[4-(Phenoxy)pyridin-3-yl]methylamines: A new class of selective noradrenaline reuptake inhibitors

Article abstract of DOI:10.1016/j.bmcl.2008.02.036

[4-(Phenoxy)pyridine-3-yl]methylamines are disclosed as a new series of selective noradrenaline reuptake inhibitors (NRI). Structure-activity relationships established that potent NRI activity could be achieved by appropriate substitution at the 2-position of the phenoxy ring. Compound 31 demonstrated potent NRI activity combined with good selectivity over serotonin and dopamine reuptake and no significant off-target pharmacology.

Full text of DOI:10.1016/j.bmcl.2008.02.036

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 1795–1798
[4-(Phenoxy)pyridin-3-yl]methylamines: A new class
of selective noradrenaline reuptake inhibitors
Paul V. Fish,* Thomas Ryckmans, Alan Stobie and Florian Wakenhut
Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
Received 28 January 2008; revised 11 February 2008; accepted 12 February 2008
Available online 16 February 2008
Abstract—[4-(Phenoxy)pyridine-3-yl]methylamines are disclosed as a new series of selective noradrenaline reuptake inhibitors
(NRI). Structure–activity relationships established that potent NRI activity could be achieved by appropriate substitution at the
2-position of the phenoxy ring. Compound 31 demonstrated potent NRI activity combined with good selectivity over serotonin
and dopamine reuptake and no significant off-target pharmacology.
ꢀ 2008 Elsevier Ltd. All rights reserved.
Release of the neurotransmitter noradrenaline (NA)
into the synaptic cleft results in adrenoceptor activation,
and is followed by reuptake of noradrenaline via the
noradrenaline transporter protein. Selective inhibition
of noradrenaline reuptake (NRI) has been shown to be
an attractive approach for the treatment of a number
of diseases.1,2 For example, atomoxetine (1) is a new
therapy for the treatment of attention deficit hyperactiv-
ity disorder (ADHD)3 and reboxetine (2) is used clini-
cally for the treatment of depression.4
Pyridinyl phenyl ethers 3 were first disclosed as selective
SRIs9 and further modification of this template afforded
dual SNRIs (e.g., 4 and 5) (Table 1).10 An emerging
understanding of the SAR showed that the aryloxy ring
played an important role in modulating SRI and NRI
activity; that is, appropriate substitution at the 2-posi-
tion conferred NRI activity whereas substitution at the
4-position gave SRI activity.7,8,10 Hence, as an initial
venture, we elected to delete the 4-Cl substituent from
the aryloxy ring of 4 and 5 with the aim of reducing
the SRI activity to furnish selective NRIs (i.e., 13 and
14; R3 = Et).
O
NHMe
NH
NR1R2
NR1R2
N
W
N
X
O
O
O
Y
O
Me
Et
Me
EtO
2
1: atomoxetine
2: ( )-reboxetine
z
4
Cl
As part of our research efforts to identify potential drug
candidates, we have reported several new templates that
inhibit monoamine reuptake.5–8 In this letter, we dis-
close pyridinyl phenyl ethers as potent NRIs with good
selectivity over serotonin (5-HT) and dopamine (DA)
reuptake inhibition (SRI and DRI, respectively).
4: NR1R2 = NHMe
3
5: NR1R2 = NMe2
Target compounds 15–32 (Table 1) were prepared using
an efficient synthesis employing 4-chloro-6-methylnicoti-
namide 10 as an advanced intermediate (Scheme 1). This
route allowed for the late stage installation of the aryl-
oxy ring and would furnish both sec- and tert-amines
13, 14, respectively. Mannich reaction of 4-hydroxypy-
ran-2-one 6 with (MeO)2CHNMe2 gave enamide 7
and aminolysis followed by rearrangement with
Keywords: Noradrenaline reuptake inhibitor; NRI; Pyridinyl phenyl
ether.
*
Corresponding author. Tel.: +44 (0)1304 644589; fax: +44 (0)1304
651987; e-mail: paul.fish@pfizer.com
0960-894X/$ - see front matter ꢀ 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.02.036

