Discovery of brain penetrant, soluble, pyrazole amide EP1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2008.05.118

We describe the discovery of a series of pyrazole amide EP₁ receptor antagonists with good aqueous solubility and CNS penetration. In order to achieve solubility we investigated the incorporation of a basic group in the region of the molecule p

Full text of DOI:10.1016/j.bmcl.2008.05.118

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4027–4032
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of brain penetrant, soluble, pyrazole amide EP1 receptor antagonists
a
b
a
a
a
Adrian Hall a, , Andy Billinton , Alan K. Bristow , Susan H. Brown , Anita Chowdhury , Leanne Cutler ,
Gerard M. P. Giblin a, Paul Goldsmith a, Thomas G. Hayhow a, Ian R. Kilford a, Alan Naylor a, Barry
Passingham a, D. Anthony Rawlings a
*
a Neurolosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
b Pharmaceutical Development, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe the discovery of a series of pyrazole amide EP1 receptor antagonists with good aqueous sol-
ubility and CNS penetration. In order to achieve solubility we investigated the incorporation of a basic
group in the region of the molecule previously occupied by a carboxylic acid, which was known to be
a key element of the pharmacophore. This study led to the identification of compounds such as 4h, 4j
and 10b which demonstrated brain-to-blood ratios of 0.8:1–2.0:1 in addition to good solubility and met-
abolic stability.
Received 21 April 2008
Revised 28 May 2008
Accepted 31 May 2008
Available online 5 June 2008
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
Non-acidic EP1 antagonist
Amide EP1 antagonist
Brain penetration
CNS penetration
Solubility
Improved solubility
Oral exposure
Oral absorption
Prostaglandin E2 (PGE2) is produced in various tissues where it
has been shown to activate four G-protein-coupled receptors
(GPCRs) known as EP1, EP2, EP3 and EP4.1 Several lines of evidence
indicate that PGE2 is the main prostanoid responsible for pain and
inflammation2 and that these undesirable effects arise via activa-
tion of the EP1 receptor subtype, thus, EP1 receptor antagonists
have the potential to act as analgesics.3
In support of this hypothesis we have demonstrated several ser-
ies of EP1 receptor antagonists have analgesic properties in preclin-
ical models of inflammatory pain, such as Complete Freund’s
Adjuvant model of inflammatory pain.4
We have previously reported on pyrazole EP1 receptor antago-
nists, for example 15 (Fig. 1). We found that it was possible to
replace the carboxylic acid in 1 by non-acidic groups, such as
amides and reversed amides, as exemplified by compounds 2 and
3.6 These analogues were able to mimic the carboxylic acid in
terms of EP1 pharmacology despite the fact that it has been con-
strued that the acid in prostaglandin ligands forms a key ionic
interaction with the receptor.1a Furthermore, despite the absence
of a key pharmacophore, these compounds retained a good binding
efficiency index (BEI)7 and good ligand efficiency (LE)8 (Fig. 1).
Despite this encouraging in vitro pharmacology, we found
that replacing the carboxylic acid by non-ionisable functional
groups unmasked the intrinsic lipophilicity of these compounds,
which was undesirable, and resulted in high lipophilicity (e.g.,
compounds 2 and 3 logD >3.7, Fig. 1) and poor solubility (see
Table 4).
As part of an ongoing medicinal chemistry programme we were
interested in identifying further non-acidic EP1 receptor antago-
nists with lower lipophilicity and better solubility. In addition,
we wished to identify compounds that could penetrate the central
nervous system (CNS) and thus we wanted to identify compounds
without a carboxylate group.
To improve the solubility of the pyrazole amide series, we used
compounds 2 and 3 as a starting point and attempted to introduce
a basic group in order to aid solubility. In SAR investigations with
related templates we had found this to be a difficult challenge as
the EP1 receptor has a strong preference for lipophilic ligands
and incorporation of even mild basicity or polarity was poorly tol-
erated (data not shown).
