Identification of a urea bioisostere of a triazole oxytocin antagonist

Article abstract of DOI:10.1016/j.bmcl.2010.01.143

A series of azetidine ureas were investigated as potential bioisosteres of previously reported azetidinyltriazole oxytocin antagonists. Although potency was somewhat reduced in several close-in analogues, one compound, 9, was both a potent oxytocin antagonist and demonstrated significant selectivity over the closely related vasopressin V_1A receptor.

Full text of DOI:10.1016/j.bmcl.2010.01.143

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1851–1853
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Identification of a urea bioisostere of a triazole oxytocin antagonist
z
*
Alan Brown , Dave Ellis, Olga Wallace , Michael Ralph
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 azetidine ureas were investigated as potential bioisosteres of previously reported azetidinyl-
triazole oxytocin antagonists. Although potency was somewhat reduced in several close-in analogues,
one compound, 9, was both a potent oxytocin antagonist and demonstrated significant selectivity over
the closely related vasopressin V1A receptor.
Received 12 January 2010
Revised 27 January 2010
Accepted 29 January 2010
Available online 2 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Oxytocin
Bioisostere
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 potential
in a number of areas including pre-term labour1; Benign Prostatic
Hyperplasia2 and sexual dysfunction.3 As a result there is significant
interest in the identification of potent, selective, orally bioavailable
OT antagonists.
We have previously reported a series of azetidinyltriazoles, as
represented by compounds 1 and 2 (Scheme 1), as potent, selective
oxytocin antagonists with good oral bioavailability in the rat.4 Dur-
ing the course of this work we established that, in systems of this
type, it was reasonably straightforward to achieve high levels of
selectivity over V2 and V1B receptors. However, achieving high lev-
els of selectivity over V1A, whilst achievable, was significantly more
challenging. Our experience4 suggested that this was best achieved
by incorporation of small electron withdrawing meta or para sub-
stituents (typically F), along with a small (methyl or chloro) ortho
substituent, in the phenyl ring of compounds such as 1 and 2.
In our quest to understand the pharmacophore for this chemo-
type, we were interested in exploring alternative systems that
probed the importance of some of the possible binding residues
of our azetidinyltriazoles. Analysis of the proposed active confor-
mation of 1 and 2 suggested an azetidine urea template (as in tar-
gets such as 3) as a potential bioisostere of the azetidinyltriazole
present in these compounds. Molecular modeling and analysis of
small molecule X-ray data on systems of this type5 suggested that
compounds such as 3 had the potential to mimic the overall shape
of triazoles such as 1 and 2 (Scheme 2).
We therefore prepared a small set of azetidine ureas carrying
orthomethyl/chloro substituents and meta/para fluoro substituents
on the phenyl ring in an attempt to identify potent OT antagonists
with high levels of V1A selectivity. Functional potency and V1A
selectivity data for these compounds is shown in Table 1, along
N
N
N
N
N
N
Me
Me
F
F
N
N
O
O
Me
Cl
N
N
OMe
OMe
1
2
OT Ki 17.5nM; V1A Ki 608nM
OT Ki 28.4nM; V1A Ki 2.4uM
Scheme 1. Azetidine triazoles previously reported by our group.
* Corresponding author.
E-mail address: Alan.D.Brown@pfizer.com (A. Brown).
Deceased.
z
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.01.143

1852
A. Brown et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1851–1853
Table 1
potency and V1A selectivity data for key analogues6
O
N
N
N
R
N
N
Me
N
N
N
Ar
Ar
O
O
OMe
OMe
ArO
R
OT Ki
V1A Ki
ArO
OT Ki
V1A Ki
O
F
O
Me
4
Me
Me–
Me–
Me–
159 nM
237 nM
112 nM
>4.2
>4.2
l
M
M
41.4 nM
>4.2 lM
F
F
F
12
O
O
l
17.5 nM
19.7 nM
28.4 nM
608 nM
Me
5
O
F
Me
F
1
O
F
Me
6
Me
1.3
l
M
>4.2 lM
F
13
O
O
Me–
Et–
Et–
Et–
Et–
67.2 nM
36.7 nM
13.9 nM
48.4 nM
43 nM
779 nM
n.t.a
2.4 lM
F
F
Cl
7
O
F
Cl
2
Me
8
F
O
>4.2
n.t.a
n.t.a
lM
Me
9
F
F
O
Cl
10
O
F
Me
11
a
Not tested.
O
O
N
NH2
HN
N
N
N
d
c
a, b
X
O
N
N
OMe
14
N
N
OMe
OMe
OMe
F
X = MsO, 19%
X = Cl, 22%
9
15
Figure 1. Synthesis of compound 9. Reagents and conditions: (a) acetyl chloride, Et3N, DCM, 0 °C, 56%; (b) 1 M LiAlH4 in diethyl ether, THF, 0 °C, 96%; (c) azetidin-3-yl-
methanesulphonateꢀHCl, bis (trichloromethyl) carbonate, N,N-diisopropyl ethylamine, DCM, 20 °C; (d) 3-fluoro-2-methylphenol, Cs2CO3, MeCN, 100 °C, 12%.
with data for representative examples of our previously reported
azetidinyltriazole series.6
Two key SAR points emerged from this compound set:
(i) 3-Fluoro-2-methyl substitution on the phenyl ring leads to
greater levels of V1A selectivity than observed for the corre-
sponding 2-methyl-4-fluoro or 2-chloro-4-fluoro analogues (com-
pare 4 and 5 with 6 and 7). This is entirely consistent with our
findings in the azetidinyltriazole series (compare 12 and 13 with
1 and 2).
(ii) Moving from a methylurea (R = Me) to the corresponding
ethylurea (R = Et) typically gives a slight increase in OT potency
(e.g., compare 6 with 11 and 4 with 9).

