Identification of amide bioisosteres of triazole Oxytocin antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.02.018

A series of amides were investigated as potential bioisosteres of previously reported triazole Oxytocin antagonists. A range of potent analogues were identified, although SAR for potency and selectivity over the related V_1A and V₂ receptors was found to be somewhat divergent from that observed for the corresponding triazole series. The high synthetic accessibility of this new amide series also facilitated the identification of a range of alternative left hand side (biaryl replacement) substituents which gave good levels of Oxytocin antagonism.

Full text of DOI:10.1016/j.bmcl.2010.02.018

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2224–2228
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Bioorganic & Medicinal Chemistry Letters
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Identification of amide bioisosteres of triazole Oxytocin antagonists
*
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 amides were investigated as potential bioisosteres of previously reported triazole Oxytocin
antagonists. A range of potent analogues were identified, although SAR for potency and selectivity over
the related V1A and V2 receptors was found to be somewhat divergent from that observed for the corre-
sponding triazole series. The high synthetic accessibility of this new amide series also facilitated the iden-
tification of a range of alternative left hand side (biaryl replacement) substituents which gave good levels
of Oxytocin antagonism.
Received 12 January 2010
Revised 1 February 2010
Accepted 3 February 2010
Available online 8 February 2010
Keywords:
Oxytocin
Bioisotere
Ó 2010 Elsevier Ltd. All rights reserved.
O
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 labor;1 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.
Me
N
N
OMe
3, OT Ki 90nM
Encouraged by this result we prepared a range of phenylpyr-
azine amide analogues, based on the precedented advantages
provided by this system in our previously reported triazole based
work.6 In addition we sought to explore the left hand side (LHS)
aryl SAR in these analogues, placing particular emphasis on incor-
poration of an ortho substituent, as well as small electron with-
drawing (cyano and fluoro) substituents—two key elements of
obtaining potency and selectivity (respectively) in our earlier tria-
zole work.
We have previously reported the biaryltriazoles
1 and 2
(Scheme 1) as potent, selective Oxytocin antagonists with good
oral bioavailability in the rat.4 In following up these compounds
we were keen to increase our understanding of the (antagonist)
pharmacophore of these systems as well as developing an alterna-
tive template where it would be possible to explore left hand side
(LHS) biaryl SAR using library chemistry.
Analysis of the proposed active conformation of 1 and 2 sug-
gested a biarylamide template (as in targets such as 3) as a poten-
tial bioisostere of the biaryltriazole 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 aryl-triazole twist present in triazoles
such as 1 and 2 (Scheme 2). In addition, this system opened up
the possibility of using library chemistry to identify alternative
LHS substituents.
Key data for a range of such analogues is presented in Table 1.7
Several key SAR points emerged from this compound set:
(i) As in the corresponding triazole series,4 a LHS pyrazine lin-
ker is well tolerated (compare 3 with 4, for example).
(ii) A range of simple right hand side (RHS) substituents (Me, Et,
i-Pr, MeOCH2CH2) are all tolerated with no significant
impact on OT potency (compounds 4–7).
(iii) LHS (phenyl) OT SAR is somewhat different from that previ-
ously observed in our corresponding triazole series.4 For
example, incorporation of a 4-F or 4-CN substituent leads,
if anything, to a slight drop off in OT potency (compare
compounds, 8, 9, 10 and 11 with compound 6). In the tria-
zole series, these substituents were present in some of our
most potent antagonists (such as 1 and 2). In addition, a
Compound 3 was initially prepared to test the validity of this
approach and was found to have a Ki of 90 nM against Oxytocin.
* Corresponding author. Tel./fax: +44 1304648240.
E-mail address: Alan.D.Brown@pfizer.com (A. Brown).
Deceased author.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.02.018

A. Brown et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2224–2228
2225
N
OMe
N
N
N
Me
N
N
N
N
N
N
N
N
F
Me
NC
Me
OMe
OMe
1
2
OT Ki 6nM; V1A Ki 388nM;
OT Ki 14nM; V1A Ki 4.3uM;
V1B >10uM; V2 Ki > 10uM
V1B >10uM; V2 Ki > 10uM
Scheme 1. Biaryltriazoles previously reported by our group.
N
N
O
N
Me
Me
N
N
N
N
N
F
Me
OMe
OMe
3
1
Scheme 2. Local minimum conformation of biaryl amides 3 alongside that of biaryltriazole 1.5
Table 1
Potency and selectivity data for key analogues7
O
N
N
R
N
N
O
Ar
Me
Ar
R
OT Ki (nM)
V1A Ki
V2 Ki
Me–
92
1.1
2.3
l
M
M
>10
>10
>10
>10
l
M
M
M
M
Me
4
Et–
129
150
115
l
l
l
l
Me
5
Pri–
>10 lM
Me
6
MeOCH2CH2–
3.3 lM
Me
7
(continued on next page)

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A. Brown et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2224–2228
Table 1 (continued)
Ar
R
OT Ki (nM)
V1A Ki
V2 Ki
Me–
218
2
lM
n.t.a
F
Me
8
Me–
Et–
620
393
>10
l
M
>10
>10
>10
l
M
M
M
NC
NC
NC
Me
9
7.2
12
l
M
l
l
Me
10
MeOCH2CH2–
433
29
lM
Me
11
Me
Et–
5.9
l
M
343 nM
F
12
Me
Et–
25
14
11
472 nM
2.83 lM
Me
13
Me
Pri–
>10
lM
2.3
2.4
l
M
Me
Me
14
Me
MeOCH2CH2–
539 nM
lM
15
a
Not tested.
O
N
O
OMe
OMe
NH2
HN
HN
N
N
OMe
N
c
a
b
N
N
Cl
N
OMe
OMe
OMe
OMe
30
29
d
O
N
OMe
N
N
N
OMe
15
Figure 1. Synthesis of compound 15. (a) ClC(O)CH2OMe, pyridine, 50%; (b) LiAlH4, THF, 89%; (c) 5-chloro-pyrazine-2-carboxylic acid, T3P, Et3N, DCM, 26%; (d) 2,3-
dimethylphenyl boronic acid, Cs2CO3, Pd catalyst, dioxane, 16%.