Based on the data in Figure 1, we first started this work with the
reversed amide 3, as it had shown more encouragement in terms of
metabolic stability. We also switched the benzyloxy group on the
A-ring to the isobutoxy group as we had found this to result in
equipotent compounds but with reduced lipophilicity.6 The results
for this segment of work are summarized in Table 1.
* Corresponding author. Tel.: +44 1279 643464.
E-mail address: adrian.2.hall@gsk.com (A. Hall).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.05.118

4028
A. Hall et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4027–4032
Na+
O
O
H
N
N
B
N
B
N
B
C
C
Cl
Cl
Cl
N
N
N
O
N
H
A
A
A
O
O
O
O
1; EP1 binding pIC50 8.0 0.2
logD 1.0
2; EP1 binding pIC50 7.4 0.4
logD >3.7
3; EP1 binding pIC50 7.8 0.1
logD >3.7
rCLi 12.0 mL/min/g liver
rat CLi 7.3 mL/min/g liver
rat CLb 50 mL/min/kg, Vdss 4.1 L/kg
rat t½ 2.5 hours
BEI: 22.4
LE: 0.44
BEI: 17.1
LE: 0.33
BEI: 18.1
LE:0.35
Figure 1. Selected GSK methylene-linked pyrazole EP1 receptor antagonists.
Despite the addition of the basic groups several compounds
retained reasonable binding efficiency, 4h BEI 16.3 and LE 0.32,
4j BEI 15.6 and LE 0.30.
Based on the success of the SAR summarized in Table 1 we
went on to investigate substitution of the benzylic position of
the methylamino group, compounds 5a and 5b (Fig. 2). Addition
of the methyl group was well tolerated in terms of binding
affinity.
Table 1
SAR for 3-substituents, compounds 4a–l
3
2
H
N
4
X
N
B
C
Cl
N
A
O
O
.HCl
Following on from this result, we found that the group on the
amine could be tied back onto the benzylic position to generate
phenyl pyrrolidine derivative 6, FLIPR pKi 7.0 0.7 (Fig. 2).
We also investigated the effect of tying the amine substituent
back to the 3-position of the phenyl ring as exemplified by the tet-
rahydroisoquinolines (7a and 7b), 7a FLIPR pKi 6.9 0.2, and ben-
zazepines (8a and 8b), 8b FLIPR pKi 7.3 0.2 (Fig. 3).
a
Compound
X
Binding pIC50
3b
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
7.8 0.1
7.6 0.1
6.3 0.1
6.2 0.1
6.9 0.3
6.3 0.1
6.6 0.2
7.9 0.2
7.0 0.1
7.0 0.2
7.3 0.2
7.4 0.0
7.3 0.1
2-CH2OH
3-CH2NHEt
3-CH2NMe2
3-CH2pyrrolidin-1-yl
3-CH2piperidin-1-yl
3-CH2morpholin-4-yl
4-CH2OH
4-CH2NHEt
4-CH2NMe2
4-CH2-pyrrolidin-1-yl
4-CH2piperidin-1-yl
4-CH2morpholin-4-yl
Next, we sought to transfer the SAR from the reversed amide
series to the amide series (Table 2). Thus, substitution of the
anilide phenyl ring (C-ring) was only investigated in the 4-posi-
tion, however, analogues were made with both the iso-butoxy
and benzyloxy groups on the phenyl A-ring, and as Table 2
shows, both groups generally resulted in equipotent com-
pounds. Interestingly, although the parent amide series (e.g.,
2) displayed slightly lower affinity in general than the reversed
amide series (e.g., 3) the 4-substituted amide derivatives were
generally slightly more potent than their reversed amide ana-
logues. Thus, the 4-hydroxymethyl derivative 9a (FLIPR pKi
7.8 0.4) retained activity of the parent unsubstituted com-
pound (2) whereas 10a (FLIPR pKi 7.4 0.2) displayed slightly
higher affinity. Again, it was found that a range of secondary
and tertiary amino groups were tolerated (9b–g and 10b–g),
9b FLIPR pKi 7.1 0.2, 10b FLIPR pKi 6.9 0.2, 10g FLIPR pKi
7.1 0.1. It was even found that further polarity could be intro-
duced in addition to the amino group, such as the hydroxyethyl
group (9h, FLIPR pKi 7.0 0.0) and dihydroxyethyl group (9i,
FLIPR pKi 7.1 0.0).
