Aryloxypyrazines as highly selective antagonists of Oxytocin

Article abstract of DOI:10.1016/j.bmcl.2009.03.160

A series of aryloxypyrazines were designed based on structural overlap with previously reported arylpyrazine Oxytocin antagonists. Similarly high levels of Oxytocin antagonism were achievable in this new series. In addition, significant improvements in se

Full text of DOI:10.1016/j.bmcl.2009.03.160

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2634–2636
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Aryloxypyrazines as highly selective antagonists of Oxytocin
*
Alan Brown , Dave Ellis, David Pearce, Michael Ralph, Nunzio Sciammetta
Discovery Chemistry, Pfizer Global Research and Development, Sandwich, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of aryloxypyrazines were designed based on structural overlap with previously reported arylpyr-
azine Oxytocin antagonists. Similarly high levels of Oxytocin antagonism were achievable in this new ser-
ies. In addition, significant improvements in selectivity over the related vasopressin V1A receptor were
also possible.
Received 2 March 2009
Revised 31 March 2009
Accepted 31 March 2009
Available online 5 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Oxytocin
Antagonist
Oxytocin (OT) is a nonapeptide hormone that acts on the OT
receptor, a seven-transmembrane (7TM) (Gq-coupled) receptor.
The OT receptor has no subtypes but is related to the vasopressin
receptors V1A, V1B and V2. OT antagonists have therapeutic poten-
tial in a number of areas including pre-term labour1; benign pros-
tatic hyperplasia2 and sexual dysfunction.3 As a result there is
significant interest in the identification of potent, selective, orally
bioavailable OT antagonists.
We have recently disclosed4 arylpyrazinotriazole 1 as a potent
OT antagonist which has an attractive in vivo pharmacokinetic pro-
file in the rat. Compound 1 shows excellent selectivity both against
a wide range of unrelated targets4 and specifically against the V1B
N
N
N
N
R1
Me
Me
N
N
N
N
N
N
O
R2
N
N
F
Me
OMe
OMe
2
1
Figure 1. (a) Related local minimum conformations of 1 and 2 (b) superimposed representation of these local minimum conformations, illustrating the subtly different LHS
aryl group orientations in these two systems.
* Corresponding author. Tel.: +44 1304648240; fax: +44 1304648240.
E-mail address: Alan.D.Brown@pfizer.com (A. Brown).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.160

A. Brown et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2634–2636
2635
Table 1
and V2 receptors. Selectivity against the V1A receptor (ꢀ65-fold) is
OT Potency, V1A selectivity data and clogP values for a range of analogues, 2
reasonable but does fall a little short of the 100-fold window that
we typically set ourselves for potential clinical candidates.
N
N
Me
N
N
N
N
Me
N
N
Ar
N
O
N
N
N
OMe
Me
F
OMe
2
1
Ar–
Compound number
OT Ki (nM)
V1A Kia (nM)
clogP
OT Ki 6nM; MWt 376; clogP2.9; L.E. 0.41
V1A Ki 388nM; V1B >10uM; V2 Ki > 10uM
3
350
2320
2.6
As part of our efforts to follow-up on 1 we targeted close-in analogues
in which we hoped to maintain the attractive features of this com-
pound whilst further improving selectivity over the V1A receptor.
Experiences in the arylpyrazine series that yielded compound 1
suggested that key OT/V1A potency/selectivity interactions were
made by the left hand side (LHS) 4-fluoro-2-methylphenyl substi-
tuent of this compound. We therefore set out to design analogues
where: (a) the trajectory of our LHS aryl substituent would be sub-
tly different from that in compound 1 and (b) it would be straight-
forward to introduce a wide range of LHS aryl substituents to fully
explore OT/V1A potency/ selectivity SAR.
Cl
4
23.6
12.5
52.3
253
198
14.6
9.4
13% I @2
l
M
3.1
3.1
3.6
2.1
2.7
3.2
3.2
3.6
3.3
3.8
Me
Et
5
n.t.b
Considerations of synthetic ease and overlap of minimized con-
6
14% I @2
10% I @2
17% I @2
lM
lM
lM
l
formation(s) with 1 suggested targets 2 (Fig. 1).5 Parent compound
6
3 was thus prepared and profiled against OT and V1A
.
Although
some OT activity was retained, this compound clearly had signifi-
cantly reduced OT potency and V1A selectivity (<7-fold) compared
to 1.
OMe
SMe
7
N
N
Me
N
N
N
8
O
N
F
OMe
Me
9
25% I @ 10
M
3
OT Ki 350nM; V1A Ki 525nM; clogP 2.6
F
Me
10
11
12
13
n.t.
We were, however, cognisant of the fact that, in the LHS SAR around
1, both OT potency and V1A selectivity could be profoundly affected
by aryl ring substituents.4 As a result we were sufficiently encour-
aged to prepare a wider range of analogues, 2. Data for a selection
of these is disclosed in Table 1.
Me
Cl
5.9
20% I @ 2 lM
Several key LHS aryl SAR points emerged from this set of
compounds:
Me
F
(i) incorporation of a Me, Et or Cl 2-substituent gave a signifi-
cant increase in OT activity with no increase in V1A activity
(compounds 4, 5, 6). 2,6-dimethyl substitution gave a fur-
ther increase in potency (compound 11). However, 2-SMe
or 2–OMe substitution gave no significant potency increase
over 3 (compounds 8 and 7).
8.8
n.t.
F
Cl
Cl
37.5
15% I @ 2 lM
(ii) Incorporation of a 3-, 4-, or 6-F substituent was well toler-
ated (compounds 9, 10 and 12). A 4-Cl substituent was, how-
ever, slightly detrimental to activity (compound 13).
a
For compounds with Ki > 1000 nM where Ki could not be detemined, % inhibi-
tion (I) at 2 M is shown.
l
b
Not tested.
All of the compounds profiled in this series had very low affinity
for the V1A receptor. Indeed, our most potent compound, 11, had
>330-fold selectivity for OT over V1A. It is also worthy of note that
compounds such as 5, 9, 10, 11 and 12 had very similar heavy li-
gand efficiencies and clogPs to our lead compound, 1.7
The preparation of compound 3 is described in Scheme 1.8 Com-
mercial chloropyrazine 14 was converted to the corresponding
hydrazide 15 by reaction with hydrazine in methanol. Acylation
followed by dehydration yielded oxazole 17 which was reacted

