O. Éliás et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2118–2122
2119
Table 1
phenoxy ring of fluoxetine and the pyridine ring in SB-200646A had
obviously been identified as shared elements of the pharmaco-
phores capable of being the common backbone of the single
template framework.
Synthesis and binding affinities for compounds 8a–f and binding affinities for the
reference compounds
CH3
CH3
Thus, elaboration of the urea linker at the 4 position of the
phenoxy ring of fluoxetine seemed to be plausible. To that end,
2-hydroxy-5-nitropyridine was first chosen as an acidic pronucle-
ophile in the Mitsunobu etherification step of the facile straightfor-
ward synthetic route5 towards the biarylureas planned (see
Scheme 1). Nitro derivatives were in turn converted into anilines.
Ureas were then synthesized via isocyanates generated in situ from
the aniline reaction partner and triphosgene in dichloromethane or
from the corresponding carboxylic acid in the presence of diphenyl
phosphorazidate and diisopropylethylamine in acetonitrile.
Disappointingly, the 8a–c pyridine compounds prepared thus
proved to be totally inactive in both assay systems.7 However,
encouragingly, omission of the pyridine nitrogen atom led us to
compounds 8d–f that exhibited remarkable affinities towards our
targets (see Table 1).
Next, we decided to elaborate compound 9a as a structural iso-
mer of 8d starting from the corresponding meta substituted nitro-
phenol (see Table 2). As a result of this modification 5-HT2C affinity
dropped dramatically. The same tendency was observed in the case
of the 9b naphthalen-2-yl derivatives. Thus, evolving the para
substituted compound family was underpinned by affinity data ac-
quired from these experiments.
N
N
CH3
CH3
O
X
O
X
O
R
NH2
NH
NH
7a-b
8a-f
Compds
R
X
SERT
5-HT2C
8a
8b
8c
8d
8e
8f
1-Methyl-1H-indol-5-yl
1-Methyl-1H-indol-6-yl
Naphthalen-2-yl
1-Methyl-1H-indol-5-yl
1-Methyl-1H-indol-6-yl
Naphthalen-2-yl
N
N
N
C
C
C
À5%
1%
3%
7%
15%
43%
15.9
10.9
1.7
109
124
6.2
9.0
19.3
62.0
5.6
Fluoxetine
SB-200646A
Ro-60-0491
>10,000
>10,000
Reagents and conditions: from 7a to 8a–c, from 7b to 8d–f, and the corresponding
carboxylic acid,6 diphenylphosphoryl azide, N,N-diisopropylethylamine, acetoni-
trile, 80 °C, 6 h. Values are binding Ki in nM or percentage inhibition of radioligand
binding at a compound concentration of 300 and 1000 nM for SERT and 5-HT2C
,
respectively.7
Early results revealed that low metabolic stability and poor
penetration seemed to be the main issue to be dealt with in con-
nection with the compound family, for example compound 8d:
Table 2
Structure and binding affinities for compounds 9a–b
Clint in human and mouse liver microsomes:8 2.66 and 3.25 mL/
9
CH3
N
CH3
N
min g liver, respectively; PappA-B
:
5.8 Â 10À6 cm/s, efflux ratio:9
CH3
NH2
CH3
NH
O
O
NH
R
R1
O
CH3
HO
i
N
+
CH3
X
9a-b
SERT
7c
R2
OH
R3
Compds
R
5-HT2C
4
9a
9b
1-Methyl-1H-indol-5-yl
Naphthalen-2-yl
9.4
28.2
652
87.6
5a-e
Reagents and conditions: corresponding carboxylic acid,6 diphenylphosphoryl
azide, N,N-diisopropylethylamine, acetonitrile, 80 °C, 6 h. Values are binding Ki in
CH3
CH3
N
nM.
N
CH3
CH3
ii
O
X
R3
O
X
R3
5.3. The human metabolic stability of 8f naphthalen-2-yl derivative
omitting the indol N-methyl group was only moderate thus far
(Clint in human and mouse liver microsomes: 1.38 and 0.03 mL/
min g liver, respectively). On the other hand, while physico-chem-
ical parameters were satisfactory Pgp liability turned out to be an
important factor concerning poor penetrability (see efflux ratio
above). It was reasoned that replacement of the indol moiety with
other appropriately substituted heterocycles or simpler phenyl
groups having a suitable substitution pattern together with adjust-
ment to the hydrogen bond donor properties might help improve
brain exposure.
Having these aims in mind, further analogues were planned and
synthesised (see Table 3). First, compound 8g the N-ethyl indol
analogue of 8d was prepared. While binding activity and penetra-
tion properties remained in the same range (SERT Ki: 37.9 nM,
5-HT2C Ki: 10.7 nM) only slightly improved metabolic stability
was observed (Clint in human and mouse liver microsomes: 2.04
and 2.84 mL/min g liver, respectively). Incorporation of hetero-
bicyclic motifs for example the imidazo[1,2-a]pyridin-6-yl group
R1
R2
R1
R2
7a-e
6a-e
R1
H
H
R2
NO2
NO2
H
NO2
H
NH2
NH2
H
R3
H
H
NO2
H
NO2
H
H
NH2
H
NH2
X
N
C
C
C
C
N
C
C
C
C
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
H
OMe
OMe
H
H
H
OMe
OMe
NH2
H
Scheme 1. Reagents and conditions: (i) triphenylphosphine, diisopropyl azodicar-
boxylate, dichloromethane, ambient temperature, 48 h; (ii) PtO2/H2, ethanol.