthmatics,3 in the nasal mucosa of allergic rhinitics4
and in the skin of patients suffering from atopic dermatitis.5 Two
high affinity binding G-protein-coupled receptors, the DP1 receptor
and the chemoattractant receptor-homologous expressed on Th2
cells (CRTH2 or DP2), have been shown to mediate the effects of
PGD2. The later receptor is expressed on cell types associated with
allergic inflammation, such as Th2 cells, basophils and eosinophils
and its activation by PGD2 triggers the migration6,7 and prevents
the apoptosis of these cell types.8 In vivo reports in rodents have
highlighted the role of CRTH2 in promoting chronic allergic skin
inflammation9 and eosinophilic airway inflammation.10 CRTH2
antagonists have shown efficacy in a murine model of allergic rhini-
tis.11 More recently, an orally bioavailable CRTH2 antagonist
(OC000459) successfully completed Phase IIa trials demonstrating
efficacy in asthma and allergic rhinoconjunctivitis12 thus unambig-
the CRTH2 receptor.15 As a result a large number of CRTH2 antago-
nists known to date are indole acetic acids16,17 bearing the acetic
acid moiety either at position 3, exemplified with compound 3
(Fig. 2)18 or at position 1, exemplified with compound 4 (Fig. 2).19
A variety of fused 6–5-membered ring chemotypes have arisen
such as 7-azaindole acetic acids,20 benzimidazolyl acetic acids,21
spiro-indolinone acetic acids,22 and indolizine acetic acids,23 how-
ever, to the best of our knowledge, fused 5,5-membered ring
systems have not been reported.
As a template for fused 5,5-membered ring systems, we have
investigated the bioisosteric replacement of the classical indole
core of CRTH2 antagonists with two regioisomeric thienopyrroles.
The affinity of the thienopyrroles towards the CRTH2 receptor
was evaluated in a radioligand binding assay using membranes
prepared from HEK293.F cells transiently transfected with
Hu-CRTH2 cDNA.24
O
O
OH
uously establishing CRTH2 as
inflammation.
a central player of airway
OH
MeO
N
A numberofmedicinalchemistry programsstartedafter theiden-
tification of non-steroidal anti-inflammatory drug indomethacin
(1, Fig. 1) as an agonist of the CRTH2 receptor,13,14 and that of throm-
boxane receptor antagonist ramatroban (2, Fig. 1) as an antagonist of
N
O
HN SO2
1
2
Cl
F
⇑
Corresponding author.
E-mail address: dominique.bonafoux@abbott.com (D. Bonafoux).
Figure 1. Structure of indomethacin (1) and ramatroban (2).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.01.008

1862
D. Bonafoux et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1861–1864
O
Br
O
O
Br
+
O
OH
OH
Br
a
OH
F
NH
N
S
S
O
O
O
N
S
O
12
11
O
10
4
3
O
O
N
O
O
O
S
O
b,c
d
N
NH
S
Figure 2. Representative examples of indole-1 and indole-3 acetic acids CRTH2
O
S
antagonists.
O
14
13
The unsubstituted methyl 2-(6H-thieno[2,3-b]pyrrol-4-yl)ace-
tate (5) and methyl 2-(4H-thieno[3,2-b]pyrrol-6-yl)acetate (8)
were synthesized as previously described,25 starting from the
Boc-protected iodothiophenes using a one-pot allylation with ethyl
4-bromocrotonate followed with an intra-molecular Heck cycliza-
tion. Subsequently 5 and 8 were reacted with the 4-(methylsulfo-
nyl)benzene-1-sulfonyl chloride and saponified to give compound
7 and 9 (Scheme 1).
Scheme 2. Reagents and conditions: (a) diphenylphosphoryl azide, Et3N, t-BuOH,
65 °C, 84%; (b) K2CO3, DMF, rt; (c) Pd2(OAc)3, PPh3, 85 °C, 36%; (d) silica gel, 85 °C
under vacuum, 46%.
I
I
I
b
a
O
O
OH
S
S
S
N
H
O
In the radioligand binding assay, thienopyroles 7 and 9 were
17
16
15
O
O
found to be weak, equipotent binders with IC50s of 4
lM and
5
l
M, respectively, unambiguously showing the bioequivalency
O
O
Br
c, d
of both regioisomers. As a result the remainder of the study was
conducted in a single series, the 6H-thieno[2,3-b]pyrroles.
e
O
O
O
+
S
S
N
N
O
With indole acetic acids, the methyl group
a to the pyrrole
H
12
nitrogen is an important structural feature since its removal
resulted in a five-fold loss in potency as reported earlier.19 We
proceeded to introduce a comparable methyl group in the 6H-thi-
eno[2,3-b]pyrrole core. The methyl 2-(5-methyl-6H-thieno[2,3-
b]pyrrol-4-yl)acetate (14) was synthesized following the route
highlighted above for the synthesis of 5, using the (E)-methyl
4-bromopent-2-enoate (12)26 in the allylation step (Scheme 2).