4j
4k
4l
a
See Ref. 4a or 9.
Benzyloxy substituent on A-ring, see Figure 1.
b
Compounds were tested in [3H]-PGE2 binding assay, selected
compounds were also tested in a functional assay (FLIPR).4a,9
Our strategy was to introduce a basic group joined by a methy-
lene linker to the phenyl ring (C-ring) and to systematically inves-
tigate its placement around the phenyl ring. We initiated our
investigation at the 2-position. Disappointingly, chemistry issues
prevented us from testing the methylamino derivatives,10 however
we were able to test the intermediate hydroxymethyl derivative
(4a) which indicated that we could at least introduce polarity into
this region of the molecule (Table 1).
Next, we turned our attention to the 3-position of the benzam-
ide moiety. Disappointingly addition of basic groups to this posi-
tion consistently decreased binding affinity by ꢀ10-fold (4b–f),
compared to the parent unsubstituted compound 3 (Table 1).
We then turned our attention to the 4-position of the benzam-
ide and were pleased to find, like the 2-position, that the hydroxy-
methyl group was tolerated (4g). Addition of a range of primary
and secondary methylamino groups was tolerated (4h–l) and had
little effect on binding affinity, leading us to conclude that this
group was not making any particular interaction with the receptor.
Compounds also showed activity in a functional antagonism assay
(FLIPR), e.g., 4h pKi 6.8 0.1, 4j pKi 6.8 0.6.
Several of the analogues in Table 2 retained good binding effi-
ciency/ligand efficiency, for example 9b BEI 18.4 and LE 0.36, 10b
BEI 16.6 and LE 0.32.
Based on a combination of in vitro potency, in vitro metabolic
stability11 and CYP450 profile, the in vivo pharmacokinetic profiles
of compounds 4h, 4j and 10b were assessed in the rat via intrave-
nous administration (Table 3). Despite the fact all three showed
improved in vitro stability relative to compounds 2 and 3 their in
vivo metabolic stability was similar as shown by the blood clear-
ance values (CLb). However, all three showed moderate blood
clearance and volumes of distribution (Vdss) which resulted in
half-lives between 1.4 and 3.0 h.

A. Hall et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4027–4032
4029
H
H
N
N
R
N
H
N
N
Cl
Cl
N
N
O
O
O
O
.HCl
.HCl
5a; R = NHi-Bu
6; binding pIC50 7.0 0.0
FLIPR pKi 7.0 0.7
binding pIC50 7.3 0.1
5b; R = pyrrolidin-1-yl
binding pIC50 7.3 0.2
Figure 2. Further 4-aminomethyl derivatives.
R
H
H
N
N
N
N
N
Cl
Cl
N
N
N
R
O
O
O
O
.HCl
.HCl
7a; R = H
8a; R = H
binding pIC50 7.4 0.1
FLIPR pKi 6.9 0.2
binding pIC50 7.1 0.2
8b; R = Et
7b; R = i-Pr
binding pIC50 7.3 0.1
binding pIC50 7.0 0.4
FLIPR pKi 7.3 0.2
Figure 3. Tetrahydroisoquinoline and benzazepeine derivatives.
We also assessed the solubility of several derivatives (Table 4)
as we had hypothesized that increasing the solubility, whilst main-
taining metabolic stability, would ultimately lead to improved oral
bioavailability.
two starting compounds (2 and 3). In particular, several derivatives
demonstrated good solubility in all four media.
