Triazole oxytocin antagonists: Identification of an aryloxyazetidine replacement for a biaryl substituent

Article abstract of DOI:10.1016/j.bmcl.2009.11.097

A series of aryloxyazetidines, aryloxypyrrolidines and aryloxypiperidines were designed based on structural overlap with previously reported arylpyrazine Oxytocin antagonists. Similarly high levels of Oxytocin antagonism were achievable in these new serie

Full text of DOI:10.1016/j.bmcl.2009.11.097

Bioorganic & Medicinal Chemistry Letters 20 (2010) 516–520
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Triazole oxytocin antagonists: Identification of an aryloxyazetidine
replacement for a biaryl substituent
*
Alan Brown , T. Bruce Brown, Andrew Calabrese , Dave Ellis, Nicholas Puhalo, Michael Ralph, Lesa Watson
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 aryloxyazetidines, aryloxypyrrolidines and aryloxypiperidines were designed based on struc-
tural overlap with previously reported arylpyrazine Oxytocin antagonists. Similarly high levels of Oxyto-
cin antagonism were achievable in these new series. Several aryloxyazetidines also showed high levels of
selectivity, with one compound, 25, displaying promising in vivo pharmacokinetics and significantly
improved aqueous solubility over related compounds containing a biaryl substituent.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 27 October 2009
Revised 18 November 2009
Accepted 19 November 2009
Available online 23 November 2009
Keywords:
Medicinal chemistry
Oxytocin
Antagonist
Oxytocin (OT) is a cyclic 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 labour;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.
As part of our efforts to follow-up 1, we targeted close-in ana-
logues in which we hoped to maintain the attractive features of
this compound whilst further improving both selectivity over the
V1A receptor and aqueous solubility.
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:
We have previously disclosed4 arylpyrazinyltriazole 1, a potent
OT antagonist that 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
and V2 receptors. Selectivity against the V1A receptor (ꢀ65-fold) is
also reasonable but falls short of the 100-fold window that we typ-
ically set ourselves for potential clinical candidates. In addition,
compound 1 also suffers from relatively low aqueous solubility.5
(a) The trajectory of our LHS aryl substituent would be very
similar to that in compound 1.
(b) The physicochemistry of our targets (specifically number of
heavy atoms/molecular weight and c log P) would be similar
to 1.6
(c) In an attempt to improve aqueous solubility, the LHS aryl-
pyrazine of
1 would be replaced by a non-biaryl
N
N
N
substituent.7
Me
N
N
Overlap of minimised conformation(s) with 1 suggested targets
2–4 (Fig. 1).8 A range of analogues of this type were therefore pre-
pared and profiled (Table 1).9
N
F
Me
OMe
1
Several key SAR points emerged from this set of compounds:
Good levels of OT potency and V2 selectivity could be obtained
in all three series (e.g, compounds 9, 16 and 25).
OT Ki 6nM; MWt 376; clogP2.9; L.E. 0.41
V
1A Ki 388nM; V1B >10uM; V2 Ki > 10uM
Aqueous solubility 6µg/ml at pH 7.4
SAR across the three series was broadly similar. Specifically
(i) Incorporation of an 2-chloro or 2-methyl on the LHS aryl
substituent gave a significant increase in OT activity but
was also typically accompanied by an increase in V1A activity
(e.g., compare compounds 5 and 6; 11 and 12; 18 and 19).
* Corresponding author.
E-mail address: Alan.D.Brown@pfizer.com (A. Brown).
Present address: Signal Pharmaceuticals, LLC, 4550 Towne Centre Court, San
Diego, CA 92121, USA.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.11.097

A. Brown et al. / Bioorg. Med. Chem. Lett. 20 (2010) 516–520
517
N
N
N
N
N
N
N
N
N
N
N
N
Me
CH2R
CH2R
CH2R
N
N
N
N
Ar
N
Ar
O
O
Ar
O
N
N
N
N
F
Me
OMe
OMe
OMe
OMe
1
2
3
4
a
b
Figure 1. (a) Related local minimum conformations of 1, 2, 3 and 4. [Ar = Ph and R = H shown for illustrative purposes], (b) superimposed representation of these local
minimum conformations, illustrating the closely related left hand side aryl group orientations in these systems.
Table 1
Key data for a range of analogues 2–4
Ar
R
Compound
OT Ki (nM)
V1A Ki (nM)
V2 Ki (nM)
c log P
HLM Cla
N
N
N
CH2R
N
Ar
O
N
OMe
2
H
H
5
6
114
5.4
127
>10,000
>10,000
2.9
3.5
n.t.b
n.t.b
Me
21.6
F
Me
H
H
7
8
4.2
2.6
111
n.t.b
>10,000
>10,000
3.7
3.7
23
24
F
Me
F
Me
H
9
0.4
2.2
175
>10,000
>10,000
3.9
2.7
n.t.b
n.t.b
F
Me
–OMe
10
24.4
N
N
N
CH2R
N
Ar
O
N
OMe
3
(continued on next page)