1796
P. V. Fish et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1795–1798
Table 1. In vitro inhibition of monoamine reuptakea and clogP for compounds 2–5, 15–32
N
NR1R2
R3
Me
O
15-32
Compound
NR1R2
R3
NA Ki (nM)
5-HT Ki (nM)
DA Ki (nM)
clogP
2
4
—
—
5
74
1400
18
>10,000
4350
NT
3.3
4.4
4.8
3.6
4.1
2.2
2.6
2.7
3.2
3.1
3.6
2.8
3.2
3.1
3.6
3.6
4.1
4.2
4.6
4.4
4.8
NHMe
NMe2
NHMe
NMe2
NHMe
NMe2
NHMe
NMe2
NHMe
NMe2
NHMe
NMe2
NHMe
NMe2
NHMe
NMe2
NHMe
NMe2
NHMe
NMe2
2-Et, 4-Cl
2-Et, 4-Cl
Et
5
22
13
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
366
27
440
279
265
1420
218
4750
136
235
133
384
88
2280
2660
4800
4060
2390
2150
1520
1410
1750
1930
834
Et
OMe
OMe
OEt
OEt
Me
921
296
461
179
951
194
232
58
Me
SMe
SMe
Cl
255
131
82
Cl
i-Pr
242
1980
1470
821
2820
823
4060
1160
2130
2880
1980
2250
1910
2640
i-Pr
13
n-Pr
n-Pr
OPh
OPh
438
159
10
10
a See Ref. 8 for complete details of assay conditions. Monoamine reuptake Ki values are geometric means of at least three experiments. Differences of
<2-fold should not be considered significant. NT denotes not tested.
O
O
O
CO2H
O
c
d
a
e
b
HN
N
N
Cl
O
N
O
N
NMe2
Me
Me
Me
Me
Cl
Me
Me
OH
O
Me
Me
O
O
O
8
9
7
6
f
g
N
NHMe
NMe2
R3
NHMe
NHMe
R3
O
O
Cl
R3
10
12
13
14
Scheme 1. Synthesis of target compounds 13 and 14. Reagents and conditions: (a) (MeO)2CHNMe2, dioxane, rt, 73%; (b) i—NH3, H2O, rt; ii—
Me2NH, H2O, rt ! 50 ꢁC; iii—HCl, H2O, rt, 70%; (c) (COCl)2, cat. DMF, CH2Cl2, rt; (d) MeNH2ÆHCl, NEt3, CH2Cl2, rt, 78% over 2-steps; (e)
ArOH (11), K2CO3, DMF, 100 ꢁC; (f) BH3ÆTHF (1 M), THF, reflux; (g) HCHO, NaBH(OAc)3, CH2Cl2, rt.
NH3–Me2NH–HCl afforded 4-pyridone 8.11 Treatment
of 8 with oxalyl chloride gave pyridine 9 and reaction
with MeNH2 furnished amide 10.9 Displacement of the
Cl group of 10 with phenols12 11 gave the aryloxy ethers
12 in good yield, reduction with borane–THF gave sec-
amines 13, and finally reductive alkylation with formal-
dehyde afforded the tert-amines 14.
as tert-amine 16 retained NRI activity whilst reducing
SRI activity by 20-fold. Compound 16 was a potent
NRI (Ki 27 nM) with selectivity over both SRI (10-fold)
and DRI (100-fold) (Table 1). In contrast, the corre-
sponding sec-amine 15 had a significant loss in both
SRI and NRI activity compared to 4. Compound 16
had drug-like physicochemical properties consistent
with CNS target space13 (m.wt. 270; clogP 4.1; logD7.4
2
˚
Deletion of the 4-Cl of tert-amine 5 proved to be suc-
cessful strategy in the identification of selective NRIs
2.1; TPSA 25 A ), combined with good metabolic stabil-
ity in human liver microsomes (HLM, Cli < 7 lL/min/