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A. Brown et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2634–2636
O
O
O
H
N
N
a
N
N
N
b
NHNH2
OMe
N
H
O
Cl
N
Cl
Cl
N
14
15
16
c
N
N
N
N
N
N
e
N
d
N
N
N
N
N
N
O
PhO
Cl
N
Cl
N
N
OMe
OMe
3
18
17
Scheme 1. Synthesis of compound 3.8 Reagents and conditions: (a) NH2NH2ÁH2O, MeOH, 50%; (b) acetyl chloride, NMM, DCM, 64%; (c) POCl3, 35%; (d) 6-methoxy-pyridin-3-
ylamine, PTSA, xylene, 36%; (e) PhOH, Cs2CO3, NMP, 34%.
with 6-methoxy-pyridin-3-ylamine under acid catalysis to give key
triazolochloropyrazine intermediate 18. Reaction with phenol in
the presence of cesium carbonate then gave 3 in moderate yield.
In analogous fashion, intermediate 18 allowed ready access to a
range of targets 2, in a single step, by reaction with the appropriate
phenol.
In summary, we have, using 1 as a starting point, designed and
prepared a series of aryloxypyrazines to explore the key LHS aryl
binding region of our initial lead. Several compounds of this new
class, 2, combined excellent OT activity with significantly im-
proved V1A selectivity (over arylpyrazines such as 1). Our subse-
quent efforts in this area will be disclosed in due course.
References and notes
1. Gullam, J. E.; Chatterjee, J.; Thornton, S. Drug Discovery Today 2005, 2,
47.
2. Tiwari, A.; Nanda, K.; Chugh, A. Expert Opin. Invest. Drugs 2005, 14, 1359.
3. See, for example, WO 2005028452 and the references therein.
4. Brown, A.; Brown, L.; Ellis, D.; Puhalo, N.; Smith, C. R. Bioorg. Med. Chem. Lett.
2008, 18, 4278.
5. (a) Conformational analysis was carried out using in-house software. Local
minimum conformations of potential targets such as 2 were overlapped with
compound 1. (b) The minimized conformation of compound 1 illustrated was, in
fact, extremely close to that observed in the small molecule X-ray of this
compound.
6. All biological data reported herein represents functional antagonism, as
measured against the corresponding cloned human receptor in
based lactamase assay, using technology licensed from Rhoto
Pharmaceuticals.
a cell
b
7. See Ref. 4 and the references therein for a discussion on heavy atom ligand
Acknowledgements
efficiency and lipophilicity versus drug-like properties for compounds such as 1.
8. Abbreviations
used
in
Scheme
1
as
follows:
NMM—N-
We would like to acknowledge the contributions of the follow-
ing co-workers: Simon Pegg and Nicola Robinson.
methylmorpholine; PTSA—p-toluenesulphonic acid; NMP—N-methyl-2-
pyrrolidinone.