A. Brown et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1851–1853
1853
O
N
N
N
R'
N
R
N
N
N
Ar
Ar
O
O
N
OMe
OMe
3
4
N
O
N
R'
R
N
N
N
N
Ar
Ar
O
O
N
N
OMe
OMe
4
3
Scheme 2. (a) Proposed azetidine urea targets 3 suggested by azetidinyltriazoles 4. (b) Local minimum conformation of azetidine urea 3 alongside that of azetidinyltriazole
4.5 (Ar = Ph; R = Me and R0 = Et shown for clarity).
Compound 9 therefore emerged from this analysis as our most
potent and V1A selective azetidine urea of this type. This compound
has a very similar potency and selectivity to the corresponding aze-
tidinyltriazole, 13, supporting the pharmacophoric overlap illus-
trated in Scheme 2.
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. Investig. Drugs 2005, 14, 1359.
3. See, for example, WO 2005028452 and the references cited therein.
4. Brown, A.; Brown, T. B.; Calabrese, A.; Ellis, D.; Puhalo, N.; Ralph, M.; Watson, L.
Bioorg. Med. Chem. Lett. 2010, 20, 516.
5. (a) Our conformational analysis was based on comparison of local minima
conformations (as assessed by in-house modeling software) as well as analysis
of in-house and publicly available small molecule X-rays of compounds
containing structural motifs similar to that in proposed target 3 and triazoles
such as 1. Both suggested that the conformation of 3 shown in Scheme 2
represents a low energy local minimum for this compound. For a discussion on
the conformation of compound 1 see Ref. 4.
The preparation of compound 97 is described in Figure 1. Com-
mercially available 5-amino-2-methoxypyridine was acylated with
acetyl chloride and then reduced with lithium aluminum hydride
to give N-ethylaminomethoxypyridine 14. One pot urea formation
using bis(trichloromethyl) carbonate and commercially available
azetidin-3-yl-methanesulphonate then gave 15 as a mixture of
chloro/mesylate azetidine. This key intermediate (mixture) was
used without purification. Unoptimised reaction with 3-fluoro-2-
methylphenol furnished compound 9.
(b) Since this work was carried out, workers at GlaxoSmithKline have reported
the utilization of a somewhat similar pharmacophoric overlap approach to
identify two structurally related classes of OT antagonists. See: (i) Barton, N. P.;
Bellenie; B. R.; Doran, A. T.; Emmons, A. J.; Heer, J. P.; Salvagno, C. M. Bioorg. Med.
Chem. Lett. 2009, 19, 528; (ii) Barton, N. P.; Bellenie; B. R.; Emmons, A. J.; Heer, J.
P.; Salvagno, C. M. Bioorg. Med. Chem. Lett. 2009, 19, 990.
In summary, we have identified azetidine ureas as bioisosteres
of our previously reported azetidinyltriazole oxytocin antagonist
template. One analogue, 9, is a potent OT antagonist with signifi-
cant selectivity over the closely related V1A receptor. Our further
efforts in this area will be reported in due course.
6. (a) All activity data reported herein represents functional antagonism of an
oxytocin stimulated agonist response, as measured against the corresponding
cloned human receptor in a cell based b lactamase assay, using technology
licensed from Rhoto Pharmaceuticals; (b) In additional studies compound 9
demonstrated no significant (<10% at 10
receptors.
lM) antagonism of the V1B and V2
7. 1H NMR of compound 9 (400 MHz, CDCl3): d 8.00 (s, 1H), 7.40 (d, 1H), 7.00 (q,
1H), 6.80 (d, 1H), 6.65 (t, 1H), 6.10 (d, 1H), 4.65 (m, 1H), 4.00 (s, 2H), 3.90 (m,
2H), 3.70 (s, q, 5H), 2.10 (s, 3H), 1.10 (t, 3H). LRMS (ES)—m/z 360 (MH+).
Acknowledgements
We would like to acknowledge the contributions of the follow-
ing co-workers: Gwen Easter; Mark Lewis; Simon Pegg and Nicola
Robinson.