P. V. Fish et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1795–1798
1797
tant selection criteria as lipophilic compounds have an
increased risk of hepatic metabolic clearance,16 off-tar-
get promiscuous pharmacology17 and in vivo toxicolog-
ical outcomes.18
Evaluation of 28, 31 and 32 in high throughput in vitro
ADME screens showed 31 to have the advantage of bet-
ter metabolic stability and weaker CYP2D6 inhibition
(Table 2).
Previously, pyridinyl phenyl ethers such as 4 and 5 had
shown an unacceptable level of promiscuous off-target
pharmacology which had been attributed to the high
lipophilicity of these structures.10 Compound 31 was
screened for off-target pharmacology against a panel
of 110 receptors, enzymes and ion channels (CEREP,
Bioprint) and was found to have binding affinity for
only the 5-HT2C, j-opioid and l-opioid receptors
(>80% inhibition at 10 lM). Further evaluation showed
31 to have no confirmed functional activity at these tar-
gets at 62.5 lM. Compounds 4 and 31 are isolipophilic
(by clogP) which suggested an important structural
component to the cleaner pharmacology profile of 31.
Figure 1. Plot of NRI activity versus clogP for sec-amines 13 (m) and
tert-amines 14 (•).
mg), and low ion channel activity as measured by bind-
ing to potassium hERG channels ([3H]-dofetilide,
IC50 > 20 lM). Hence 16 was selected as a lead for our
drug discovery programme.
Additional screening in vitro19 showed 31 to have good
membrane permeability (CaCO-2 11/19) with low affin-
ity for P-gp efflux transporters (MDCK-mdr1 25/41)
suggesting the potential for good oral absorption and
CNS penetration. Compound 31 had good metabolic
stability in human liver microsomes (Cli < 7 lL/min/
mg) and human hepatocytes (Cli 8 lL/min/mg) consis-
tent with low predicted clearance. Compound 31 had
no significant inhibition of CYP450 enzymes (1A2,
2D6, 3A4; IC50s > 3 lM) and modest ion channel activ-
ity as measured by binding to potassium hERG ([3H]-
dofetilide, Ki 5.8 lM), sodium (site 2, Ki 3.4 lM) and
calcium (L-type diltiazem site, Ki 1.2 lM) channels.
Further, SAR was directed at improving NRI activity
by exploring a broader set of 2-substituents on the aryl-
oxy ring in both the sec- and tert-amine series 17–32
(Table 1).14 NRI activity was clearly dependant on the
lipophilicity of the 2-substituent15 with potent NRI
activity tracking with increased lipophilicity (Fig. 1).
In addition, clear trends in SAR of the sec- and tert-
amines also emerged: tert-amines invariably showed a
significant advantage in NRI activity compared to the
corresponding sec-amines (e.g., 16 vs 15; 28 vs 27)
(Fig. 1, • vs m) and tert-amines were generally weaker
SRIs compared to sec-amines (e.g., 18 vs 17; 20 vs 19).
No compound demonstrated any significant DRI activ-
ity. The combination of these SARs resulted in tert-
amines yielding the most potent NRIs with better selec-
tivity for SRI and DRI. Two exceptions to these trends
were the 2-n-Pr group (29, 30) which under performed
relative to clogP, and the 2-OPh substituent which gave
sec- and tert-amines (31, 32) with equivalent NRI
potencies.
Further pharmacological evaluation in vivo, in microdi-
alysis experiments,20 showed 31 increased NA levels in
interstitial fluid of the prefrontal cortex of conscious rats
by 400% above pre-drug baseline levels (0.3 mg/kg
administered sc, n = 4).21
In summary, pyridinyl phenyl ethers are disclosed as a
new series of selective NRIs. Structure–activity relation-
ships established that potent NRI activity could be
achieved by appropriate substitution at the 2-position
of the phenoxy ring. Compound 31 demonstrated potent
NRI activity combined with good selectivity over sero-
tonin and dopamine reuptake and no significant off-tar-
get pharmacology. Based on this profile, 31 (PF-
3665343)22,23 was selected as a candidate for further
evaluation in pre-clinical disease models. The results of
these studies will be reported in future publications.
From these experiments, 28, 31 and 32 emerged as hav-
ing a superior combination of NRI activity (Ki < 15 nM)
combined with selectivity over SRI and DRI (>80-fold).
Compound 31 offered the benefit of lower lipophilicity
as measured by octanol-buffer distribution coefficients
(logD) (Table 2). Minimising lipophilicity was an impor-
Table 2. Physicochemical and ADME properties of 28, 31 and 32a,b
28
31
32
logD7.4
pKa
2.5
1.6
2.4
Acknowledgments
ND
17
9.0 and 4.4
<7
3.4
8.7 and 4.4
29
0.61
HLM, Cli lL/min/mg
CYP2D6 inhib., IC50 lM
MDCK-mdr1, AB/BA
ND
38/39
We thank Yann Lecouturier and Malcolm Mackenny
for compound synthesis. We are grateful to Stephen
Phillips (Discovery Biology), Fidelma Atkinson
(PDM) and Robert Webster (PDM) for screening data.
25/41
41/36
a See Ref. 19.
b ND denotes not determined.

