Pyridyl-phenyl ether monoamine reuptake inhibitors: Impact of lipophilicity on dual SNRI pharmacology and off-target promiscuity

Article abstract of DOI:10.1016/j.bmcl.2008.03.082

A novel series of pyridyl-phenyl ethers are disclosed, which possess dual 5-HT and NA reuptake pharmacology with good selectivity over dopamine reuptake inhibition. An analysis of the relationship between lipophilicity and pharmacology highlighted that potent dual SNRI activity was only achievable at c log P > 3.5. The series was found to possess significant polypharmacology issues, and we concluded that this off-target promiscuity was related to lipophilicity.

Full text of DOI:10.1016/j.bmcl.2008.03.082

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Bioorganic & Medicinal Chemistry Letters 18 (2008) 2896–2899
Pyridyl-phenyl ether monoamine reuptake inhibitors:
Impact of lipophilicity on dual SNRI pharmacology
and off-target promiscuity
Gavin A. Whitlock,* Paul V. Fish, M. Jonathan Fray, Alan Stobie and Florian Wakenhut
Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
Received 18 January 2008; revised 28 March 2008; accepted 29 March 2008
Available online 8 April 2008
Abstract—A novel series of pyridyl-phenyl ethers are disclosed, which possess dual 5-HT and NA reuptake pharmacology with good
selectivity over dopamine reuptake inhibition. An analysis of the relationship between lipophilicity and pharmacology highlighted
that potent dual SNRI activity was only achievable at clogP > 3.5. The series was found to possess significant polypharmacology
issues, and we concluded that this off-target promiscuity was related to lipophilicity.
Ó 2008 Elsevier Ltd. All rights reserved.
We recently disclosed a number of novel series with dual
serotonin (5-HT) and noradrenaline (NA) reuptake inhi-
bition (SNRI), exemplified by piperazine 1,1 amino-pyr-
rolidine 22 and diphenylether 33 (Fig. 1). This CNS
mediated dual pharmacology mechanism has been
shown to be an attractive approach for the treatment
H
N
O
NH
N
N
1
2
of a number of diseases, such as depression,4,5 neuro-
Me
OEt
6,7
pathic pain
and urinary incontinence.8,9
Me
O
The diphenylether series, exemplified by carboxamide 3,
delivered potent and selective SNRI activity. However,
further testing demonstrated that this series had meta-
bolic stability issues. Non-P450 mediated enzymatic
hydrolysis of the amide to the corresponding carboxylic
acid was observed as the major route of metabolism in
human hepatocyte assays. Further modification of the
amide substituents did not improve metabolic stability.
To circumvent this metabolic pathway, we decided to re-
place the amide with a pyridyl nitrogen atom, leading to
the compounds of structure 4.10
Me
Me2N
NHMe
N
N
R3
R2
O
O
OMe
3
4
R1
Cl
Figure 1. Structures of recently disclosed SNRIs 1–3, and new
template 4.
We now wish to report our results on this novel series,
focussing on SAR for dual SNRI pharmacology. In
addition the relationship between clogP, SNRI activity
and off-target polypharmacology will be discussed.
The target compounds were prepared in a short syn-
thetic sequence (Scheme 1). For those targets with
R2 = H, pyridyl chloro-aldehyde 5 was displaced with
phenols 6, and then reductive amination conditions were
employed to introduce the benzylic amine. For targets
with R2 = Me, a different intermediate was employed.
Chloro-amide 810 was displaced with the required phe-
nols 6, then borane-THF reduction of amides 9 gave
the secondary amines. Reductive alkylation with
Keywords: Pyridyl-phenyl ether; 5-HT reuptake; NA reuptake; Lipo-
philicity; Polypharmacology; Off-target promiscuity.
*
Corresponding author. Tel.: +44 1304 649174; fax +44 1304
651987; e-mail: gavin.whitlock@pfizer.com
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.03.082