518
A. Brown et al. / Bioorg. Med. Chem. Lett. 20 (2010) 516–520
Table 1 (continued)
Ar
R
Compound
OT Ki (nM)
V1A Ki (nM)
V2 Ki (nM)
c log P
HLM Cla
n.t.b
H
11c
170
1840
>10,000
3.2
Me
H
12c
13c
14c
15c
35.9
31.8
28.5
17.9
734
941
255
586
>10,000
>10,000
>10,000
>10,000
3.4
3.7
2.9
3.2
32
F
F
F
Me
H
95
Me
–OMe
–OMe
n.t.b
>440
Me
Me
F
–OMe
–OMe
16c
17d
5.8
1000
522
>10,000
>10,000
3.4
2.9
107
n.t.b
Me
207
N
N
N
CH2R
N
Ar
O
N
OMe
4
H
18
304
>10,000
>10,000
2.8
<7.0
Cl
Cl
H
19
20
55.1
32.5
1940
1340
>10,000
>10,000
3.5
3.0
n.t.b
21
–OMe
F
F
Cl
H
H
21
22
28.4
17.5
2430
608
>10,000
>10,000
3.7
3.6
22
Me
n.t.b
Me
Me
Cl
H
23
24
40
1680
719
2770
1190
3.6
3.1
n.t.b
n.t.b
F
F
–OMe
18.4
F
–OMe
25
9.5
1120
>10,000
3.2
10
a
b
c
Human liver microsome intrinsic clearance value in lL/min/mg.
Not tested.
(R)-enantiomer.
(S)-enantiomer.
d
Table 2
Oral pharmacokinetic data for compounds 25 and 1
(ii) Additional incorporation of a 3, 4 or 5-fluoro on the LHS
aryl substituent gave a further increase in OT potency. This
was typically accompanied by a slight drop off in V1A activ-
ity, leading to compounds with significantly improved
selectivity (e.g., compare compounds 6 and 9; 17 and 16;
19 and 21).
(iii) Incorporation of a methoxy right hand side substituent
(R = H to R = MeO) typical led to a slight increase in OT
potency (e.g, compare compounds 6 and 10; 13 and 15;
19 and 20).
Compound
Species
Cl (mL/min/kg)
T1/2 (h)
Vd (L/Kg)
Fa (%)
25
25
1
Ratb,c
Dogb,c
Ratd,c
36
8
50
0.9
1.9
1.0
2.5
1.3
4.4
62
81
24
a
Oral bioavailability, measured by comparison with iv pharmacokinetic data (not
shown).
b
Doses were 2 mg/Kg and 0.2 mg/Kg for rat and dog, respectively.
Both studies were carried out using a suspension of fully crystalline material.
Dose 0.5 mg/Kg.
c
d