Solubility data (Table 3) revealed that the amides generally had
better solubility than the corresponding reversed amides (cf. 9c to
4h). Within the amide series, the iso-butoxy derivatives had better
solubilitythantheirbenzyloxyanalogues(cf.9bto10band9fto10f).
As Table 4 shows, most compounds had moderate to good sol-
ubility in the media tested,12 which was markedly better than the
Table 2
SAR for 4-substituted anilides 9a–i and 10a–g
3
3
2
O
2
O
X
N
B
C
X
N
B
4
C
4
Cl
Cl
N
N
N
H
N
H
A
A
O
O
.HCl
template 10
.HCl
template 9
a
Compound
X
Binding pIC50
2b
9a
9b
9c
9d
9e
9f
9g
n/a
OH
NHMe
NHEt
NMe2
Pyrrolidin-1-yl
Piperidin-1-yl
Morpholin-4-yl
NHCH2CH2OH
N(CH2CH2OH)2
OH
NHMe
NHEt
NMe2
Pyrrolidin-1-yl
Piperidin-1-yl
Morpholin-4-yl
7.4 0.4
7.5 0.1
8.1 0.1
8.1 0.1
8.3 0.0
8.2 0.1
8.2 0.1
8.1 0.1
7.6 0.3
7.8 0.2
8.2 0.3
7.9 0.1
7.9 0.2
8.1 0.3
7.9 0.1
7.9 0.2
8.0 0.1
9h
9i
10a
10b
10c
10d
10e
10f
10g
a
See Ref. 4a or 9.
For structure, see Figure 1.
b

4030
A. Hall et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4027–4032
Table 3
Table 5
Rat microsomal intrinsic clearance data and intravenous pharmacokinetic data for
Rat CNS penetration assaya
compounds 2, 3, 4h, 4j and 10b
Compound
Br:Bl
Blood concentration (nM)
Brain concentration (nM)
Compound
CLia
CLb (mL/min/kg)b
Vdss (L/kg)b
t1/2 (h)b
4hAb
4hf
0.8:1c
0.9:1c
1.2:1c
2.0:1
1.4:1
107d
114c
25d
21
60e
92c
43e
41
2
3
4h
4j
10b
12.0
7.3
1.8
3.2
1.8
n.d.c
50
29
46
46
n.d.c
4.1
6.3
4.6
9.7
n.d.c
2.5
2.8
1.4
3.0
4jb
4jg
10bh
145
201
a
Rats dosed orally and blood and brain samples taken 1 or 3 h post-dose.
10 mg/kg dose, samples taken 1 h post-dose.
Ratio is an average from three animals where blood and brain samples taken
a
b
c
Intrinsic clearance measured in rat liver microsomes (mL/min/g liver)11
1 mg/kg iv infusion.
Not determined.
.
b
c
from same animal.
d
Value is a mean from seven animals.
Value is a mean from three animals.
3 mg/kg dose, samples taken 3 h post-dose, values are the mean from three
e
f
Table 4
animals.
Solubility data for selected compoundsa
g
3 mg/kg dose, samples taken 3 h post-dose, values are the mean from two
animals.
Compound
H2O
SGFb
FaSSIFc
FeSSIFd
h
5 mg/kg dose, samples taken 3 h post-dose, values are the mean from three
animals.
2e
0
2
0
2
0
38
0
50
3e
4hf
4jf
4kf
9b
9c
9f
10b
10f
690
>1000
>1000
474
>1000
811
253
373
62
14
154
520
240
589
>1000
315
185
64
n.d.g
30
n.d.g
90
Although all three compounds had good brain-to-blood ratios
all exhibited low systemic exposure after oral dosing.
364
905
662
n.d.g
n.d.g
483
812
164
57
As the blood clearance was moderate, we hypothesized that the
low exposure was possibly due to poor absorption, even though
the in vitro permeability was good.13,14 To prove this hypothesis
a hepatic portal vein (HPV) study was conducted with 4j and 10b
and demonstrated that the pre-systemic and systemic concentra-
tions of both compounds were low, thus discounting the possibility
that the low oral exposure was due to hepatic extraction and dem-
onstrating the low exposure was due to poor absorption.