We also introduced a methyl group on the thiophene ring in
order to mimic the substitution pattern of known potent 2-(2,5-
dimethyl-1H-indol-1-yl)acetic acids antagonists such as 4.19 The
methyl 2-(3,5-dimethyl-6H-thieno[2,3-b]pyrrol-4-yl)acetate (19)
(Scheme 3) and the methyl 2-(2,5-dimethyl-6H-thieno[2,3-b]
pyrrol-4-yl)acetate (24) (Scheme 4) cores were prepared using
our standard route using the tert-butyl 3-iodo-4-methylthiophen-
2-ylcarbamate (17) and tert-butyl 3-bromo-5-methylthiophen-2-
ylcarbamate (22) as starting materials. The tert-butyl 3-iodo-4-
methylthiophen-2-ylcarbamate (17) was obtained from the
commercially available methyl 3-iodo-4-methylthiophene-2-
carboxylate (15) through a saponification/Curtius rearrangement
sequence while the tert-butyl 3-bromo-5-methylthiophen-2-ylcar-
18
O
19
O
Scheme 3. Reagents and conditions: (a) NaOH, THF/MeOH, rt, 100%; (b) diphen-
ylphosphoryl azide, Et3N, t-BuOH, 65 °C, 83%; (c) K2CO3, DMF, rt; (d) Pd2(OAc)3,
PPh3, 85 °C, 28%; (e) silica gel, 85 °C under vacuum, 67%.
O
a
b
OH
N
S
S
O
H
O
21
20
O
Br
Br
O
O
c,d
+
O
N
S
O
H
O
N
O
S
22
11
23
O
O
O
e
NH
S
24
OH
Cl
O
O
O
S
Scheme 4. Reagents and conditions: (a) diphenylphosphoryl azide, Et3N, t-BuOH,
65 °C, 75%; (b) Br2, MeOH, 0 °C, 76%; (c) K2CO3, DMF, rt; (d) Pd2(OAc)3, PPh3,
85 °C,25%; (e) silica gel, 85 °C under vacuum, 64%.
O
a
S
O
+
N
S
b
S
O
O
N
H
O
S
O
5
6
S
7
O
O
O
O
OH
R2
R1
O
R2
OH
a, b, c
Cl
O
O
S
O
N
S
S
O
S
S
R1
c
L
NH
S
O
R3
+
N
S
d
O
O
N
H
14: R1 = R2 = H
19 : R1 = H, R2 = Me
25: R1 = R2 = H
26 : R1 =H, R2 = Me
O
24 : R1 = Me, R2 = H
27 : R1 = Me, R2 = H
S
O
9
8
5
O
O
Scheme 5. Reagents and conditions: L = SO2: (a) t-BuOK, THF, 0 °C; (b) sulfonyl
chloride, rt; (c) KOH, MeOH/H2O: 1/1, rt; L = CH2: NaH, DMF, 0 °C, 1 h; (b) benzyl
halide, NaI, rt; (c) NaOH, MeOH, rt.
Scheme 1. Reagents and conditions: (a) t-BuOK, 18-crown-6, 0 °C–rt, 15%; (b) KOH,
EtOH/THF: 1/1, rt, 64%; (c) NaH, THF, rt; (d) KOH, EtOH/H2O, rt, 13%.

D. Bonafoux et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1861–1864
1863
Table 2
bamate (22) was obtained via Curtius rearrangement of the
Selected in vitro data
RLM/HLMa (%)
100/100
commercially available 5-methylthiophene-2-carboxylic acid (20)
followed by a bromination.
Final derivatization of thienopyrroles 14, 19 and 24 with a vari-
ety of sulfonyl chlorides or benzyl halides, followed by saponifica-
tion afforded the analogs 25, 26 and 27 (Scheme 5).
Dofetilide IC50 (lM)
25e
25j
25k
25l
>100
31
31
57/62
90/91
99/97
45
The substitution pattern of the thienopyrrole core was found to
be critical for activity. As expected, the introduction of the methyl
a
% remaining after 30 min incubation.
group
a to the pyrrole nitrogen of 7, led to 25e and a 46-fold
improvement in affinity to the receptor with an IC50 of 0.09
lM
(Table 1).