G. A. Whitlock et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2896–2899
2897
O
O
OH
Me
N
H
N
N
(a)
(b)
H
N
R3
+
R1
O
O
Cl
7
5
6
10,11,14,15,18,19,22,23,27-29
R1
R1
O
O
O
OH
Me
Me
N
N
N
NHMe
N
N
H
(c)
(d)
(e)
N
NHMe
Me
+
Me
O
Me
R1
Me
O
Me
Cl
9
8
6
R1
R1
12,16,20,24-26
R1
13,17,21
Scheme 1. Synthesis of target compounds. Reagents and conditions: (a) K2CO3, DMF, 60 °C; (b) R3 = H; i—8 M methylamine in ethanol, rt; ii—
NaBH4, EtOH, rt; R3 = Me AcOH, Me2NHÆHCl, Et3N, NaBH(OAc)3, CH2Cl2, rt; (c) K2CO3, DMF, 100 °C; (d) 1 M BH3–THF solution, THF,
reflux; (e) HCHO, NaBH(OAc)3, CH2Cl2, rt.
Table 1. In vitro inhibition of monoamine reuptakea,b and clogP calculations for compounds 10–29
Me
N
N
R3
R2
O
R1
Compound
R1
R2
R3
5-HT IC50 (nM)
NA IC50 (nM)
DA IC50 (nM)
clogP
1
—
—
—
—
—
H
—
—
—
H
14
9
18
7
>4000
727
4.2
2.4
2.5
2.5
3.0
3.0
3.5
2
3
—
7
32
282
47
83
26
>4000
NT
10
11
12
13
2-OMe 4-Cl
2-OMe 4-Cl
2-OMe 4-Cl
2-OMe 4-Cl
14
6
H
Me
H
10,200
NT
5040
Me
Me
4
13
Me
14
15
16
17
2-Et 4-Cl
2-Et 4-Cl
2-Et 4-Cl
2-Et 4-Cl
H
H
46
11
20
19
86
18
22
30
NT
3.8
4.4
4.4
4.8
H
Me
H
>38,000
34,100
>34,000
Me
Me
Me
18
19
20
21
2-Me 4-Cl
2-Me 4-Cl
2-Me 4-Cl
2-Me 4-Cl
H
H
14
3
246
36
NT
3.3
3.8
3.8
4.3
H
Me
H
3230
NT
Me
Me
6
51
26
Me
6
1680
22
23
24
2-Br 4-Cl
2-Br 4-Cl
2-Br 4-Cl
H
H
23
4
85
26
38
NT
3.5
3.9
4.0
H
Me
Me
H
1970
NT
10
25
26
27
28
29
2-OMe 4-Me
2-Me 4-F
2,4 di-Cl
Me
Me
H
H
18
231
39
257
>400
159
25
NT
NT
NT
2430
NT
2.7
3.3
3.3
3.8
3.1
H
H
2,4 di-Cl
2-OEt 4-Cl
H
Me
H
8
24
H
394
NT denotes not tested.
a See Refs. 1–3 for description of assay conditions.
b Monoamine reuptake IC50 values are geometric means of at least three experiments.
paraformaldehyde then yielded the corresponding ter-
tiary amines ( Table 1).
tution on the phenyl ring of the pyridyl-phenyl ether ser-
ies. The incorporation of a small group ortho to the
pyridyl nitrogen was also investigated, due to the poten-
tial for unflanked pyridines to inhibit CYP450
enzymes.11 The secondary amine 10 possessed potent
Based on the SAR for dual SNRI activity from the
diphenylether series,3 we chose to focus on 2,4-disubsti-

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G. A. Whitlock et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2896–2899
Table 2. ADME properties of compounds 3, 13 and 21
3
13
21
clogP
2.5
15
3.5
<7
4.3
<7
HLM, Cli (lL/min/mg)
Hheps, Cli (lL/min/million cells)
CaCO-2 flux, AB/BA
CYP2D6 IC50
21
<5
<5
NT
NT
NT
34/34
>10 lM
>10 lM
34/30
>10 lM
>10 lM
CYP3A4 IC50
5-HT reuptake inhibition, with weak NA reuptake
activity. Dual potency could be improved by the incor-
poration of the tertiary amine (examples 11 and 13) or
a methyl group on the pyridyl ring, example 12. The best
balance of SNRI pharmacology with good DA selectiv-
ity was achieved with example 13. A similar SAR trend
was then observed for other 2,4-disubstituted phenyl
rings, such as 2-Et 4-Cl examples 14–17, 2-Me 4-Cl ana-
logues 18–21 and 2-Br 4-Cl compounds 22–24. Other
variations to the 4-substituent did not successfully
achieve balanced SNRI activity, with both 4-Me and
4-F reducing NA reuptake activity (examples 25 and
26). Other variations to the 2-position offered no
potency advantage, for example, 2,4-di Cl analogues
27 and 28 and 2-OEt analogue 29.
Figure 3. Plot of clogP against 5-HT reuptake IC50
.
HT IC50 was totally different, with excellent SRI po-
tency being achieved across a wide clogP range (Fig. 3).
Having to increase lipophilicity to achieve balanced dual
SNRI potency was a concern, because of the potential of
high lipophilicity to adversely impact pharmacokinet-
ics,12 polypharmacology13 and toxicity.14
To determine if this series had polypharmacology issues,
examples 13, 16 and 21 were submitted to a wide range
of receptor and ion channel screens (CEREP/BioprintTM
panel, 150 assays across receptor, ion channel and en-
zyme targets). All three examples were found to possess
significant polypharmacology issues, hitting 19 targets
above 50% at a screening concentration of 10 lM
(Fig. 4). Importantly, many of the single point activities
were potent (>80% inhibition), and these translated into
multiple Ki’s < 1000 nM and therefore a narrow TI be-
tween desired activity and off-target pharmacology
(Fig. 5). As a comparison, the more polar amino-pyrrol-
idine 2 (clogP 2.4)15 was submitted to the same panel,
and showed a very different profile. Although the num-
ber of hits >50% at 10 lM was still quite high (Fig. 4),
there were no potent hits and none of the single point
data translated to Ki’s of <1000 nM (Fig. 5). As a result
of the off-target activity, this series of pyridyl-phenyl
In addition to potent SNRI activity, with good selectiv-
ity over DA reuptake inhibition, examples from this ser-
ies also possessed excellent in vitro metabolic stability,
both in human liver microsomes and in hepatocytes (Ta-
ble 2). This demonstrated that the strategy for the re-
moval of the labile amide had successfully delivered
improved metabolic stability, despite an increase in lipo-
philicity. Good membrane permeability with no P-gp
mediated efflux (which may be predictive of good oral
absorption and BBB penetration) was also achieved,
along with weak P450 inhibition.
However, during this SAR investigation it became
apparent that dual SNRI reuptake activity was highly
dependent on lipophilicity (Fig. 2), with a clogP above
3.5 being required for NA activity less than 30 nM.
Interestingly the relationship between clogP and 5-
Figure 4. Plot of number of actives >50% at 10 lM in CEREP/
BioprintTM panel for compounds 2, 13, 16, 21.
Figure 2. Plot of clogP against NA reuptake IC50
.