A. Brown et al. / Bioorg. Med. Chem. Lett. 20 (2010) 516–520
519
Ph
Cl
OH
Cl
a, b
O
Ph
N
+
NH.HCl
F
F
MsO
28
27
26
NH2
NCS
N
c
d
N
OMe
OMe
29
S
N
N
N
OMe
N
NH
Cl
N
N
Cl
e, g
O
O
N
O
F
F
OMe
OMe
OMe
H2NHN
25
30
31
f
O
OMe
MeO
Scheme 1. Synthesis of compound 25. Reagents and conditions: (a) K2CO3, CH3CN, reflux, quant; (b) (i) CH3(Cl)CHOCOCl, Et2NPri, CH2Cl2, reflux, (ii) MeOH, reflux, 62%; (c)
thiocarbonyldiimidazole, THF, quant; (d) N-methylmorpholine, CH2Cl2, 0–25 °C, quant; (e) KOBut, methyl p-toluenesulfonate THF; (f) NH2NH2, methanol, reflux, quant; (g)
THF, CF3CO2H, reflux, 56% (for steps e and g).
In the pyrrolidine series, 3, the (R)-enantiomers prepared were
typically more potent than the corresponding (S)-enantiomers
(compare compounds 14 and 17).10
Of the three series, azetidines 4 carried the highest levels of
inherent V1A selectivity. Compare, for example, parent compounds
5 versus 11 versus 18.
Of the analogues prepared, compound 25 was, on the basis of
potency, selectivity and human liver microsomal stability, selected
for further progression. Profiling against a wide range of receptors,
enzymes and ion channels identified no significant off target activ-
ity.11 Fully crystalline material was produced and this material was
The preparation of compound 25 is described in Scheme 1. 2-
Chloro-4-fluorophenol 27 was alkylated with commercially avail-
able azetidine mesylate 26. Following deprotection the resulting
NH azetidine, 28, reacted smoothly with 29, the isothiocyanate
from 5-amino-2-methoxy pyridine, to give thiourea 30 in excellent
yield. Conversion to the corresponding S-methylisothiourea, fol-
lowed by acid catalysed condensation with hydrazide 31, then
gave 25 in an overall yield of 35%.12
In summary, we have, using 1 as a starting point, designed and
prepared a series of potent, aryl ether triazole Oxytocin antago-
nists. One of these compounds, 25, has significantly improved
V1A selectivity and aqueous solubility over 1, as well as a promising
pharmacokinetic profile in both rat and dog. As a result of this data
and subsequent profiling, a decision was taken to progress 25 as a
candidate for subsequent clinical studies.
found to have an aqueous solubility of 59
icantly greater than that observed for lead compound 1 (6
l
g/mL at pH 7.5—signif-
g/mL at
l
pH 7.4), supporting our strategy of moving away from a biaryl LHS
substituent to promote increased solubility. In addition, profiling
of 25 in the rat and dog showed that this compound demonstrated
promising oral pharmacokinetics. Across these species clearance
was moderate (rat) to low (dog) and high levels of oral bioavailabil-
ity were observed. Moreover, comparison with 1 indicated a signif-
icantly improved profile with respect to rat oral pharmacokinetics
(Table 2).
Acknowledgements
We would like to acknowledge the contributions of the follow-
ing co-workers: Mark Lewis, Simon Pegg and Nicola Robinson.
N
N
References and notes
CH2OMe
F
N
N
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.
O
Cl
N
OMe
5. All solubilities disclosed in this paper were measured on fully crystalline
material, as assessed by powdered X-ray diffraction analysis.
25
OT Ki 9.5nM; V1A Ki 1,120nM; clogP 3.2

520
A. Brown et al. / Bioorg. Med. Chem. Lett. 20 (2010) 516–520
6. See reference 4 and the references therein for a discussion on heavy atom
9. (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)
No significant V1b activity was observed for any of the compounds profiled.
10. This trend was repeated across a range of additional (R)/(S) enantiomers (data
not shown).
ligand efficiency and lipophilicity versus drug-like properties for compounds
such as 1.
7. For a discussion on the strategy of removing the biaryl substituent from
systems of this type to improve aqueous solubility see: Brown, A.; Brown, L.;
Brown, T. B.; Calabrese, A.; Ellis, D.; Puhalo, N.; Smith, C. R.; Wallace, O.;
Watson, L. Bioorg. Med. Chem. Lett. 2008, 18, 5242. and the references and notes
therein.
11. The only activities identified below 10
lM were affinity for NK1,
j-opiod and
Ghrelin receptors, where binding Ki’s were 6.5
l
M,
3
lM
and 4.4 M,
l
8. (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 minimised conformation of compound 1 illustrated was,
in fact, extremely close to that observed in the small molecule X-ray of this
compound.
respectively.
12. Spectroscopic data for compound 25 as follows: 1H NMR (CDCl3, 400 MHz) d 3.32
(s, 3H), 4.00 (s, 3H), 4.02 (dd, 2H), 4.15 (dd, 2H), 4.32 (s, 2H), 4.90 (m, 1H), 6.53
(dd, 1H), 6.83-6.86 (m, 2H), 7.12 (d, 1H), 7.60 (d, 1H), 8.20 (s, 1H); mass
spectroscopy (APCI+): m/z 420 [MH+].