The preferred substituents for that position were found to be
the (N-cyclohexyl-N-methylsulfonyl)phenyl in 25j and the 2-
This methyl group most likely forces the carboxylic acid to
adopt an optimal position to interact with the receptor.
chloro-4-(methylsulfonyl)phenyl in 25l with IC50s of 0.02
0.01 M, respectively.
lM and
Contrarily to the SAR reported in the indole series, an additional
methyl on the core at position 2 (27a, 27b) or at position 3 (26a,
26b) of the thiophene ring was not tolerated and led to significant
losses in activity compared to the desmethyl analogs (14-fold and
33-fold between 27a/25k and 27b/25l, respectively, and 15-fold
and 30-fold between 26a/25e and 26b/25k, respectively).
The linker L could be changed from a sulfone to a methylene
without affecting the affinity to the receptor, as shown with the
4-(methylsulfonyl)phenyl-analogs 25e and 25k, with IC50s of
l
Antagonistic activity of these thienopyrroles was verified for
analog 25k in a calcium flux assay using CHO/Ga16 cells stably
transfected with Hu-CRTH2.27 In this assay, 25k displayed an IC50
of 0.13 lM.
Selectivity over the DP1 receptor24 was evaluated for a sample
of analogs (25e, 25j, 25k and 25l) which were found to have no
activity on this receptor (IC50 >50 lM).
An early in vitro ADME assessment showed good stability in rat
and human liver microsomes as well as no significant activity in a
dofetilide binding assay (Table 2).
0.09
4-(morpholinosulfonyl)phenyl-analogs 25f and 25i were also found
to be equipotent with IC50s of 0.23 M and 0.07 M, respectively.
lM and 0.05 lM, respectively. The more sterically hindered
l
l
Thienopyrrole 25e was dosed orally, at 30 mpk as a solution in
Tween 80 (0.2%)/HPMC (0.5%), in female balbc mice to provide an
early assessment on bioavailability. Compound 25e displayed an
The substitution pattern of the phenyl ring (R3) was found to be
important. The unsubstituted analog (25a) as well as the analogs
substituted in the para position of with fluorine (25b), a trifluoro-
methyl-group (25c), or a cyano-group (25d) showed only weak
activity. Compounds bearing a sulfone or sulfonamide at the para
position of the phenyl group were the most active.
encouraging profile with a Cmax of 7.8
lg/mL at 0.5 h and a signif-
icant systemic exposure of 16.4 g.h/mL.
l
In conclusion, thienopyrrole acetic acids provide potent CRTH2
antagonists. They are selective over DP1, display good metabolic
stability and do not inhibit dofetilide binding. This chemotype is
also attractive as a result of its bioavailability which was demon-
strated by dosing 25e orally in mice.
Table 1
Receptor assay data for thienopyroles
a
L
R1
R2
R3
Hu-CRTH2 IC50
(
lM)
25a
25b
25c
25d
25e
SO2
SO2
SO2
SO2
SO2
H
H
H
H
H
H
H
H
H
H
Ph
2.75
1.63
1.13
3.00
0.09
Acknowledgments
p-F–C6H4
p-CF3–C6H4
p-CN–C6H4
p-SO2Me–C6H4
The authors thanks Dr. Charles Hutchins for molecular model-
ing support and Dr. Salam Shaaban for support with the radioli-
gand binding assays.
O
S
O
N
O
25f
SO2
H
H
0.23
References and notes
O
O
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S
25g
25h
SO2
CH2
H
H
H
H
0.39
0.19
N
p-SO2NMe2 –C6H4
O
S
O
N
O
25i
CH2
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0.07
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S
25j
CH2
CH2
H
H
H
H
0.02
0.05
N
25k
p-SO2Me–C6H4
O
S
O
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CH2
H
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0.01
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Cl
26a
26b
27a
SO2
CH2
CH2
H
H
Me
Me
Me
H
p-SO2Me–C6H4
p-SO2Me–C6H4
p-SO2Me–C6H4
1.30
1.50
1.8
O
S
O
27b
CH2
Me
H
0.33
Cl
a
Values are means of n = 2–4 experiments.

1864
D. Bonafoux et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1861–1864
18. Armer, R. E.; Ashton, M. R.; Boyd, E. A.; Brennan, C. J.; Brookfield, F. A.; Gazi, L.;
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in DMSO and assays run at a final DMSO concentration of 1% (v/v). [3H]-labeled
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1 nM for CRTH2 or 2 nM for DP-1.
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the G
compounds were dissolved in DMSO and assays run at
concentration of 1% (v/v). PGD2 was purchased from Cayman Chemicals and
used at a final assay concentration of 1 M.
a
16 coupling protein using a FLIPR instrument (Molecular Devices). All
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a
final DMSO
l