G. A. Whitlock et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2896–2899
2899
for useful discussions. We also thank CEREP for selec-
tivity data.
References and notes
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Figure 5. Plot of Ki’s < 1000 nM in CEREP/BioprintTM panel for
compounds 2, 13, 16, 21.
ethers as dual SNRIs was halted. However, given that
potent and selective SRI activity can be achieved at
much lower lipophilicity, this template may deliver
SSRIs with good drug-like properties, and this will be
the subject of further publications.16
8. (a) Moore, K. Int. J. Gynecol. Obstet. 2004, 86, S53; (b)
Thor, K. B. Int. J. Gynecol. Obstet. 2004, 86, S38; (c)
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10. For examples of SSRIs based on pyridyl-phenyl ethers, see
Adam, M. D.; Andrews, M. D.; Gymer, G. E.; Hepworth,
D.; Howard, H. R., Jr.; Middleton, D. S.; Stobie, A.
WO2002083643.
11. (a) Wang, H.; Orth, P. Abstracts of Papers, 233rd ACS
National Meeting, Chicago, IL, United States, March 25–
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In summary, we have described a novel series of dual 5-
HT/NA reuptake inhibitors with excellent selectivity
over DA reuptake activity. The replacement of a meta-
bolically labile amide with a pyridyl nitrogen was well
tolerated pharmacologically and did deliver improved
in vitro metabolic stability. Analogues from this series
also possessed excellent membrane permeability and
did not inhibit P450 enzymes. Potent SRI activity was
achieved across a wide lipophilicity range, whereas bal-
anced SNRI potency was only achieved at clogP > 3.5.
This high lipophilicity contributed to a poor polyphar-
macology profile for the series, with examples 13, 16
and 21 all hitting multiple targets when screened in the
CEREP/BioprintTM panel. In contrast, the more polar
amino-pyrrolidine SNRI 2 demonstrated fewer off-tar-
get hits at 10 lM, no measured Ki’s of <1000 nM but
retained good membrane permeability. This study high-
lights the issues associated with chemical series, where
primary potency is highly dominated by lipophilicity.
Maximizing potency whilst retaining good drug-like
properties is still a challenge within the monoamine
reuptake inhibitor field, and additional publications will
describe further advances in balancing these properties.
14. Hughes, J. D.; Blagg, J., et al. Nat. Drug Disc., in press.
15. Despite having a much lower clogP, compound 2
retained good membrane permeability with no evidence
of P-pg mediated efflux. CaCO-2 flux A–B 31, B–A 30.
This compound therefore retained the potential for good
oral absorption and BBB penetration.
16. One example from this series with potent and selective SRI
activity (clogP 2.7)10 was also screened in the CEREP/
BioprintTM panel and showed 8 hits with >50% inhibition
at 10 lM and one measured Ki < 1000 nM. This result
reinforced the hypothesis that lipophilicity was the main
contributor to the promiscuous nature of examples 13, 16
and 21.
Acknowledgments
We thank Stephen Phillips for screening data, and Deb-
bie Lovering and Edel Evrard for compound synthesis.
We also thank Mark Andrews and David Hepworth