No further work was conducted to decipher whether the poor
absorption was due to permeability or solubility. Related com-
pounds with improved solubility relative to 4h, 4j and 10b, failed
to yield higher exposures after oral administration suggesting that
low exposure was not due to poor solubility.
n.d.g
a
1 h, units = lg/mL.
b
c
d
e
f
Simulated gastric fluid.12
Fasted state simulated intestinal fluid.12
Fed state simulated intestinal fluid.12
0.5 h.
2 h.
Not determined.
g
Based on the pharmacokinetic data (Table 3) and solubility data
(Table 4) the CNS penetration of compounds 4h, 4j and 10b was as-
sessed in the rat (Table 5).
H
H
N
N
N
N
NH2
N
a
Cl
Cl
b
Cl
O
N
N
N
SiMe3
O
O
c
O
O
O
O
11
12
13
d
4e
H
N
O
N
Cl
N
e
4j
O
O
O
14
O
O
O
O
O
f
HO
Cl
HO
Cl
f
O
O
15
16
17
18
o
Scheme 1. Conditions and reagents: (a) TBAF, THF, 50 °C, 1 h, 92%; (b) 16, CH2Cl2, 4-(dimethylamino)pyridine, NEt3, 23%; (c) piperidine, CH2Cl2, AcOH then NaBH(OAc)3,
MeOH, 1M HCl in Et2O, 17%; (d) 18, CH2Cl2, 4-(dimethylamino)pyridine, NEt3, 21%; (e) pyrrolidine, CH2Cl2, AcOH, NaBH(OAc)3, MeOH, 1 M HCl in Et2O, 73%; (f) PhMe, SOCl2,
reflux, 16 h, then evaporation.

A. Hall et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4027–4032
4031
O
O
O
a
O
b
HO
O
N
I
NHBoc
O
19
21
22
c
O
O
N
H
O
N
N
N
Cl
N
d
O
6
20
O
23
Scheme 2. Conditions and reagents: (a) THF, i-PrMgCl, ꢁ60 °C to ꢁ45 °C, then 20, warm to rt, 65%; (b) THF, 5 M HCl, 70 °C, 1 h, 29%; (c) 12, CH2Cl2, N-(3-
dimethylaminopropyl)-N0-ethylcarbodiimide hydrochloride, 1-hydroxy-7-azabenzotriazole, rt, 22%; (d) CH2Cl2, AcOH, NaBH(OAc)3 then 1 M HCl in Et2O, 93%.
Compounds 5a and 5b were prepared in an analogous manner
to that described in Scheme 1, via reductive amination with the
corresponding acetophenone.
O
c
a, b
HO
7b
7a
The synthesis of 6 started from methyl 4-iodobenzoate (19)
(Scheme 2). Reaction with i-PrMgCl under Knochel’s conditions16
and quenching with 1-Boc-pyrrolidinone (20) gave 21(Scheme 2).
Heating 21 in THF with HCl effected ester hydrolysis, amine depro-
tection and cyclisation to give imine 22. Amide formation with 12,
to give23, followed by imine reduction delivered compound 6.
Tetrahydroisoquinoline (7a) was prepared as outlined in
Scheme 3, 7b in turn was prepared from 7a via reductive amina-
tion. Derivatives 8a and 8b were prepared from 25 (Scheme 3)
via analogous procedures.
The anilides described in Table 2 were prepared as shown for
derivative 10b (Scheme 4). Carboxylic acid 1a5,6,9 was converted
to the corresponding acid chloride and reacted with 4-aminoben-
zyl alcohol to give 26. Dess–Martin oxidation,17 reductive amina-
tion and salt formation gave 10b (Scheme 4).