A. Brown et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2224–2228
2227
O
R'
R'
N
HN
R
N
RCO2H
Couple
N
OMe
OMe
16: R' = Me
17: R' = Et
18: R' = CH2CH2OMe
O
O
O
Me
Me
H
N
R
N
R
N
Et
N
MeO
N
N
N
N
N
N
N
N
OMe
OMe
OMe
20: R = Et, OT Ki 85nM
21: R = MeOCH2CH2-, OT Ki
98nM
Me
22: R = Et, OT Ki 91nM
19: OT Ki 41nM
O
O
O
Et
N
O
R
N
O
O
Et
N
N
N
N
MeO
OMe
OMe
OMe
25: OT Ki 251nM
26: OT Ki 48nM
23: R = Me, OT Ki 232nM
24: R = Et, OT Ki 85nM
O
O
O
O
Et
N
Et
N
HN
N
HN
N
MeO
OMe
OMe
27: OT Ki 97nM
28: OT Ki 84nM
Scheme 3. Library strategy and OT potency data for alternative amide analogues identified by this approach.
2,3-dimethyl substituted LHS phenyl substituent was found
to give a good balance of potency and selectivity (com-
pounds 13, 14 and 15). This is again, somewhat at odds with
the SAR observed in our triazole series where this substitu-
ent lead to relatively poor V1A and V2 selectivity.4
zofurans (23, 24), aryloxyacetic acids (25, 26) and pyridones (27,
28) (Scheme 3). These systems clearly offer a range of alternative
starting points in the identification of further OT ligands with
desirable physicochemical properties.
In summary, we have identified N-pyridylbiarylamides as bios-
isosteres of our previously reported biaryltriazole Oxytocin antag-
onist template. In addition, library chemistry has been utilized to
identify several attractive biaryl replacements in these leads. Our
further efforts in this area will be reported in due course.
The preparation of compound 158 is described in Figure 1. Com-
mercially available 2-methoxy-5-aminopyridine was reacted with
methoxyacetyl chloride in pyridine to give amide 29. Reduction
with LiAlH4 followed by 1-propanephosphonic acid anhydride
(T3P) mediated coupling9 with commercially available 5-chloro-
pyrazine-2-carboxylic acid then gave amide 30, a key intermediate.
Unoptimised Suzuki coupling then furnished compound 15.
Given the high synthetic accessibility of amides of this type we
were also able to utilize library synthesis to search for alternative
LHS substituents (beyond the simple biaryl substituents present in
compounds such as 15). Several focused libraries were therefore
prepared (Scheme 3), coupling amines 16, 17 and 18 to a range
of acids designed to explore close-in chemical space around the
LHS substituent of leads such as 15. Several promising new leads
emerged from this library, including aryl pyrazoles (19–22), ben-
Acknowledgments
We would like to acknowledge the contributions of the follow-
ing co-workers: Gwen Easter; Mark Lewis; Simon Pegg and Nicola
Robinson.
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.

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A. Brown et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2224–2228
4. (a) Brown, A.; Brown, L.; Ellis, D.; Puhalo, N.; Smith, C. R. Bioorg. Med. Chem. Lett.
2008, 18, 4278; (b) Closer inspection of our pharmacophoric overlap (as
illustrated in Scheme 2) suggests that the LHS aryl substituents in our amide
systems gives a subtly different trajectory to this ring as compared to that in
corresponding triazole analogues. In addition, our previous triazole work (Ref.
4a) revealed a poor toleration of substituents with more than one or two heavy
atoms on this LHS aryl substituent. The subtle differences in amide and triazole
SAR observed here are consistent with these two facts.
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: Brown, A.; Ellis, D.; Pearce, D.; Ralph, M.;
Sciametta, N. Bioorg. Med. Chem. Lett. 2009, 19, 2634.; (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.
6. Moving from a phenyl to a pyrazine linker had, in our previously reported
triazole series, lead to a significant improvement in metabolic stability as well as
an increase in V2 selectivity. See Ref. 4 for details.
7. (a) All activity data reported herein represents functional antagonism, as
measured against the corresponding cloned human receptor in a cell based b
lactamase assay, using technology licensed from Rhoto Pharmaceuticals. (b) As
with our previous triazole based OT antagonists (see Ref. 4), no significant V1b
activity (<20% antagonism) was observed at 10 lM for a range of compounds,
including 13 and 15, profiled in this series.
8. 1H NMR of compound 15 (CDCl3; 400 MHz): d 8.76 (s, 1H), 8.31 (s, 1H), 7.82 (s,
1H), 7.48 (d, J = 10.2 Hz), 1H), 7.2–7.09 (m, 3H), 6.60 (d, J = 8.6 Hz, 1H), 4.03 (t,
J = 5.5 Hz, 2H), 3.80 (s, 3H), 3.64 (t, 2.5 Hz, 2H), 3.30 (s, 3H), 2.26 (s, 3H), 2.07 (s,
3H).
9. For example, see: Kopach, M. E.; Singh, U. K.; Kobierski, M. E.; Trankle, W. G.;
Murray, M. M.; Pietz, M. A.; Frost, M. B.; Stephenson, G. A. Org. Process Res. Dev.
2009, 13, 209. and the references therein.