1798
P. V. Fish et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1795–1798
14. The Me group adjacent to the pyridine N atom was
retained in all targets in order to reduce the liability of
CYP450 inhibition. See Blagg, J. Annu. Rep. Med. Chem.
2006, 41, 353.
We thank Alan Brown and Gavin Whitlock for helpful
discussions.
15. The relative lipophilicities of the 2-substituents were evalu-
ated by clogP calculations and by comparison of hydro-
phobic fragmental constants (p), see: Rekker, R. F.;
Mannhold, R. Calculation of drug lipophilicity; VCH: New
York. R3 (p): OMe (ꢀ0.02); OEt (0.38); Me (0.56); SMe
(0.61); Cl (0.71); Et (1.02); i-Pr (1.53); n-Pr (1.55); OPh (2.08).
16. van de Waterbeemd, H.; Smith, D. A.; Beaumont, K.;
Walker, D. K. J. Med. Chem. 2001, 44, 1313.
References and notes
1. Babu, R. P. K.; Maiti, S. N. Heterocycles 2006, 69, 539.
2. For a recent review of new chemical entities, see Walter,
M. W. Drug Dev. Res. 2005, 65, 97.
3. Ledbetter, M. Neuropsychol. Dis. Treat. 2006, 2, 455.
4. Hajos, M.; Fleishaker, J. C.; Filipiak-Reisner, J. K.;
Brown, M. T.; Wong, E. H. F. CNS Drug Rev. 2004, 10,
23.
5. (a) Fray, M. J.; Bish, G.; Brown, A. D.; Fish, P. V.; Stobie,
A.; Wakenhut, F.; Whitlock, G. A. Bioorg. Med. Chem.
Lett. 2006, 16, 4345; (b) Fray, M. J.; Bish, G.; Fish, P. V.;
Stobie, A.; Wakenhut, F.; Whitlock, G. A. Bioorg. Med.
Chem. Lett. 2006, 16, 4349.
6. Fish, P. V.; Fray, M. J.; Stobie, A.; Wakenhut, F.;
Whitlock, G. A. Bioorg. Med. Chem. Lett. 2007, 17,
2022.
7. Whitlock, G. A.; Fish, P. V.; Blagg, J. Bioorg. Med. Chem.
Lett. 2008, 18, 596.
8. Fish, P. V.; Mackenny, M. C.; Stobie, A.; Wakenhut, F.;
Whitlock, G. A. WO Patent 105100, 2005.
9. Adam, M. D.; Andrews, M. D.; Gymer, G. E.; Hepworth,
D.; Howard, H. R., Jr.; Middleton, D. S.; Stobie, A. WO
Patent 083643, 2002.
10. Whitlock, G. A.; Fish, P. V.; Fray, M. J.; Stobie, A.;
Wakenhut, F. Bioorg. Med. Chem. Lett., submitted for
publication.
17. Leeson, P. D.; Springthorpe, B. Nat. Rev. Drug Disc. 2007,
6, 881.
18. Hughes, J. D.; Blagg, J.; Bailey, S.; De Crescenzo, G. A.;
Dalvie, D.; Devraj, R. V.; Doubovetzky, M.; Ellsworth,
E.; Fobian, Y. M.; Gibbs, M. E.; Gilles, R. W.; Grant, D.;
Greene, N.; Huang, E.; Kreiger-Burke, T.; Lee, L.; Loesel,
J.; Nahas, K.; Price, D. A.; Wager, T.; Whiteley, L.;
Zhang, Y., Nat. Biotechnol., in press.
19. CaCO-2: human colon adenocarcinoma cell line. MDCK-
mdr1: Madin-Darby canine kidney cell line expressing the
P-glycoprotein transporter (P-gp). Flux across cells were
measured at 10 lM substrate concentrations. Figures
quoted correspond to the flux rates (Papp · 10ꢀ6 cm sꢀ1
)
for apical to basolateral (AB) and basolateral to apical
(BA) directions. The minimum measurable intrinsic clear-
ance (Cli) in human liver microsomes and human hepa-
tocytes was 7 lL/min/mg protein. The in vitro metabolic
stability as expressed by Cli is derived from the measured
half-life (T1/2). For 31, T1/2 > 120 min.
20. Deecher, D. C.; Beyer, C. E.; Johnston, G.; Bray, J.; Shah,
S.; Abou-Gharbia, M.; Andree, T. H. J. Pharmacol. Exp.
Ther. 2006, 318, 657.
11. Li, Y.; Wang, D.; Yu, X.; Xu, S. Shenyang Yaoke Daxue
Xuebao 2005, 22, 17, CAN 146:121716.
12. Phenols (11) are commercially available except for 11:
R3 = OPh which was prepared as shown.
21. Rat NA functional transporter activity was measured in
HEK293 cells expressing the rat NA transporter with [3H]-
NA as substrate. For 31, rNRI, IC50 = 2.5 nM (n = 7).
22. Data for 31: 1H NMR (CD3OD, 400 MHz) d 2.19 (s, 3H),
2.39 (s, 3H), 3.58 (s, 2H), 6.44 (s, 1H), 6.78 (d, 2H), 7.05
(m, 1H), 7.20 (m, 1H), 7.22–7.41 (m, 5H), 8.20 (s, 1H);
LRMS APCI m/z 321 (MH+). For 31 PhSO3H salt: mp
155 ꢁC.
1. PhOH,K2CO3,
DMF, 95%
CHO
F
OH
2a. mCPBA
2b. HCl, MeOH, 80%
OPh
23. There is a significant discrepancy between calculated
clogP (4.4) and measured logP (3.2) values for 31. It is
our hypothesis that 31 undergoes hydrophobic collapse to
adopt a folded structure and so reduce the exposure of
lipophilic faces.
13. Mahar Doan, K. M.; Humphreys, J. E.; Webster, L. O.;
Wring, S. A.; Shampine, L. J.; Serabjit-Singh, C. J.;
Adkison, K. K.; Polli, J. W. J. Pharmacol. Exp. Ther.
2002, 303, 1029.