In conclusion, we have modified a series of amides and reversed
amides to incorporate a basic solubilising group. In doing this, we
succeeded in placing the basic group in the region of the molecule
where a carboxylic acid normally forms a key interaction. Despite
this, compounds still maintained high BEI and LE. In so doing we
identified several compounds with good solubility, good pharma-
cokinetic properties and good CNS penetration. Despite these
desirable characteristics, these compounds failed to show accept-
able oral exposure. This low oral exposure was attributed to poor
absorption from the gastrointestinal tract.
O
N
O
24
O
O
O
e
d, b
HO
8b
8a
N
25
Scheme 3. Conditions and reagents: (a) 12, N-(3-dimethylaminopropyl)-N0-ethyl-
carbodiimide hydrochloride, 1-hydroxy-7-azabenzotriazole, CH2Cl2, 77%; (b) 4 M
HCl in dioxan, 100%; (c) CH2Cl2, AcOH, Me2CO, NaBH(OAc3), then 1 M HCl in Et2O,
35%; (d) 12, N-(3-dimethylaminopropyl)-N0-ethylcarbodiimide hydrochloride, 1-
hydroxy-7-azabenzotriazole, CH2Cl2, 81%; (e) CH2Cl2, AcOH, MeCHO, NaBH(OAc3),
46%.
Compounds were synthesized as outlined in Schemes 1–4. Full
experimental details and characterizing data for key compounds
has been described.9
Reversed amides such as 4e and 4j were prepared as outlined in
Scheme 1. Carbamate 12 was generated from the corresponding
carboxylic acid6,9 via Curtius rearrangement15 in the presence of
trimethylsilyl ethanol. Subsequent deprotection delivered amino
pyrazole 12. Reaction with acid chlorides 16 and 18 gave aldehydes
13 and 14, respectively. Reductive amination with 13 and piperi-
dine provided compound 4e, whereas reductive amination with
pyrrolidine and 14 provided 4j.
Acknowledgements
We thank Shiyam Mohamed and Sadhia Mahmood for perme-
ability measurements.
O
O
N
N
OH
Cl
Cl
N
N
OH
N
H
a, b
c, d
10b
O
O
1a
26
Scheme 4. Conditions and reagents: (a) (COCl)2, DMF, CH2Cl2, rt, 90% (b) 4-aminobenzyl alcohol, CH2Cl2, NEt3, rt, 67–98% (c) 12, Dess–Martin periodinane, CH2Cl2, rt, 86%; (d)
methylamine, CH2Cl2, AcOH, NaBH(OAc)3 then CH2Cl2, 1 M HCl in Et2O, 39%.

4032
A. Hall et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4027–4032
7. Abad-Zapatero, C.; Metz, J. T. Drug Discov. Today 2005, 10 7, 464.
References and notes
8. Hopkins, A. L.; Groom, C. R.; Alex, A. Drug Discov. Today 2004, 9, 432.
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P.; Hurst, D. N.; Kilford, I. R.; McKeown, S. C.; Naylor, A.; Price, H. S.; Rawlings,
D. A. WO2006/114313A1, 2006.
10. Attempts to oxidise the benzylic alcohol 4a resulted only in formation of
phthalimide 27(oxidation with PDC was also attempted but resulted in no
detectable aldehyde formation). Attempts to convert the hydroxyl group to a
leaving group and displace with amines resulted in formation of lactam 28
1. (a) Coleman, R. A.; Smith, W. L.; Narumiya, S. Pharmacol. Rev. 1994, 46, 205; (b)
Breyer, R. M.; Bagdassarian, C. K.; Myers, S. A.; Breyer, M. D. Annu. Rev.
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O
O
Cl
Cl
N
Dess-Martin
periodinane
N
N
N
N
N
H
O
O
OH
CH2Cl2
O
4a
27
(i) MsCl, Et3N, CH2Cl2
3. Hall, A.; Billinton, A.; Giblin, G. M. P. Curr. Opin. Drug Discov. Dev. 2007, 10, 597.
4. (a) Hall, A.; Atkinson, S. A.; Brown, S. H.; Chessell, I. P.; Chowdhury, A.;
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